PATENT ABSTRACT
The present invention relates to an environmentally benign process for the preparation of (S)-α-cyano-3-phenoxybenzyl-(S)-2-(4-chlorophenyl)isovalerate from its diastereomeric mixture (RS)-α-cyano-3-phenoxybenzyl-(S)-2-(4-chlorophenyl) isovalerate.

PATENT DESCRIPTION
FIELD OF INVENTION 
     The present invention relates to an environmentally benign process for the preparation of (S)-α-cyano-3-phenoxybenzyl-(S)-2-(4-chlorophenyl)isovalerate from its diastereomeric mixture (RS)-α-cyano-3-phenoxybenzyl-(S)-2-(4-chlorophenyl) isovalerate. More particularly, the present invention deals with the method for preparation of diastereomeric mixture of (RS)-α-cyano-3-phenoxybenzyl-(S)-2-(4-chlorophenyl)isovalerate (herein after referred as diastereomer-A) and its subsequent conversion to (S)-α-cyano-3-phenoxybenzyl-(S)-2-(4-chlorophenyl)isovalerate (hereinafter referred as S,S isomer), the most biologically active isomer of racemic fenvalerate via the crystallization induced dynamic kinetic resolution. The method provides a process for preparation of S,S isomer besides effectively converting the undesired isomer (R)-α-cyano-3-phenoxybenzyl-(S)-2-(4-chlorophenyl)isovalerate (hereinafter referred as SR isomer) via epimerization of the alcohol moiety using inexpensive catalyst to a desired diastereomeric mixture. Thus the method provides a simpler and efficient process for the industrial preparation of the biologically active SS isomer obviating the use of costly reagents such as cyclic dipeptides, enzymes as described in the prior art. This method also provides a route to green process in the sense that the undesired SR isomer is converted to a useful entity within the process parameters thus reducing chemical burden on environment 
     BACKGROUND OF THE INVENTION 
     As regards of SS isomer of general formula (I) 
                                
Where the * indicate asymmetric carbon atom having “S” configuration on both acid and alcohol moieties is of great interest, as the resolved isomer, esfenvalerate (SS) is biologically most active and has fourfold higher insecticidal activity than that of racemic fenvalerate a commercially important synthetic pyrethroid. An economically viable process for its preparation (SS isomer) is of great utility as it eliminates use of large quantity of a.i., thereby reducing chemical burden on environment.
 
     Reference is made to EP Patent application 0,040,991 wherein a method for preparation of an enantiomeric pair (SS-RR) having insecticidal activity is described. The main draw-back of this process is that it yields a pair of enantiomers (SS-RR) instead of a single stereo isomer (SS). 
     Reference is made to the Patent application DE 2830031 wherein the process for preparation of esfenvalerate from its diastereomeric mixture is described. It describes a method for crystallization of SS isomer with or without using catalyst by four different processes. 
     The method A describes a process wherein SS isomer is crystallized without using a catalyst. The method B describes a process where in epimerisation at asymmetric carbon atom of alcohol moiety is effected by using a protic solvent or/and base catalyst. The method C describes a process wherein mother liquor after separating SS isomer is subjected to epimerisation with or without a catalyst. The method D performs the same procedure as in method C using a catalyst. 
     The main draw back of this process is that it employs protic solvents like methanol, ethanol with bases viz triethylamine, ammonia at temperature 0° C. to −5° C. At this temperature decomposition of the product, along with side reactions is observed. Another draw back is that the experimental conditions described are not completely reproducible albeit the procedure described is strictly followed. 
     EP patent 0050521, by Sumitomo Chemical Company Ltd. Japan, claims a method for preparation of SS isomer starting from a super saturated solution of diastereomeric mixture having respectively S configuration on acid moiety and (S), (R) configuration on Alcohol moiety using pure seed crystal solution of S-S isomer in presence or absence of basic catalyst. However the method could not be reproduced with consistency albeit the experimental conditions are followed as described in the patent. 
     Another drawback of this method is that when base catalyst like ammonia, triethylamine is used as described in experimental procedure of the patent, many a time product degeneration is observed in contrast to the crystallization of SS-isomer. 
     Preparation of (S)-α-cyano-3-phenoxy benzylalcohol by different methods viz. cyclic dipeptide, enzymes are known in prior art, reference is made to U.S. patent application Ser. No. 4,526,727 wherein a process is described for synthesis of (S)-α-cyano-3-phenoxy benzylalcohol using cyclic dipeptide, cyclo (D-phenylalanyl-D-histidine) and its subsequent esterification with (RS)-2-(4-chlorophenyl)isovaleric acid or its reactive derivatives to form a diastereomeric ester, followed by crystallization in a protic solvent to obtain SS isomer. The draw back of this process is that though cyclic dipeptide catalyst is used to synthesise the desired (S)-alcohol, the scale up operations for these processes are not yet commercially viable. Yet another draw back is that the process described for synthesis of the di peptide depend upon many physical characteristics like non-crystallinity, cohesiveness of the cyclic dipeptide which require stringent controls in preparation of the cyclic di peptide and are difficult to attain on scale up process leading to restriction of process parameters on a multi kilo scale preparation. Reference is made to U.S. patent application Ser. No. 5,177,242 where in a method to prepare optically active (S)-cyano-3-phenoxybenzylalcohol by reacting corresponding aldehyde with hydrocynic acid using an enzyme S-oxynitrilase immobilized on a membrane is described. 
     The draw back of this method is that though it may be performed with reasonable success on a laboratory scale, it is difficult to obtain the enzyme of desired activity, level on a multi scale operations as the enzyme activity is variant w.r.t. source of its isolation. 
     Another disadvantage of this method is the stringent physical parameters to be maintained for immobilization of enzyme on the membrane with out effecting denaturation may practically pose problems on a commercial process. 
     OBJECTS OF THE INVENTION 
     The main object of the present invention is to develop a process for production of SS isomer [(S)-α-cyano-3-phenoxybenzyl-(S)-2-(4-chlorophenyl)isovalerate]. 
     It is another object of the invention to provide a process for preparation of diastereomeric mixture of (RS)-α-cyano-3-phenoxybenzyl-(S)-2-(4-chlorophenyl) isovalerate (hereinafter referred as diastereomer-A) in an effective manner which consistently yields the desired isomer on crystallization. 
     It is another objective of the invention to utilize an inexpensive catalyst to convert the undesired isomer (R)-α-cyano-3-phenoxybenzyl-(S)-2-(4-chlorophenyl)isovalerate (hereinafter referred as SR Isomer) via epimerisation of the alcohol moiety to useful entity. 
     A further objective of the invention is to provide an environmentally benign process for production of biologically active SS isomer avoiding costly reagents known in prior art. 
     A further object of the invention is to provide a process for conversion of undesired isomer into useful entity with in the process parameters and recycle it to the processes of crystallization, thus reducing chemical burden on environment resulting in enhancing cost effectiveness of the process. 
     SUMMARY OF THE INVENTION 
     The present invention relates to an environmentally benign process for the preparation of (S)-α-cyano-3-phenoxybenzyl-(S)-2-(4-chlorophenyl)isovalerate from its diastereomeric mixture (RS)-α-cyano-3-phenoxybenzyl-(S)-2-(4-chlorophenyl) isovalerate. 
    
    
     
       BRIEF DESCRIPTION OF THE FIGURE 
         FIG. 1  illustrates a second-order asymmetric transformation. 
     
    
    
     DETAILED DESCRIPTION OF THE INVENTION 
     Accordingly the present invention provides a process for manufacture of (S)-α-cyano-3-phenoxybenzyl-(S)-2-(4-chlorophenyl)isovalerate which comprises preparation of a diastereomeric ester (RS)-α-cyano-3-phenoxybenzyl-(S)-2-(4-chlorophenyl)isovalerate (diastereomer-A), a supersaturated solution of which in a hydrophilic organic solvent like alcohol having 1-5 carbon atoms in presence of pure SS seed crystals on controlled crystallization yields the desired SS isomer which was separated and the mother liquor enriched with unwanted SR isomer was epimerised and recycled into further batches of crystallization. 
     In one embodiment of the invention, the diastereomeric ester (Diastereomer-A) is prepared either by addition of (S)-2-(4-chlorophenyl) isovaleroyl chloride to aqueous solution (RS)-α-cyano 3-phenoxybenzylalcohol or addition of a premixed solution of (RS)-3-phenoxybenzaldehyde and (S)-2-(4-chlorophenyl) isovaleroyl chloride to aqueous solution of sodium cyanide under PTC conditions, more preferably by addition of (S)-2-(4-chlorophenyl)isovaleroylchloride to aqueous solution of (RS)-α-cyano3-phenoxybenzylalcohol under PTC conditions. 
     In another embodiment of the invention the choice of solvent is selected from the group consisting of aromatic hydrocarbon, chlorinated hydrocarbons like toluene, benzene, hexane, chloroform, 1,2-dichloroethane, dichloromethane respectively, more preferably 1,2-dichloroethane. 
     In another embodiment of the invention the phase transfer catalyst is quarternary ammonium salt selected from the group consisting of tertabutylammoniumbromide (TBAB), tertiarybutylammoniumhydrogensulphate (TBAHS), Benzyltriethylammonium chloride (TEBA) benzyltributylammoniumchloride, N-butyl-N,N-dimethyl-α-phenylethylammoniumbromide. 
     In yet another embodiment of the invention, the quaternary ammonium salt is tetrabutylammoniumbromide. 
     In yet another embodiment of the invention, sodium cyanide is used in amount of 1.0 to 1.60 mole per mole of 3-phenoxybenzaldehyde. 
     In further embodiment of the invention, (S)-2-(4-chlorophenyl). isovaleroylchloride is used in amount of 1.0 to 1.03 mole per mole of 3-phenoxybenzaldehyde. 
     In yet another embodiment of the invention, the (S)-2-(4-chlorophenyl) isovaleroyl chloride is added over a period of time ranging from 100-120 minutes. 
     In yet another embodiment of the invention, the (S)-2-(4-chlorophenyl) isovaleroylchloride is added to an aqueous solution of (RS)-α-cyano-3-phenoxy benzylalcohol at a temp. ranging from −2° C. to −4° C. 
     In another embodiment of the invention the course of the esterification reaction is followed by HPLC analysis drawing samples at intervals of time ranging from 30-90 minutes. 
     In a further embodiment of the invention, the reaction is continued after addition of acid chloride for a further period of time ranging from 60-120 minutes. 
     In a further embodiment of the invention, the diastereomeric ester formed (dilute-diastereomer-A) is concentrated under pressure ranging from 80-60 mm Hg to obtain diastereomer-A. 
     In another embodiment of the invention, the solvent recovered from distillation of dilute diastereomer-A is recycled for further batches of diastereomer-A formation. 
     In another embodiment of the invention, the diastereomeric ester (diastereomer-A) is subjected to the process of crystallization either by equilibration at a temperature range of 200°-220° C. under vacuum ranging from 100-50 mm Hg or without such operation more preferably without equilibration, by preparing a saturated solution in an organic solvent or solvent mixtures thereof and cooling the solution in such a manner that when seed/slurry of SS isomer is introduced, the added crystals remain thereafter in solution, in undissolved state and only crystals of required isomer (SS) alone crystallizes from the solution. 
     In yet another embodiment of the invention, the process of crystallization is controlled by predetermined rate of cooling the solution to a temperature range and maintaining the solution at that temperature range for sufficient period such that the rate of crystallization of SS isomer is conspicuous and the process is continued for sufficient period of time, till the crystallization of desired SS isomer is completed as indicated by enrichment of SR isomer in supernatant liquid. 
     In yet another embodiment of the invention, the progress of crystallization is monitored by chiral HPLC analysis, drawing samples at regular intervals of time to find the enrichment of SR isomer. 
     In yet another embodiment of the invention, the process of crystallization is stopped when the analysis of SR isomer is in the range of 50-55%. 
     In a further embodiment of the invention, the process of crystallization is preferably increased either by stirring or shaking the solution more preferably by stirring. 
     In another embodiment of the invention, the process of crystallization can be carried out at a temperature range +10° C. to −15° C. and most advantageously at a range of +2° C. to −8° C. 
     In another embodiment of the invention, the reaction time is such that it should be adequate to ensure that desired product (SS-isomer) of sufficient purity is obtained, generally in the range of 24-80 hrs more preferably 30-60 hrs. 
     In yet another embodiment of the invention, the organic solvent selected is from the group comprising of lower alcohols and/or aromatic aliphatic hydrocarbons or mixtures thereof. 
     In another embodiment of the invention, the solvent is selected from alcohols consisting of methanol, ethanol, isopropanol and hydrocarbon solvents like Hexane, Toluene, Heptane. 
     In another embodiment of the invention, the solvent is more preferably lower alkanol like methanol. 
     In another embodiment of the invention, the concentration of the diastereomer-A in solution is preferably in the range of 12-40% w/w w.r.t. solvent and more preferably in the range of 12-30%. 
     In further embodiment of the invention, the mother liquor enriched with SR isomer obtained after separation of the desired SS isomer is concentrated under reduced pressure to remove the solvent and then heated to a temperature of 50°-90° more preferably at 60°-70° C. under vacuum for a period of 1-4 hrs more preferably 2-3 hrs, cooled to room temperature and subjected to process of crystallization to obtain further quantity of the desired isomer (SS)-isomer. 
     In another embodiment of the invention, the mother liquor enriched with SR isomer is treated with a catalyst to effect equilibration of the isomers thus conveniently avoiding the tedious process of concentration of the mother liquor and subsequent heating thus reducing reaction times. The equilibrated mother liquor having almost equal ratio&#39;s of both isomers (SS:SR) is further subjected to process of crystallization of desired (SS) isomer. 
     In another embodiment of the invention, the mother liquor equilibrated is replenished with an amount of diastereomer-A equivalent to the weight of SS isomer obtained from process of crystallization and further subjected to process of crystallization maintaining the same concentration of the solution. This process is iterative and continued till crystals of SS isomer is obtained, thus, quite advantageous from the commercial point of view. 
     In another embodiment of the invention the catalyst employed for equilibration can either be organic or inorganic bases like alkali and alkaline earth metal hydroxides and carbonates like sodium hydroxide, potassium hydroxide, sodium carbonates and nitrogen containing bases like ammonia, dimethylamine, triethylamine, quaternary ammonium hydroxide like tetrabutylammoniumhydroxide, triethylbenzyl ammonium chloride or optically amines like (−) phenylethylamine or halides of alkali metals or ammonium halides. The more preferred base being fluorides of alkali metals or ammonium halides most preferably potassiumfluoride. 
     In yet another embodiment of the invention, with regard to the quantity of catalyst used it can be employed in the range of 2-10 mole %, more preferably in the range of 4-6 mole % w.r.t. the SR enriched mother liquor. 
     The process of the invention involves the preparation of diastereomeric mixture (diastereomer-A) in such a manner when it is subjected to process of crystallization, only crystals of SS isomer precipitates out and the mother liquor enriched with undesired isomer (SR isomer) is epimerised using an inexpensive catalyst and recycled to the process of crystallization in an iterative manner till crystals of SS isomer is obtained. In this quest for development of a suitable technology, a comprehensive search for solvent system and catalyst was undertaken to circumvent the problems encountered in referred EP 0,050,521. The results are tabulated in Table-1. 
     Despite many methods known in literature for the preparation of (S)-α-cyano-3-phenoxy benzylalcohol-(S)-2-(4-chlorophenyl)isovalerate, they have not yet been developed to the level where they can be carried out in an economic manner. In the present method of crystallization induced dynamic kinetic resolution (CIDKR), the SR isomer enriched mother liquor is epimerised at the benzyllic carbon atom using inexpensive catalyst and iteratively subjected to the process of crystallization by replenishing with fresh diastereomer-A equal to the quantity of SS isomer obtained. This approach is more practicable and quite appealing for small preparations (mg g) to pilot and process scale production (kg tonnes). 
     Many a time the results obtained from crystallization experiments as performed following the procedure described in EPO 0,050,521 are not reproducible albeit the conditions described therein are adhered to without deviation. Several modifications like varying of concentration of diastereomer-A, solvents, addition of additives like FeO, H 3 PO 3 , glacial acetic acid, process impurities like methyl ester of (S)-2-(4-chlorophenyl)isovalericacid, PTC catalyst, mother liquor were incorporated to the crystallizing solution of diastereomer-A as described in experimental part without any success in obtaining the required SS isomer in a consistent manner. Physical parameters like heating the diastereomer-A at temperatures ranging from 60°-120° C. and subsequent crystallization showed improved measure of success, though not to the manner where it can be useful entity on an industrial scale. Hence, a re-visit to the preparation of diastereomer-A (Table-2) was resorted to, and attempts were directed to modify the procedure of diastereomer-A preparation. In the present process a solution of (S)-2-(4-chlorophenyl)isovaleroylchloride in dichloroethane was added to a preformed solution of (RS)-α-cyano-3-phenoxybenzylalcohol, and after usual work up, this diastereomer-A was subjected to crystallization induced dynamic kinetic resolution (CIDKR) as such without resorting to any further operations like heating under vacuum etc., thus more importantly saving energy. The crystallization process can be performed at relatively high temperature than described in prior art. 
     In an embodiment of the invention, the process of crystallization of diastereomeric mixture (diastereomer-A) is performed via a phenomena known as crystallization induced dynamic kinetic resolution. It is known that enantiomers/diastereomers of compounds possessing acidic hydrogen atom on an asymmetric carbon atom can be epimerized with bases. In this process they pass briefly through the flat state. [P. Sykes; Explanations of reactions—methods and criteria of organic reaction mechanisms; verlag chemie 1973, page 133, and D. J. Cram. Fundamentals in Carbanion Chemistry, page 85-105, [Academic Press 1965] which is also observed in the case of the readily base catalyzed epimerisation of optically active mandelic acid nitrile (a) and of the corresponding methylether (b) to the racemic compounds. 
     
       
                 
         
             
             
         
      
     
     It is also known that formation of inter convertible diastereomers may lead to the preferential and possibly even to sole crystallization of one of the two isomers. The necessary instability of the compounds (species) involved in this special type of crystallization process may however, also make the isolation of pure enantiomer or diastereomers difficult. In spite of this potential draw back, the use of crystallization induced asymmetric transformation is very appealing, particularly when separations are attempted on industrial scale. It is observed that when two diastereomers in a mixture which are related as epimers in a super saturated solution are in equilibrium ( FIG.1 ) the presence of base catalyst causes epimerisation of a diastereomer at chiral carbon which has acidic hydrogen as in the case of synthetic pyrethroid esters bearing cyano group on chiral carbon, the diastereomeric equilibrium is continually displaced by slow crystallization of one of the two species upon addition of homochiral crystals of an isomer. The species which crystallizes is not necessarily that which predominates at equilibrium. This phenomena is described as crystallization induced asymmetric disequilibration in which the rate of crystallization of less soluble diastereomer is slower than the rate of equilibration of the two species in solution. This phenomena known as crystallization induced asymmetric transformation of second order even though the work “order” is improperly used, the correct meaning in context is kind as asymmetric transformation of second kind. 
     The diastereomeric ester (diastereomer-A) is prepared either by reaction of aqueous sodium cyanide with a premixed solution of 3-phenoxybenzaldehyde and (S)-(+)-2-(4-chlorophenyl)-isovaleroylchloride or by reaction of the acid chloride with a preformed α-cyano-3-phenoxybenzylalcohol under PTC conditions more preferably by latter method to obtain a diastereomeric ester which consistently yields the crystals of desired isomer (SS) on crystallization. 
     The esterification is carried out in a solvent system selected from the group consisting of chlorinated hydrocarbons, aliphatic hydrocarbons, aromatic hydrocarbons like chloroform, dichloromethane 1,2-Dichloroethane, hexane, heptane, octane, toluene, benzene respectively more preferably, 1,2-Dichloroethane using PTC catalyst belonging to quaternary ammonium salt selected from the group consisting of tetrabutyl ammoniumbromide (TBAB), tetrabutylammoniumhydrogensulphate (TBAHS), Benzyltriethylammoniumchloride (TEBA), Benzyltributylammoniumchloride, N-butyl-N,N, dimethylphenylethylammoniumbromide, more preferably tetrabutylammonium bromide by addition of 3-phenoxybenzaldehyde to an aqueous solution of sodium cyanide at ambient or low temperature followed by the addition of (S)-2-(4-chlorophenyl) isovaleroyl chloride over a period of time ranging from 60-180 minutes more preferably from 90-120 minutes at a temperature range of −6° to +4° C., more preferably −3 to 0° C. under stirring, preferably maintaining the temperature of reaction for a further period of time ranging from 60-120 minutes after reaction, following the course of the reaction by HPLC analysis, drawing samples at intervals of time ranging from 30-120 minutes. The diastereomeric ester (diasteromer-A) formed is recovered from its dilute solution by stripping of the solvent under vacuum (80-60 mm Hg) and purging Nitrogen gas to ensure complete removal of the last traces of the solvent. 
     The diastereomeric ester (diastereomer-A) thus obtained is subjected to crystallization in a saturated solution containing solvent/solvent mixtures selected from the group comprising of lower alcohols and/or aromatic, aliphatic hydrocarbons and mixed solvents thereof, preferably alcohols containing 1 to 5 carbon atoms such as methanol, ethanol, isopropanol, aromatic hydrocarbons benzene, toluene, aliphatic hydrocarbons, hexane, heptane, octane, more preferably methanol in a concentration in the range of 12-40% w/w more preferably in the range of 12-30% w/w by following a programmed rate of cooling viz stepwise decreasing the temperature to 20° C. from ambient temperature, thereby cooling to 10° C. at intervals of time preferably 2-8° C. per hour more preferably 4-6° C. per hour. At this temperature (10° C.) pure crystals of SS isomer or slurry more preferably pure crystals (SS isomer) is introduced, wherein the added crystals/slurry remain in solution in undissolved state, decrease in temperature is continued to reach the onset temperature of crystallization at the rate of 2-1° C. per hour preferably 1° C. per hour and maintained around the onset of crystallization (2-5° C.) wherein the crystallization of SS isomer is conspicuous. 
     Further decrease in temperature is effected by maintaining the solution at a temperature range of +2 to 18° C. for a sufficient time ranging from 24-72 hrs, preferably 24-36 hrs by shaking or stirring the solution preferably stirring until crystallization is substantially completed as indicated by chiral HPLC analysis wherein samples of supernatant liquid indicate enrichment of undesired SR isomer. The crystallization process is stopped when SR isomer is in the range of 50-55% separating the crystals of SS isomer from solution either by filtration, decantation, or centrifugation, more preferably by filtration. 
     The mother liquor separated from the desired SS isomer is either concentrated under reduced pressure and heated to 60°-70° C. under vacuum for 2-3 hrs and subjected to process of crystallization or the mother liquor is epimerised using either an organic or inorganic base catalyst, which is stable under reaction conditions, examples include nitrogen containing bases like Ammonia, Triethylamine, 1-naphthylamine, quinoline, quaternary ammonium hydroxides like TEBA, TBAH also useful are inorganic bases like alkali and alkaline earth metal hydroxides carbonates, halides more preferably potassium fluoride in 2-10 mole % by heating generally for 4-6 hrs preferably 3-5 hrs till the ratio of two isomers is almost equal as indicated by chiral HPLC analysis. The contents are cooled and subjected to the process of crystallization or more conveniently the equilibrated mother liquor is replenished with an amount of diastereomer-A equal to the wt. of crystals of SS isomer obtained in earlier cycle and subjected to process of crystallization as described above. This step is iterative and continued by addition of diastereomer-A each time till crystals of SS isomer is obtained. 
     Thus consecutively using the equilibrated mother liquor of one cycle in another cycle as such avoids many process steps and enriching mother liquor with diastereomer-A to the extent of crystals (SS isomer) obtained maintains the saturated state of solution as also the catalyst is reused more often, with out isolation. By the use of combined enrichment and crystallization process, all the desired isomer (SS) may be effectively recovered from the diastereomeric mixture (diastereomer-A). 
     The following examples are given by way of examples and therefore should not construed to limit the scope of the present invention. 
     EXPERIMENTAL 
     Part-A 
     Example-1 
     Preparation of (RS)-α-cyano-3-phenoxybenzyl-(S)-2-(4-chlorophenyl) isovalerate (diastereomer-A): 
     81.37 gms of NaCN and 815.5 gms of water is charged into a suitable reactor equipped with cooling system, mechanical stirrer, dropping funnel and thermometer. The contents are mixed well and 49.6 g of dichloroethane and 10.2 gms of tetrabutylammonium bromide is charged into the reactor under stirring and cooled to +5° C. 246.98 g of (S)-(+)2-4(-chlorophenyl)isovaleroyl chloride and 205.4 gms of metaphenoxybenzaldehyde was mixed with 803 ml of dichloroethane and added over a period of 90 mts. through a dropping funnel under vigorous stirring. The temperature of the reaction mixture was maintained at +4° C. for a further period of 4 hrs and brought to room temperature. The organic layer (DCE) is separated out and washed with distilled water (3×200 ml) till pH of aqueous layer is neutral. The dilute organic layer (DCE) is concentrated to obtain crude ester (diastereomer-A) of composition of SS:SR ratio 46:48 in 95% yield.
     Wt. of ester=441.5   Ratio of SS:SR=46:48   

     This material is used for preferential crystallization of esfenvalerate. 
     Example-2 
     10 gms of diastereomer-A of having SS/SR ratio 46.1/48.4 is dissolved in 13.13 gms of Heptane, toluene mixture containing 10% of toluene by heating and transferred to a suitable R.B flask provided with thermovel, and stirrer. At room temperature the solution was turbid to which 7.0 g of methanol was added and cooled to −16° C. under stirring for about 65 hrs. by adding a seed crystal (99.3) of SS-isomer at −13° C. at the end of which a viscous mass was observed. No preferential crystallization was noticed.
     Wt. of crude=10.0 gms   % purity of SS isomer=46.1   

     Example-3 
     To 9.84 of liquid diastereomer-A was added 17.76 gms of methanol to form a 35% w/w solution of diastereomer-A which was refluxed for 1 hr at 65° C. and cooled to room temperature. The resulting solution was subjected to crystallization by cooling in a cryogenic bath to +6° C. A seed crystal of SS isomer of 99.9% purity was added to the solution at 15° C. and process of crystallization was continued for 18 hrs. at 6° C. The crystals obtained were filtered off.
     Wt. of crystals=8.86   % purity of SS-isomer=46.57   Wt. of ML=16.31 gms   

     Example-3A 
     The mother liquor obtained (16.3 g) in the above example-3 was further subjected to the crystallization by adding a seed crystal at 2° C. and the process of crystallization was continued for 22 hrs. at +6° C. At the end of which the crystals obtained were filtered off and analyzed.
     Wt. of crystals=0.51 g   % purity of SS-isomer=95   

     Example-4 
     52.2 gms of liquid diastereomer-A of Fenvalerate was dissolved in 110 g of Methanol to obtain a solution of 32% w/w diastereomer-A which was refluxed for 1 hr and cooled to room temperature. The solution was filtered off and cooled under stirring form 23° C. to −15° C. A seed crystal of pure SS-Isomer of 99% purity was introduced into the system at −14° C. The process of crystallization is continued for a period of 170 hrs at the end of which the crystals obtained were separated and filtered off.
     Wt. of crystals=20.0 g   % purity of SS-isomer=42.89   Wt. of ML=115.86 gms   

     Example-4A 
     The ML of example 4 (115.88 g) is concentrated and divided into two parts. To 10.7 gms of Diasdtereomer-A was added 14.6 gms of heptane toluene mixture of composition as described in example-2 and refluxed for 2 hrs. The contents were cooled to room temperature and 7.7 g of methanol was added and cooled to −10° C. in a cryogenic bath. A scoop of seed crystals of SS isomer of 99.9% was added at −10° C. The solution was cooled to −14° C. and maintained at that temperature for 144 hrs. The precipitated crystals were removed by filtration and ML was separated out.
     Wt. of crystals=0.9 g   % purity of SS isomer=98   

     Example-5 
     To 19.96 gms of liquid diastereomer-A obtained from ex-1 was added 61 ml of MeOH heated to reflux, cooled to room temperature and filtered off. The solution was cooled in a cryogenic bath under stirring by setting the temperature to −15° C. seed crystals of SS-Isomer (99.3%) was introduced after temperature reached to −15° C. and further cooling was continued for 96 hrs. At the end of which the precipitated crystals were separated out.
     Wt. of crystals=9.2 2  g   % purity of SS-isomer=45.2%   Wt. of ML=87.20 gms   

     Example-5A 
     The ML obtained from the above example-5 was further subjected to crystallization by cooling to −15° C. At −11° C. a slurry of seed crystals (0.07248 g; 99%) of SS-isomer was introduced. The solution is stirred at −15.5° C. for a period of 96 hrs. The separated out crystals were weighed and air dried.
     Wt. of crystals=6.80 g   % purity of SS-isomer=57.1   

     Example-6 
     20.0 g of Mother liquor obtained from experiments where no preferential crystallization has not occurred was dissolved in 143 gms of Methanol to obtain a 12% w/w solution of diastereomer-A and subjected to process of crystallization by cooling to −8° C. under stirring in a reactor with a provision for temperature recording and addition of seed crystals. A seed crystal of 99.3% of SS-Isomer was introduced at −8° C., followed by 4 ml of (6% w/w) methonolic ammonia. The cooling at −8° C. was continued for 87 hrs and solids obtained were analyzed for SS-isomeric content.
     Wt. of crystals=7.40 g   % purity of SS-isomer=97.45%   Wt. of ML=155.88 g   

     Example-7 
     The mother liquor obtained from above example-6 was subjected to preferential crystallization as described below: 
     7.36 g of diastereomer-A obtained after concentration of Mother liquor (155.8 g) from above example-6 was dissolved in MeOH to obtain a 12% solution of diastereomer-A which was cooled under stirring in a cryogenic bath from +4° C. to −15° C. 2.3 ml of methonolic ammonia of 6% (w/w) was introduced into the system at −4° C. followed by SS-isomer seed crystal (99%). The process of cooling is continued for a period of 42 hrs and the crystals obtained were separated out.
     Wt. of crystals=2.95 g   % purity of SS-isomer=98.4%   

     Example-8 
     16.07 g of solids of isomeric ratio of SS:SR (1:1) obtained from experiments 30, 33, 34 (Table-1) was dissolved in MeOH to get a solution of 12% and subjected to crystallization in a cryogenic bath by cooling from room temperature to −5° C. A pure seed crystal of SS-isomer (99%) was introduced at 0° C. followed by 3.2 ml of 6% w/w methanolic ammonia. The solids obtained were filtered off at the end of 94 hrs and analyzed.
     Wt. of crystals=8.86 g   % purity of SS-isomer=43.2%   Wt. of ML=116.4 gms   

     Example-9 
     5.14 g of diastereomer-A was dissolved in MeOH to obtain 12% solution. To the above solution 0.06 g (2 mol %) of TBAOH (tetrabutylammoniumhydroxide) was added and cooled to −5° C. At that temperature a seed crystal of SS-isomer (99.3%) was introduced into the system and further cooling was subjected in a stepwise manner to −17° C. (−5° C. for 18 hr; −10° C. for 24 hrs, −15° C. for 29 hrs and −17° C. for 40 hr) at the end of which the crystals obtained were filtered off and analyzed.
     Wt. of crystals=0.81 g   % purity of SS-isomer=96.38%   

     Example-10 
     5.03 g of diastereomer-A was dissolved in MeOH to obtain 17.4% solution which was subjected to crystallization in a cryogenic bath at −15° C. to −18° C. for a period of 81 hrs by adding 2.0 ml of 6% methonolic ammonia and seed crystal (99.3%) at −15° C. The crystals obtained were separated.
     Wt. of crystals=1.28 g   % purity of SS-isomer=92.9%   

     Example-11 
     23.25 gms of diastereomer-A whose composition consists of 5.0 g liquid diastereomer-A and the rest obtained from mother liquor of KR-92 (Table-1) was dissolved in 97.45 gms of MeOH to obtain 19.26 w/v solution which was subjected to cooling in a cryogenic bath from room temperature to −8.6° C. in 48 hrs. A seed of pure SS isomer (99.3%) was introduced at −8° C. followed by 10 ml of MeOH/NH 3  of 6% w/w. At the end of reaction time (48 hrs) 2.0 ml of acetic acid was added and the crystals obtained were separated out.
     Wt. of crystals=1.16 g   % purity of SS-isomer=97.6%   

     Example-12 
     2.0 gms of diastereomer-A having SS:SR 45:46 ratio was mixed with 0.5 gms of SS-isomer and 22.5 g of MeOH was added to obtain 10% w/w solution of diastereomer-A which was enriched with 20% of SS isomer. This solution was subjected to crystallization under at a stepwise cooling from +5° C. to −3° C. by adding a seed crystal at 0° C. The process of crystallization was continued for a period of 147 hrs, at the end of which the crystals obtained gave a purity of 70% of SS-isomer.
     Wt. of crystals=1.43 g   % purity of SS-isomer=69%   Wt. of ML=21.09   

     Example-13 
     
         
         a. In a suitable reactor provided with a provision for measurement of temperature was added 8.0 g of diastereomer-A and 12 g of heptane, toluene mixture (Hep:Tol=1: 1) to obtain 40% w/w solution. The solution was cooled to −5° C., a seed crystal of SS isomer (99%) was introduced and further cooling at that temperature was continued for 90 hrs. the crystals were separated out and analyzed for their SS-isomer content. 
         Wt. of crystals=0.1 g 
         % purity of SS-isomer=77.2% 
         Wt. of ML=20.46 
         b. The mother liquor (40%) was further subjected to crystallization following the procedure described above except that the solution was cooled to −13° C. for 240 hrs. the crystals obtained were separated out by filtration. 
         Wt. of crystals=2.85 g 
         % purity of SS-isomer=54.2% 
       
    
     Example-14 
     In a suitable reactor was placed diastereomer-A (36.33 g) obtained form the experiments where the preferential crystallization has not been achieved and methanol (2.38 g), and stirred well to obtain a 13% w/w solution of diastereomer-A. This solution was cooled in a cryogenic bath under stirring from +5° C. to −10° C. at the rate of one degree per hour. Seed crystal of SS-isomer (99.3%) was introduced into the system at −1° C. and further cooling after reaching −10° C. was continued for 36 hrs. The solids obtained were separated out by filtration and analyzed.
     Wt. of crystals=13.31 g   % purity of SS-isomer=96.5   

     Example-15 
     In a 250 ml round bottom flask was placed 10.08 gms of diastereomer-A and 67.0 gms of a mixture of IPA and hexane (45:55) heated to reflux (90° C.) for 1 hr. The solution was cooled to room temperature, filtered into a 250 ml round bottom flask, having provision for temperature measurement, stirrer and cooled to 5° C. in a cryogenic programmed temperature bath. Further cooling from +5 to −10° C. was effected in such a manner that there was a decrease of one degree for every 60 minutes. A seed crystal of SS-isomer was added to the solution at +1° C. and cooling is continued till −10° C. After remaining at −10° C. for 24 hrs. The solids obtained were separated out and analyzed.
     Wt. of solids=6.43 g   % purity of SS-isomer=49.83   

     Example-16 
     To 17.69 gms of concentrated, mother liquor obtained from experiments after separating the solids (SS:SR 1:1) was added 0.11 g of methyl ester, of (S)-2-(4-chlorophenyl)isovaleric acid, and 116 gms of methanol to obtain 13.3% w/w homogeneous solution of diastereomer-A and refluxed for 1 hr; The contents were cooled to room temperature and subjected to crystallization in a cryogenic bath by cooling in a stepwise manner from RT to +3° C. in 4 hrs. Further cooling was effected to −4° C. at the rate of 1° C. for 60 minutes. A seed crystal of SS-isomer (99.3%) was introduced at −2° C. The solution was held at −3° C. for a further period of 72 hrs at the end of which solids obtained were separated and analyzed.
     Wt. of crystals=7.84 g   % purity of SS-isomer=44.5   

     Example-17 
     8.82 g of diastereomer-A (SS:SR 1:1) was mixed with 1.5 gm of mother liquor of earlier experiments and dissolved in methanol (55 g), heated to reflux for one hr to obtain 13.9% solution of diastereomer-A which was cooled to room temperature and transferred to a suitable reactor provided with thermovel to measure temperature and a stirrer. The stirred solution was cooled in a cryogenic bath at a stepwise rate of cooling of one degree centigrade for one hour from +50 to −7° C. Pure SS isomer (99.3%) was added to the cooling solution at +1° C. After keeping the solution at −7° C. for 1 hrs the solids obtained were filtered and separated.
     Wt. of Solids=5.63 g   % purity of SS-isomer=45.23   

     Example-18 
     15.05 gms of diastereomer-A having ratio of SS:SR 45:48 obtained from unsuccessful experiment of preferential crystallization was dissolved in 101 gms of methanol to obtain a 13% solution of diastereomer-A to which 0.01 g of iron rust was added. This solution was subjected to crystallization in a 250 ml round bottom flask having provision for temperature recording and stirring by placing in a cryogenic bath and decreasing the temperature at the rate of +1° C./hr from +12° C. to −5° C. A slurry of seed crystals crystallized from pet ether was introduced into the system at +1° C. and further cooling is effected till temperature was reached to −5° C. The solution was held at −5° C. for a further period of 10 hrs. The crystals obtained at −5° C. were dissolved while filtering.
     Wt. of crystals=0.63 g   % purity of SS-isomer=43.62   Wt. of ML=110.68   

     Example-19 
     15.04 g of diastereomer-A was equilibrated at 120° C. under vacuum for 2 hrs, cooled to room temperature and 95 gms of methanol was added to obtain 13.6% solution of diastereomer-A. This solution was subjected to crystallization, in a 250 ml round bottom flask fitted with a stirrer, a thermovel and an arrangement to add a slurry of seed crystals, by cooling the solution at a programmed rate from +10° C. to −13° C. at the rate of 1° C./3 hrs. When the temperature reached +10° C., slurry of seed crystals in hexane obtained by fresh crystallization of 200 mg of SS-isomer of 99.3% was added at once. After reaching −13° C. the solution was continued to be kept at that temperature for 48 hrs and the solids obtained were filtered off.
     Wt. of crystals=2.13 g   % purity of SS-isomer=94.7   Wt. of ML=106.29   

     Example-20 
     Diastereomer-A having SS:SR in the ratio of 1:1 obtained from crystallization experiments wherein preferential crystallization has not taken place was pooled together and 13.0 g of that material was equilibrated at 120° C. for 2 hrs under vacuum (200-300 mm) and cooled to room temperature and was dissolved in 85 gm of MeOH to obtain a 13.0% solution of diastereomer-A. This solution was filtered off and transferred to a suitable reactor having provision for stirring, temperature measurement and introduction of slurry seed of crystals. This solution was gently stirred from +10° C. to −13° C. in a cryogenic bath following a rate of cooling of 1° C./3 hr after addition of about 200 mg of slurry of seed crystals (SS-isomer) and 100 mg iron rust at +10° C. After reaching −13° C. the solution was continued to be at that temperature for a further period of 52 hrs and crystals were separated out by filtration.
     Wt. of crystals=2.13 g   % purity of SS-isomer=94.7   

     Example-21 
     60.0 g of diastereomer-A was equilibrated at 110° C. for 1½ hrs and cooled to room temperature. To the above liquid diastereomer-A was added 400 g of MeOH to obtain 13.0% solution. This solution was subjected to programmed rate of cooling 1° C./5 hr from +10° C. to +2° C. while introducing a seed crystal of SS-isomer (99.3%) at +10° C. under gentle stirring in a 500 ml round bottom flask by keeping in a temperature programmed cryogenic bath. After attaining the temperature of +2° C. the solution was further held at that temperature for 40 hrs. and crystals obtained were separated by filtration.
     Wt. of crystals=1.67 g   % purity of SS-isomer=98.2   

     Example-22 
     10.0 g of diastereomer-A having a ratio of SS:SR in 1:1 was dissolved in 66 g of methanol to obtain 13.0% solution of diastereomer-A. This solution was subjected to crystallization by addition of slurry seed crystals in hexane at +10° C. and cooling the solution from that temperature to 4° C. in a phased manner while introducing 0.01 g of quinide at 6° C. and further cooling the reaction mass to 4° C. and holding the solution at that temperature for 36 hrs. At the end of which the crystals obtained were analyzed.
     Wt. of crystals=0.95 g   % purity of SS-isomer=42.0   

     Example-23 
     10.0 g of diastereomer-A was equilibrated at 120° C. for 2 hrs and cooled to room temperature. To the liquid isomer-A was added 67.0 g of methanol to obtain 12.8% solution of diastereomer-A which was subjected to crystallization by addition of 0.33 g of glacial acetic acid and cooling the solution from +18° C. to +3° C. under stirring at a rate of cooling of 2° C./hr by addition of a slurry of seed of crystals (200 mg) at 14° C. After reaching +7° C. the solution was cooled to +3° C. at the rate of 1° C. per every 3 hrs. and held at that temperature for 48 hrs and the crystals were separated by filtration.
     Wt. of crystals=3.46 g   % purity of SS-isomer=47.02   

     Example-24 
     99.5 gms of liquid isomer prepared on a 3.0 kg batch scale as described in example-1 was heated at 120° C. for 3 hrs and cooled to RT. Thus obtained material was dissolved in 618 gms of methanol to obtain 13.8 solution of diastereomer-A which was cooled at a programmed rate of 1° C./hr from −10° C. to −8° C. in a suitable reactor having provision for stirring, introduction of slurry seed and measurement of temperature slurry seed of crystals freshly crystallized in hexane of SS isomer were introduced at +8° C. Further cooling to −12° C. from −8° C. was affected at the rate of 1° C./3 hrs, after reaching −12° C. the solution was held at that temperature for 48 hrs and solids obtained were filtered off and analyzed.
     Wt. of solids=1.39 g   % of SS-isomer=94.0   Wt. of ML=704.68   

     Example-25 
     The mother liquor of example-24 (704.68 g) after separating the 1.39 g of crystals was concentrated and made to a solution of 19.8% in methanol. 140.0 g of heptane was added to the solution and the programmed rate of cooling from +6° to −13° C. was continued by introduction of slurry seed of SS isomer at 5° C. as described in above example. The reaction mixture was kept at −13° C. for a period of 90 hrs. the separated crystals were analyzed for SS-isomer content by HPLC.
     Wt. of solid: 9.54   % purity of SS isomer=97.5   

     Example-26 
     17.36 g of liquid isomer-A melted at 120° C. was dissolved in 90.3 g in methanol-toluene mixture (87:3.2) to obtain a 16.87% diastereomer-A solution. This solution was cooled from +20° C. to 14° C. at a programmed rate of cooling of 2° C./hr in a cryogenic bath while stirring and seeded with a crystal of 99.9% SS-isomer at +14° C. Further cooling from +14° C. to +2° C. was performed at the rate of +1° C./90 minutes. After reaching the temperature of +2° C. the solution was held at that temperature for a period of 12 hrs under gentle stirring. The crystals obtained are filtered and analyzed for SS-isomer content by HPLC.
     Wt. of solids−7.05 g   % of SS-isomer=43.3 g   

     Example-27 
     20.0 g of diastereomer-A was equilibrated at 120° C. for 4 hr cooled to RT and made to 11.5% diastereomer-A solution in methanol-toluene mixture containing 3% of toluene. This solution was cooled from +15° C. to −6° C. in a suitable reactor provided with a stirrer, thermovel, and provision for introduction of seed crystals by placing in a cryogenic bath having programmed temperature cooling facility. A seed crystal of 99.3% of SS-isomer was added at +9° C. and cooling is continued from −6° C. at 1° C./hr. 1.0 ml of 9% w/w methonolic ammonia was added at −3° C. The solution was held at −6° C. for a period of 16 hrs and crystals were separated out and analyzed for SS isomer content.
     Wt. of solids=6.7 g   % of SS-Isomer=42.27   

     Example-28 
     40.02 gms of diastereomer-A prepared on a 3.0 kg scale batch prepared according to procedure described in example-1 was dissolved in a mixture of Heptane (65 g), N,N-DEA (28.0 g) and hexane (18.9 g) to obtain 30% solution. Prior to this, the diastereomer-A was equilibrated at 120° C. for 4 hr as described in above examples. Thus obtained solution was cooled in an appropriate reactor having provision for seed crystal addition, thermovel and stirrer following a programmed cooling in a cryogenic bath at the rate of 1° C./hr from +10° C. to −10° C. A seed crystal of 99.3% of SS-isomer was added at +6° C. After reaching −10° C., the reaction mixture was held at that temperature for a further period of 24 hrs, at the end of which solids were separated by filtration.
     Wt. of solids−2.54 g   % of SS-isomer=81.35   

     Example-29 
     10.26 g of diastereomer-A was dissolved in 31.26 gms of methanol to obtain a 25% w/w solution which was cooled in a reactor provided with a provision for seed crystal addition, thermovel and stirrer 0.03 g of tetrabutylammoniumbromide (TEBA) and 4.0 ml of glacial acetic acid was added at 21° C. followed by addition of pure SS-isomer crystals of 99.3%. Further cooling was followed by a temperature programme designated at the rate of 1° C./4 hr to +15° C. The solution was kept at that temperature for 19 hrs wherein growth of crystals was conspicuous and started increasing. At the end of 19 hrs at 15° C., the crystals were separated by filtration.
     Wt. of solids−4.75 g   % of SS-Isomer=47.02   

     Example-30 
     10.04 gms of diastereomer-A was dissolved in 30 gms of MeOH to obtain 25.0%w/w solution. To which was added 0.520 g of fenvaleric acid and 0.018 g of PTC catalyst (TBAB) and refluxed for 2½ hrs. This solution was transferred to a suitable reactor provided with a stirrer, thermovel, provision for seed crystal addition and kept in a cryogenic bath for cooling from +25° C. to +19° C. at 1° C./2 hrs. A seed crystal was introduced at +19° C. After reaching +19° C. the solution was held at that temperature for 20 hrs. The crystals obtained were separated and analyzed for SS-isomer content.
     Wt. of solids=4.4 g   % of SS-Isomer=46.88   

     Example-31 
     7.0 g of diastereomer-A recovered from earlier experiments having SS:SR (46:47) was equilibrated at 115° C. for 4 hrs and cooled to RT. This material was dissolved in 41.54 g of IPA:MeOH (10:30) mixture to obtain a 14.5% w/w solution of diastereomer-A which was subjected to preferential crystallization in a 250 ml round bottom flask fitted with a stirrer, thermovel to measure temperature and provision for addition of seed crystals. This solution was cooled in a cryogenic bath from +23° C., by decreasing temperature at the rate of 2° C. for every 3 hrs. A seed crystal of 99% purity of SS-isomer was introduced into the system at 20° C. and temperature was decreased hereafter at 1° C. for 2 hrs. It was observed that crystal was dissolved at 18° C. A fresh seed crystal was added to the solution at that temperature and process of crystallization was continued by decreasing temperature to 14° C., where in the increase of crystals was conspicuous and the solution was held at that temperature for 10 hrs and solids obtained were filtered off and analyzed for SS isomer content by HPLC.
     Wt. of solids=2.8 g   % of SS-isomer=44.7   

     Example-32 
     279.0 g of diastereomer-A having SS:SR ratio 432:435 was equilibrated at 120° C. under vacuum (200-100 mm of Hg) for 2 hrs, cooled to room temperature and made to 29.9% w/w solution of diastereomer-A in methanol. This solution was transferred to a 2.0 lit round bottom flask equipped with a stirrer, thermovel and a provision for addition of slurry of seed crystals. This solution is cooled in a cryogenic bath under stirring at a temperature programme such that the rate of crystallization is conspicuous and continuous without getting abrupt crystallization, from +20° C. to +5° C. at the rate of 1° C./hr upto +12° C. wherein slurry of seed crystals of SS-isomer obtained from crystallization of SS-isomer in hexane was added together with mother liquor. After keeping the solution at 12° C. for 1 hr, further cooling is continued by decreasing the temperature at the rate of 1° C. while observing the process of crystallization once in 2 or 3 hrs. Thus after reaching 5° C. the solution was held at that temperature (5° C.) for 34 hrs and crystals were separated out and analyzed for SS-isomer content.
     Wt. of crystals=49.44 g   % purity of SS-isomer=95.67   Wt. of ML=857.10 g   

     Example-33 
     To the mother liquor obtained (857 g) from example example-32 was added 610 mg of KF and heated at 49° C. for 60 hrs and concentrated to 30% w/w solution and subjected to process of crystallization from +20° C. to 0° C. as described in above example and holding the solution for a further period of 72 hrs at 0° C. The crystals obtained were filtered off and analyzed for SS-isomer content by chiral HPLC.
     Wt. of crystals=64.3 g   % purity of SS-isomer=65.23   Wt. of ML=670.84 g   

     Example-34 
     The mother liquor (670.0 g) of example 33 was heated under stirring at 55° C. for 20 hrs, concentrated the solution to 30% w/w and kept for cooling in an appropriate reactor as used in above example following a temperature programme from +15° C. to −6° C. at the rate of 2° C./hr. initially i.e. from +15° C. to +12° C., where upon a slurry of seed crystals of SS-isomer (99.3%) prepared as described in above example was introduced into the system. The process of cooling was continued till the onset of cooling at the rate of 1° C./hr i.e. up to +4° C. Further cooling was continued to −6° C. by observing the rate of crystallization and decrease of temperature is performed in such a manner that it does not initiate abrupt crystallization. After keeping the solution at −6° C. for 24° C. hrs, the crystals obtained were found to form a lump which was dissociated by raising the temperature to +4° C. where in it was broken and the crystals were separated by usual manner as described in above examples.
     Wt. of crystals=14.03 g   % purity of SS-isomer=89.79   Wt. of ML=518.2 g   

     Example-35 
     The ML (518 g) obtained from example 34 was heated at 55° C. for 20 hrs and concentrated to 30% w/w solution of diastereomer-A and filtered before subjecting to the process of crystallization in a reactor as described in ex. KR-301 under programmed cooling from +15° C. to −10° C. following the procedure described in ex. KR-308. After attaining the temperature of −10° C., the solution was maintained at that temperature for 20 hrs. The solids were separated and analyzed for SS-isomer content by chiral HPLC analysis.
     Wt. of solids=10.22 g   % purity of SS-isomer=95.63   Wt. of ML=857.10 g   

     Example-36 
     The ML (857 g) obtained from example 35 was equilibrated at 55° C. for 4 hrs cooled, filtered and used for process of crystallization in a 1.0 lit round bottom flask provided with a thermovel, stirrer and provision for addition seed slurry. The reactor was cooled in a cryogenic bath, at a programmed rate of cooling from +22° C. to −10° C. by adding slurry a seed as prepared as described in ex. 301 was introduced at 8° C. Further cooling is done by decreasing the temperature while observing rate of crystallization at the rate of 1° C. for every 5 hrs till temperature is reached to −10° C. and holding the solution at that temperature for a further period of 50 hrs. At the end of which crystals were separated out, and analyzed for SS-isomer content.
     Wt. of crystals=3.94 g   % purity of SS-isomer=93.9   Wt. of ML=429.06   

     
       
         
               
               
               
             
               
               
               
             
           
               
                 TABLE 
               
               
                   
               
               
                   
                 Wt. of Crystals 
                 % purity 
               
               
                 Expt. No. 
                 (in gms) 
                 (SS isomer) 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                 32 
                 49.44 
                 95.67 
               
               
                 33 
                 64.3 
                 65.23 
               
               
                 34 
                 14.03 
                 89.79 
               
               
                 35 
                 10.02 
                 93.63 
               
               
                 36 
                 3.94 
                 93.9 
               
               
                   
               
             
          
         
       
     
     Part B 
     Preparation of diastereomer-A 
     Example-37 
     8.32 g of NaCN and 78.8 gms of H 2 O was charged simultaneously into a 500 ml reactor equipped with a provision for cooling the reaction mass to −4° C. to −5° C., a mechanical stirrer, thermovel, dropping funnel and a vent tube. The contents are stirred well, Dichloromethane (80 g) and tetrabutylammonium bromide (1.08 g) was added to the solution while stirring after which metaphenoxybenzaldehyde (21.7 g) was added to the solution under stirring through a droping funnel over a period of 15 minutes at 20-25° C. minutes. This solution was cooled to −4° C. and 25.54 gms of (S)-(2)-(4-chlorophenyl)isovaleroylchloride diluted with 40 ml of dichloroethane was added, keeping the temperature between −1 to −4° C. in two hrs. the temperature of reaction mass was further maintained at that temperature for another two hrs during which period the reaction was monitored by chiral HPLC after which the reaction temperature was brought to room temperature and layers were allowed to separated out. The lower organic layer (DCE) was separated and washed thrice with (3×2000 ml) distilled water, each time checking the pH of aqueous layer, and continued washings if pH is not neutral. The upper aqueous layer (NaCN) is detoxified separately. The DCE layer is concentrated at 40° C.-50° C. at 35-40 mm of Hg and purged with nitrogen intermittently to yield 48.18 gm of diastereomer-A of composition SS:SR 43:87:46.44. 
     Example-38 
     20.2 g of the liquid diastereomer-A (SS/SR 45.2/45.5) prepared as described in the above example-37 is such without any further modifications by dissolving in 60.0 gms of methanol to obtain a 25% w/w solution of diastereomer-A. This solution was cooled in a suitable reactor equipped with a provision for seed crystal addition, thermovel and stirrer; by placing in a temperature programmed cryogenic bath in a stepwise manner from +20° C. to +15° C. at 2° C./hr. A slurry of seed crystals of SS isomer was added at +15° C. and solution was held at that temperature for 12 hrs. Further cooling was effected by decreasing temperature @ 1° C./hr till temperature reached to +7° C. The solution was held at 7° C. for 24 hrs and the crystals obtained were filtered off, analyzed for SS-isomer content by chiral HPLC.
     Wt. of crystals=2.58   90% purity of SS-isomer=96.4   

     Example-39 
     106.79 gms of liquid diastereomer-A obtained following the procedure described in example 37 wherein a new PTC catalyst was used instead of TEBA. This material was dissolved in 430 gms of methanol in a 1000 ml round bottomed flask equipped with a stirrer, thermovel and provision for addition of seed crystal to obtain a into 32.35 (w/w) solution of diastereomer-A. This solution was cooled in a cryogenic bath under stirring following a programmed rate of cooling (from +20° C. to 16° C. in 2 hrs (2° C./hr) at the end of which temperature was decreased in one step to 7° C. and a seed crystals of SS-isomer (99.3%) was introduced into the reactor. Further cooling was effected from +7° C. to −7° C. at the rate of 1 + ° C./hr and the solution was kept at −7° C. for 60 hrs at the end of which the crystals obtained were separated by filtration, dried and analyzed for SS-isomer content.
     Wt. of crystals=16.5 g   % purity of SS-isomer=95.2%   Wt. of ML=506.0 gms   

     Example-40 
     The mother liquor obtained in the above experiment (example 39) was equilibrated with 0.37 g of potassium thioxide at 63° C. for 18 hrs. cooled to room temperature and was replenished with 16.0 gms of liquid isomer-A as used in example above and made up to 19.7% w/w solution by adding 20.0 gms of methanol. The process of crystallization was repeated as described in above example except that instead of decreasing temperature from 16° C. to 7° C. at once it was effected at the rate of 4° C. per hr. and further cooling is done as described in above example upto −6° C. and the solution was held at that temperature (−6°) for 2 hrs. After separating the crystals, and ML, the crystals were analyzed by chiral HPLC for SS-isomers content.
     Wt. of crystals=12.16   % purity=96.7%   Wt. of ML=515.84 g   

     Example-41 
     The ML (515.84 gms) of example 40 was equilibrated at 60° C. for 18 hrs at 65° C., cooled to room temperature and replenished with 16.0 gms of liquid diastereomer as used in above example and made upto 20% w/w solution by addition of 21 gms of methanol. This solution was subjected to crystallization by decreasing the temperature from 18° to 5° C. at the rate of 3° C./hr. and introducing SS-isomer (99.3%) seed crystal at 5° C. Further cooling to −8° C. was effected at the rate of 1° or 2° C. while observing the rate of crystallization. The solution was held at −8° C. for 24 hrs. The crystals obtained were separated out by filtration, dried and analyzed for SS-isomer content.
     Wt. of crystals=11.0 g   % purity of SS-isomer=97.5   Wt. of ML=530.06 g.   

     Example-42 
     The mother liquor 530.06 gms obtained in above example-41 was equilibrated at 60° C. for 6 hrs cooled to room temperature and replenished with 15.8 gms of liquid diastereomer as used in above example and replenished with 23.0 g of methanol respectively to obtain 20% w/w solution of liquid diastereomer A. This solution was subjected to stepwise cooling following the method described in above example from +16 to +3° C., at which temperature (3° C.) seed crystals of SS-isomer (99%) was added and further cooling to −8° C. was continued by decreasing the temperature while observing the rate of crystallization in such a manner at the rate of 1° C./5 h upto −2° C. from +3° C. and there after at the rate of 1° C. for 90 minutes and holding the solution at −8° C. for 12 hrs at the end of which the crystals obtained were separated and analyzed by chiral HPLC for their SS-isomer content.
     Wt. of crystals=11.33 g   % purity of SS=98.55   Wt. of ML=552.29 g   

     Example-43 
     The ML (552.9) obtained in above example-42 was equilibrated for 10 hrs at 65° C., cooled and replenished with 15.07 g of liquid isomer as used for the above example and 15.0 g of methanol respectively to obtain a 20% w/w solution of diastereomer-A, which was subjected to step-wise cooling following the temperature programme as described in above example except that cooling was continued upto −11° C. and holding the solution between −10° C. to −11° C. for 48 hrs. The crystals obtained were separated by filtration and analyzed for SS-isomer content by chiral HPLC.
     Wt. of crystals=6.91   % purity=95.9   wt. of ML=567.54 g   

     
       
         
               
               
               
             
               
             
           
               
                 TABLE 
               
               
                   
               
             
             
               
                   
                 Wt. of SS isomer 
                   
               
               
                 Expt. No. 
                 (gms) 
                 % purity 
               
               
                   
               
               
                 39 
                 16.5 
                 96.5 
               
               
                 40 
                 12.16 
                 96.7 
               
               
                 41 
                 11.0 
                 97.58 
               
               
                 42 
                 11.33 
                 98.5 
               
               
                 43 
                 6.91 
                 95.9 
               
               
                   
               
             
          
           
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
             
          
         
       
     
     Example-44 
     51.4 g of liquid diastereomer-A prepared as described in example-37 except that instead of tetrabutylammonium bromide (TBAB) a new phase transfer catalyst N-butyl-N,N dimethyl-α-(S)-phenyl ethylammoniumbromide, was used and dissolved in 104.45 g of MeOH to obtain a 33% w/w solution of diastereomer-A. This solution was transferred to a 500 ml round bottom flask equipped with a thermovel, stirrer and provision for addition of slurry seed and cooled in a cryogenic bath from +20° to +8° C. at the rate 2° C./hr till temperature is reached to +13° C., at which a slurry seed crystals of SS-isomer (99.3%) crystallized from SS-isomer in hexane together with mother liquor was introduced into the system. Further cooling to +8° C. is effected at the rate 1° C./4 hrs and the solution was held at that temperature for 20 hrs and filtered. The crystals obtained were analyzed for SS-isomer content. 
     Wt. of crystals=11.2 g 
     % purity of SS-isomer=95.3 
     wt. of ML=140.45 g 
     Example-45 
     The mother liquor 140.45 gms obtained from above example-44 was equilibrated with KF (250 mg) at 60° C. for 5 hrs, cooled to room temperature and replenished with 11.23 g of diastereomer-A, and subjected for crystallization by cooling the solution from +20° to +9° in a suitable reactor as described in above example-40 following the same procedure and the solution was held at +9° C. for 20 hrs and filtered. The crystals were analyzed for SS-isomer content.
     Wt. of solid=9.65 g   % Purity of crystals=96.5   Wt. of ML=144.04 gms   

     Example-46 
     Preparation of Diastereomer-A 
     0.66 kg of Sodium cyanide and 6.24 kg of distilled water is charged simultaneously into a 20.0 lit. glass stirred reactor, equipped with a provision to cooling the reaction mass to −4° C., a mechanical stirrer, thermovel, dropping funnel and a vent tube. The contents are stirred well till a clear solution is obtained. 4.4 kg Dichloroethane, and 0.084 kg of tetrabutylammonium bromide (PTC) are charged in to the reactor under stirring, after which 1.75 kg of metaphenoxybenzaldehyde (MPBA) is added through a dropping funnel over a period of 25-30 mnts. at a temp. of 20-25° C. The reaction mixture is cooled to −3° to −5° C., 2.15 kg of (S)-fenvaleroylchloride is diluted with 2.2 kg of dichloroethane (DCE) and added over a period of 1½ to 2 hrs. through a dropping funnel maintaining the temperature between −3 to −4° C. under vigorous stirring. The temperature of reaction mass is maintained at this temperature for a further period of 2 hrs. The reaction is monitored by HPLC analysis (conversion of MPBA). The reaction mixture is brought to room temperature and the layers were allowed to separate out. The lower DCE layer is discharged weighed (11.19 kg) and kept aside. The upper aqueous layer (7.75 kg) containing sodium cyanide is discharged weighed and detoxified separately. The DCE layer (11.19 kg) is washed with (3×3.0 kg) distilled water, each time checking the pH of aqueous layer. The washings of DCE layer is continued till the pH of aqueous layer is neutral. The dilute DCE layer (11.19 kg) is taken for recovery of diastereomer-A. 
     The dilute DCE layer (11.19 kg) is weighed and fed into a Rotary evaporator equipped with a condenser provision for circulating cold water, vacuum system and a heater. The solvent DCE is removed at 40°-50° C. at 35-40 mm of Hg. After removing the last traces of DCE, nitrogen is purged into the system intermittently by applying vacuum to ensure the complete removal of solvent for a further period of 1 hr. The contents are cooled to room temperature, weighed (3.89 kg) and discharged into storage tank.
     Wt. of diastereomer-A=3.89 kg   Ratio of SR:SS=45.2:43.5   

     Example-47 
     The material obtained from example 46 is used for preferential crystallization of esfenvalarate in an iterative manner as described below: 
     2.878 kg of Diastereomer-A (1:1 diastereomeric mixture) is charged into a crystallizer having provision for mechanical stirrer, thermovel, a calcium chloride guard tube and external cooling system. 8.684 kg of methanol is charged into the reactor to obtain about 25% solution and the contents are mixed well to obtain a homogeneous solution. The solution is initially cooled to 22° C. under stirring from room temperature, thereafter cooling is effected to 10° C. by decreasing the temperature at the rate of 4° C. per hour, at this temperature (10° C.) pure crystals of esfenvalerate (99.5%) is introduced into the system. Further cooling is effected carefully to reach the temperature (5-2° C.) at the rate of 1° C. per hour wherein the onset of crystallization is conspicuous. The solution is maintained around the onset of crystallization and the progress of crystallization is monitored by HPLC analysis wherein the concentration of SR-isomer in supernatant liquid is in the range of 55-60%. At this stage the solution is filtered off (ML-1) and the crystals obtained are weighed and air dried. This step is iterative and continued till esfenvalerate is obtained by crystallization process (5 cycles).
     Wt. of crystals=0.516 kg   % Purity of crystals=96.5   Wt. of ML=10.67 kg   

     Example-47A 
     The filtrate enriched with SR-isomer ML-1 (10.67 kg) is charged into all glass jacketed stirred reactor provided with provision for temperature recording and heating system and the contents are heated to 62-65° C. for 5 hrs. The process of epimerization is monitored by HPLC analysis, drawing samples at regular intervals of time and the reaction is stopped when the sample showed a ratio of 1:1 with respect to SR:SS isomers. The solution is cooled to 30° C. and diastereomer-A (0.558 kg)equivalent to esfenvalerate obtained in earlier cycle is added and the solution is made up to 25% by adding methanol (0.424 kg). The process of crystallization is repeated by following the process of cooling from 30 to 3° C. as per the procedure described in example 47 for a period of 60 hrs. at the end of which the crystals obtained were separated weighed and dried
     Wt. of crystals=0.432 kg   % Purity of crystals =97.2   Wt. of ML=10.887 kgs   

     Example-47B 
     The filtrate enriched with SR-isomer ML-2 (10.88 kg) obtained from example 47A is charged into all glass jacketed stirred reactor provided with provision for temperature recording and heating system and the contents are heated to 62-65° C. for 5 hrs. The process of epimerization is monitored by HPLC analysis, drawing samples at regular intervals of time and the reaction is stopped when the sample showed a ratio of 1:1 with respect to SR:SS isomers. The solution is cooled to 30° C. and diastereomer-A (0.452 kg) equivalent to esfenvalerate obtained in earlier cycle is added, solution is made up to 25% by adding methanol (0.504 kg). The process of crystallization is repeated by following the process of cooling from 24 to 1° C. as per the procedure described in example 47 for a period of 64 hrs. at the end of which the crystals obtained were separated weighed and dried.
     Wt. of crystals=0.408 kg   % Purity of crystals=97.5   Wt. of ML=11.122 kgs   

     Example-47C 
     The filtrate enriched with SR-isomer ML-3 (11.12 kg) obtained from 47B is charged into all glass jacketed stirred reactor provided with provision for temperature recording and heating system and the contents are heated to 62-65° C. for 5½ hrs. The process of epimerization is monitored by HPLC analysis, drawing samples at regular intervals of time and the reaction is stopped when the sample showed a ratio of 1:1 with respect to SR:SS isomers. The solution is cooled to 30° C. and diastereomer-A (0.436 kg) equivalent to esfenvalerate obtained in earlier cycle is added, solution is made up to 25%. The process of crystallization is repeated by following the process of cooling from 26 to 1° C. as per the procedure described in example 47 for a period of 64 hrs. at the end of which the crystals obtained were separated weighed and dried.
     Wt. of crystals=0.384 kg   % Purity of crystals=96.8   Wt. of ML=10.89 kgs   

     Example-47D 
     The filtrate enriched with SR-isomer ML-4 (10.89 kg) obtained from example 47C is charged into all glass jacketed stirred reactor provided with provision for temperature recording and heating system and the contents are heated to 62-65° C. for 5½ hrs. The process of epimerization is monitored by HPLC analysis, drawing samples at regular intervals of time and the reaction is stopped when the sample showed a ratio of 1:1 with respect to SR:SS isomers. The solution is cooled to 30° C. and diastereomer-A (0.398 kg) equivalent to esfenvalerate obtained in earlier cycle is added, solution is made up to 25%. The process of crystallization is repeated by following the process of cooling from 25 to −1° C. as per the procedure described in example 47 for a period of 65 hrs. at the end of which the crystals obtained were separated weighed and dried.
     Wt. of crystals=0.184 kg   % Purity of crystals=92.4   Wt. of ML=10.826 kgs   

     Example-47E 
     The filtrate enriched with SR-isomer ML-5 (10.826 kg) obtained from example 47D is charged into all glass jacketed stirred reactor provided with provision for temperature recording and heating system and the contents are heated to 62-65° C. for 6½ hrs. The process of epimerization is monitored by HPLC analysis, drawing samples at regular intervals of time and the reaction is stopped when the sample showed a ratio of 1:1 with respect to SR:SS isomers. The solution is cooled to 30° C. and diastereomer-A (0.280 kg) equivalent to esfenvalerate obtained in earlier cycle is added, solution is made up to 25%. The process of crystallization is repeated by following the process of cooling from 29 to −5° C. as per the procedure described in example 47 for a period of 75 hrs. at the end of which the crystals obtained were separated weighed and dried.
     Wt. of crystals=0.256 kg   % Purity of crystals=94.5   Wt. of ML=10.520 kgs   

                                                       TABLE                           Wt. of Crystals               Expt. No.   (SS Isomer)   % purity                                        47   0.516   96.5           47A   0.432   97.2           47B   0.408   97.5           47C   0.384   96.8           47D   0.184   92.4           47E   0.256   95.4                        
The Main Advantages of the of the Present Invention Are:
         1. The present invention makes it possible to obtain high optically pure (&gt;95%) SS isomer in an iterative manner   2. The another advantage of the invention is the effective use of the unwanted SR isomer from the ML by epimerisation process using catalyst and recycling the same iteratively as such   3. Another advantage is consecutively using thus equilibrated ML of one cycle in another cycle as such avoids many process steps. Replenishing the ML with fresh diastereomer-A to the extent of crystals of SS isomer obtained maintains the saturated state of the solution.   4. Yet another advantage is the catalyst used for epimerisation is reused without isolation for further batches.   5. Yet another advantage is that the method effectively combines the enrichment and crystallization process without isolation of the catalyst and thereof all the desired isomer (SS isomer) can be effectively obtained from diastereomer-A.       
     
       
         
               
               
               
               
               
               
               
               
               
               
             
               
               
               
               
               
               
               
               
               
               
             
               
               
               
               
               
               
               
               
               
               
             
               
               
               
               
               
               
               
               
               
               
               
             
               
               
               
               
               
               
               
               
               
               
               
             
               
               
               
               
               
               
               
               
               
               
               
             
               
               
               
               
               
               
               
               
               
               
               
             
               
               
               
               
               
               
               
               
               
             
               
               
               
               
               
               
               
               
               
             
               
               
               
               
               
               
               
               
               
               
               
             
               
               
               
               
               
               
               
               
               
               
             
               
               
               
               
               
               
               
               
               
               
             
               
               
               
               
               
               
               
               
               
               
               
             
               
               
               
               
               
               
               
               
               
               
             
               
               
               
               
               
               
               
               
               
               
             
               
               
               
               
               
               
               
               
               
               
             
               
               
               
               
               
               
               
               
               
               
             
               
               
               
               
               
               
               
               
               
               
             
               
               
               
               
               
               
               
               
               
               
             
               
               
               
               
               
               
               
               
               
               
             
               
               
               
               
               
               
               
               
               
               
             
               
               
               
               
               
               
               
               
               
               
             
               
               
               
               
               
               
               
               
               
               
             
               
               
               
               
               
               
               
               
               
               
             
               
               
               
               
               
               
               
               
               
               
             
               
               
               
               
               
               
               
               
               
               
             
               
               
               
               
               
               
               
               
               
               
             
               
               
               
               
               
               
               
               
               
               
             
               
               
               
               
               
               
               
               
               
               
             
               
               
               
               
               
               
               
               
               
               
             
               
               
               
               
               
               
               
               
               
               
             
               
               
               
               
               
               
               
               
               
               
             
               
               
               
               
               
               
               
               
               
               
             
               
               
               
               
               
               
               
               
               
               
             
               
               
               
               
               
               
               
               
               
               
             
           
               
                 TABLE 1 
               
               
                   
               
             
             
               
                   
                   
                   
                   
                   
                   
                   
                   
                 % 
                   
               
               
                   
                 Wt. of 
                   
                   
                 Seeding 
                 Temp. 
                   
                 Wt. of 
                 Purity of 
               
               
                 Expt. 
                 dia-A 
                 % solution 
                 Solvent 
                 Temp. 
                 profile 
                 Time 
                 crystals 
                 crystals 
               
               
                 No. 
                 (gms) 
                 w/w 
                 system 
                 (° C. 
                 (° C.) 
                 hrs. 
                 (gms) 
                 (SS) 
                 Remarks 
               
               
                   
               
               
                 KR-1 
                 6.78 
                 31.5 
                 MeOH 
                 No seed 
                 −6 
                 47 
                 No crystals 
                 — 
                 The R.M. warmed to 41° 
               
               
                   
                   
                   
                   
                 crystals 
                   
                   
                   
                   
                 turbid solution at R.T. two 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 layers; TEA 3 ml 
               
               
                 KR-Ia 
                 6.78 
                 33 
                 MeOH 
                 — 
                 23 to −3 
                 19 
                 Crystals 
                 40.37 
                 At −2° C. solid lump formed. 
               
               
                   
                   
                   
                   
                   
                   
                   
                 dissolved 
                   
                 Solution became white turbid 
               
               
                 KR-2 
                 5.01 
                 50 
                 Ethanol 
                 5 
                 5-0 
                 90 
                 0.5 
                 43.14 
                 Crystallization started after 24 hrs 
               
               
                 KR-3 
                 4.98 
                 21.4 
                 Hexane 
                 +5 
                 21 to −5 
                 52 
                 3.44 
                 41.39 
                 TPP added 71 mg 2 mole % 
               
               
                 KR-4 
                 10.04 
                 33 
                 MeOH 
                 +5 
                 10 
                 24 
                 — 
                 — 
                 No preferential crystallisation 
               
               
                 KR-5 
                 10.00 
                 33 
                 MeOH 
                 +5 
                 — 
                 — 
                 — 
                 — 
                 No data 
               
               
                 KR-6 
                 10.0 
                 33.18 
                 Heptane 
                 −13 
                 25 to −16 
                 65 
                 No crystals 
                 44.1 
                 Added 7 gr of dry MeOH 
               
               
                   
                   
                   
                 Toluene/ 
                   
                   
                   
                 Viscous mass 
               
               
                   
                   
                   
                 MeOH 
               
               
                 KR-7 
                 12.39 
                 33 
                 MeOH 
                 −22 
                 24 to −22 
                 163 
                 No crystals 
                 — 
                 — 
               
               
                 KR-8 
                 5.0 
                 30 
                 Isopropanol 
                 −12 
                 5 to −12 
                 102 
                 No crystals 
                 — 
                 Precipitate formed 
               
               
                 KR-9 
                 9.84 
                 35.6 
                 MeOH 
                 — 
                 +15 
                 18 
                 8.86 
                 46.57 
                 Refluxed for 1 hr at 65° C. 
               
               
                 KR-9a 
                 1.31 
                 −8.03 
                 MeOH 
                 2 
                 5 to −15.6 
                 22 
                 0.51 
                 95 
                 Crystals at −15° C. ML of KR-9 
               
               
                 KR-10 
                 10.01 
                 33 
                 MeOH 
                 −5 
                 5 to −15.6 
                 95 
                 2.10 
                 45.4 
                 Refluxed for 1 hr at 65° C. 
               
               
                 KR-10a 
                 7.9 
                 35 
                 MeOH 
                 −15 
                 −15 
                 90 
                 3.57 
                 51.27 
                 ML of KR-10 
               
               
                 KR-11 
                 26.23 
                 7 
                 MeOH 
                 14 
                 14 to −16 
                 40 
                 18.00 
                 51.4 
               
               
                 KR-12 
                 9.2 
                 7 
                 MeOH 
                 −13 
                 +5 to −16 
                 114 
                 0.5 
                 47.7 
                 ML of Kr-9 + ML of KR-11, 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 concentrated to get 7% 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 solution 
               
               
                 KR-13 
                 8.82 
                 33 
                 MeOH 
                 −10 
                 20 to −5 
                 20 
                 4.75 
                 48.17 
                 Crystals of KR-11 dissolved, 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 refluxed for 1 hr at 67° C. 
               
               
                   
               
             
          
           
               
                   
                 Wt. of 
                   
                   
                   
                   
                   
                 Wt. of 
                 % Purity 
                   
               
               
                 Expt. 
                 Dia-A 
                 % solution 
                   
                 Seeding 
                 Temp. 
                   
                 Crystals 
                 of crystals 
               
               
                 No. 
                 (in gms) 
                 (w/w) 
                 Solvent 
                 Temp. (° C.) 
                 profile (° C.) 
                 Time (hrs.) 
                 (in gms) 
                 (SS) 
                 Remarks 
               
               
                   
               
               
                 KR-14 
                 4.1 
                 20 
                 MeOH 
                 −15 
                 15 
                 92 
                 1.2 
                 46.17 
                 ML of KR-13 
               
               
                 KR-15 
                 10.94 
                 33 
                 MeOH 
                 −13 
                 5 to −17 
                 140 
                 0.26 
                 92 
                 Crystals washed with cold 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 hexane 
               
               
                 KR-16 
                 11.74 
                 33 
                 MeOH 
                 5 
                 5 to −1 
                 35 
                 9.40 
                 47.59 
                 Crystals of KR- 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 14, 10, 12, 11 melted and 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 dissolved in MeOH. 
               
               
                 KR-17 
                 2.3 
                 12 
                 MeOH 
                 −18 
                 −17 to−18 
                 76 
                 1.75 
                 48 
                 ML of KR-16 
               
               
                 KR-18 
                 53.91 
                 33.8 
                 MeOH 
                 10 
                 22 to −8 
                 24 
                 23.87 
                 48.01 
                 Refluxed for 1 hr; at 8° C. 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 crystals observed 
               
               
                 KR-19 
                 30.04 
                 27.8 
                 MeOH 
                 −14 
                 5 to −15 
                 67 
                 1.07 
                 90 
                 ML of KR-18 
               
               
                 KR- 
                 29 
                 30 
                 MeOH 
                 −15 
                 −15 
                 66 
                 8.05 
                 48.28 
                 ML of KR-19 
               
               
                 19A 
               
               
                 KR-20 
                 10.01 
                 25 
                 MeOH/ 
                 −10 
                 RT to −16 
                 138 
                 3.29 
                 95.32 
                 0.9 ml MeOH/Ammonia 
               
               
                   
                   
                   
                 Heptane/ 
                   
                   
                   
                   
                   
                 KR-6 
               
               
                   
                   
                   
                 Toluene 
               
               
                 KR-21 
                 10.06 
                 33 
                 Heptane 
                 −15 
                 5 to −16 
                 48 
                 8.65 
                 47.32 
                 0.9 ml MeOH/NH 3  crystal 
               
               
                   
                   
                   
                 Toluene/ 
                   
                   
                   
                   
                   
                 of KR-9, 10 
               
               
                   
                   
                   
                 MeOH 
               
               
                 KR-22 
                 52.82 
                 32.18 
                 MeOH 
                 −14 
                 −14 
                 170 
                 20.0 
                 47.5 
                 Refluxed dia-A for 1 hr at 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 65° C. 
               
               
                 KR-23 
                 11.16 
                 30 
                 MeOH/ 
                 14 
                 23 to −14 
                 240 
                 0.43 
                 97.39 
                 KR-22 ML compound 
               
               
                   
                   
                   
                 Toluene/ 
               
               
                   
                   
                   
                 Heptane 
               
               
                 KR-24 
                 10.85 
                 32.6 
                 MeOH/ 
                 −14 
                 −15 
                 144 
                 0.9 
                 98 
                 KR-22 ML compound 
               
               
                   
                   
                   
                 Toluene/ 
               
               
                   
                   
                   
                 Heptane 
               
               
                   
               
             
          
           
               
                   
                 Wt. of 
                   
                   
                 Seedling 
                   
                   
                 Wt. of 
                 % Purity 
                   
               
               
                 Expt. 
                 dia 
                 % solution 
                 Solvent 
                 Temp. 
                 Temp. profile 
                   
                 Crystals 
                 of  
               
               
                 No. 
                 (gms) 
                 (w/w) 
                 system 
                 (° C.) 
                 (° C.) 
                 Time (hrs.) 
                 (in gms) 
                 crystals (SS) 
                 Remarks 
               
               
                   
               
               
                 KR-25 
                 21.14 
                 33 
                 Heptane/ 
                 −15 
                 −15 
                 280 
                 Gummy 
                 83.91 
                 Crystal of KR-22 
               
               
                   
                   
                   
                 Toluene/ 
                   
                   
                   
                 material 
               
               
                   
                   
                   
                 MeOH 
               
               
                 KR-26 
                 10.11 
                 40 
                 Heptane/ 
                 −15 
                 −15 
                 24 
                 No 
                 — 
                 KR-18 crystals, No 
               
               
                   
                   
                   
                 Toluene/ 
                   
                   
                   
                 crystals 
                   
                 preferentials of 
               
               
                   
                   
                   
                 MeOH 
                   
                   
                   
                   
                   
                 crystallization 
               
               
                 KR-27 
                 2.46 
                 30 
                 Heptane/ 
                 — 
                 — 
                 — 
                 1.5 
                 99 
                 Recrystallizaion of pure 
               
               
                   
                   
                   
                 Toluene 
                   
                   
                   
                   
                   
                 material 
               
               
                 KR-28 
                 4.18 
                 14 
                 Heptane/ 
                 10 
                 25 to 10 
                 24 
                 0.73 
                 98.28 
                 Recrystallization 
               
               
                   
                   
                   
                 Toluene 
               
               
                 KR- 
                 3.31 
                 24 
                 Heptane/ 
                 RT 
                 — 
                 24 
                 1.03 
                 97.55 
                 ML of KR-28 
               
               
                 28C 
                   
                   
                 Toluene 
               
               
                 KR-29 
                 20.0 
                 24.6 
                 MeOH 
                 −15 
                 −15 
                 72 
                 9.22 
                 45 
                 KR-16 + KR-18 material 
               
               
                 KR-30 
                 10.0 
                 11.46 
                 MeOH 
                 −11 
                 −15 to 18 
                 96 
                 6.80 
                 57 
                 ML of KR-29; 0.0724 gms 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 of seed 99.3% added 
               
               
                 KR-31 
                 40.0 
                 33 
                 Heptane/ 
                 −50 
                 0 
                 22 
                 28.41 
                 42 
                 Refrigerator temp. KR-27 
               
               
                   
                   
                   
                 Toluene 
                   
                   
                   
                   
                   
                 crystals as seed (99.31) and 
               
               
                   
                   
                   
                 MeOH 
                   
                   
                   
                   
                   
                 NH 3 . then −15° C. for 5 hrs 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 material filtered 
               
               
                 KR-32 
                 9.0 
                 14.8 
                 MeOH 
                 0 
                 −10 
                 48 
                 9.0 
                 41 
                 1 ml ammonia; pure seed 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 99.3% was added 
               
               
                 KR-33 
                 22.5 
                 12 
                 MeOH 
                 5 
                 −15 
                 96 
                 10.89 
                 39.3 
                 No base was added; large 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 seed crystals were added, 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 KR-29, 31 material 
               
               
                 KR-34 
                 6.8 
                 42.2 
                 Heptane/ 
                 0 
                 0-7° 
                 24 
                 3 
                 49 
                 Solids of KR-30 
               
               
                   
                   
                   
                 Toluene 
               
               
                   
               
             
          
           
               
                   
                   
                   
                   
                 Wt. of 
                   
                   
                   
                   
                   
                   
               
               
                   
                 Wt. of 
                   
                 % 
                 crystals 
                 % Purity 
                 Time of 
                 Temp. 
                 Seeding 
               
               
                 Expt. 
                 dia-A 
                 solvent 
                 solution 
                 (SS) 
                 of 
                 Reaction 
                 Profile 
                 Temp. 
               
               
                 No. 
                 (gms) 
                 system 
                 (w/w) 
                 (gms) 
                 crystals 
                 (hrs) 
                 (° C.) 
                 (° C.) 
                 Base 
                 Remarks 
               
               
                   
               
               
                 KR-35 
                 152.57 
                 MeOH 
                 ≈7.6 
                 — 
                 — 
                 — 
                 — 
                 — 
                 1.0 ml 
                 No data 
               
               
                   
                 (ML) 
                   
                   
                   
                   
                   
                   
                   
                 NH 3 /MeOH 
               
               
                 KR- 
                 20.0 
                 MeOH 
                 12.34 
                  5.6 
                 93.2 
                  87 
                 −7 to −14 
                 −11 
                 4.0 ml 
                 23% yield 
               
               
                 36A 
                   
                   
                   
                   
                   
                   
                   
                   
                 NH 3 /MeOH 
                 ML of KR, 31, 32, 33, 34 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 without stirring 
               
               
                 KR- 
                 20.0 
                 MeOH 
                 12 
                  7.0 g 
                 97.4 
                  87 
                 4 to −8 
                 −4 
                 4.0 ml 
                 35% yield with stirring 
               
               
                 36B 
                   
                   
                   
                   
                   
                   
                   
                   
                 NH 3 /MeOH 
                 ML of KR-31, 32, 33, 34 
               
               
                 KR-37 
                 27.91 
                 MeOH 
                 12 
                  0.03 
                 86 
                 140 
                 −15 
                 −15 
                 9.0 ml 
                 ML of KR 36A + 36B. 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 NH 3 /MeOH 
                 Crystals observed were 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 at low temp. dissolved 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 at ≈RT 
               
               
                 KR-38 
                 16.07 
                 MeOH 
                 12 
                  8.86 
                 43.2 
                  94 
                 0 to −5 
                 0 
                 3.2 ml, 
                 KR-30, 34, 33 solids 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 NH 3 /MeOH 
               
               
                 KR-39 
                 7.36 
                 MeOH 
                 11.88 
                  2.95 
                 98.46 
                  42 
                 −6 to −15 
                 −8 
                 2.0 ml 
                 39% ≈38 hrs. ML of 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 NH 3 /MeOH 
                 KR-38 
               
               
                 KR-40 
                 143 
                 MeOH 
                 25 
                 116.9 
                 41.0 
                  18 
                 −18 
                 1.25 
                 11.17 
                 SAF-18 material 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 NH 3 /MeOH 
               
               
                 KR-41 
                 26.4 
                 MeOH 
                 6.36% 
                  ≈2.0 g 
                 35% 
                  68 hrs 
                 −18 
                 0.22 g of 
                 NH 3 /MeOH 
                 ML of KR-40 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                 99.7% at 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                 −15 
               
               
                   
               
             
          
           
               
                   
                 Wt. of 
                   
                   
                 Wt. 
                 % Purity of 
                 Time of 
                 Temp. ° 
                 Seeding 
                   
                   
               
               
                   
                 Dia-A 
                 solvent 
                 % solution 
                 of crystals 
                 crystals 
                 Reaction 
                 Profile 
                 Temp. 
               
               
                 Expt. No. 
                 (in gms) 
                 system 
                 (w/w) 
                 (SS) 
                 (SS) 
                 (hrs) 
                 (° C.) 
                 (° C.) 
                 Base 
                 Remarks 
               
               
                   
               
               
                 KR-42 
                 24.81 
                 MeOH 
                 12 
                  3.28 
                 99.4 
                 184 
                 −7 to −17 
                 Seed 
                 2 ml 
                 ML of KR-41 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                 crystal 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                 99.7 (LC) 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                 at −14° C. 
               
               
                 42-A 
                  21.6 
                 MeOH 
                 35 
                 77.97 
                 31.4 
                 45 
                 −2 to −10 
                 Pure 
                 4 ml 
                 ML of KR-42 solids, 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                 crystal at 
                 NH 3 / 
                 dissolved conc. to give 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                 −15° C. 
                 MeOH 
                 17.97 g KR-47 
               
               
                 KR-43 
                  40.0 g 
                 MeOH 
                 12 
                 13.56 
                 37.12 
                 ≈24 
                 −8 
                 99.7 at −5 
                 — 
                 @−8.5° after 2 hrs. 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 crystallization started. 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 SM SAF-18 
               
               
                 KR- 
                  26.5 
                 MeOH 
                 8.75 
                 — 
                 — 
                 220 
                 −14 to 
                 Seed 
                 — 
                 3 days at −15 kept in 
               
               
                 43A 
                   
                   
                   
                   
                   
                   
                 −18 
                 crystal 
                   
                 fridge for one day; SM 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                 99.7 at 
                   
                 is ML-KR-43. No 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                 −14 
                   
                 crystals 
               
               
                 KR-44 
                 56.66 g 
                 MeOH 
                 33 
                 45.46 
                 43.58 
                 23 
                 0 to −2 
                 0 
                 — 
                 SAF-18 solids 
               
               
                 KR- 
                 11.10 
                 MeOH 
                 12 
                  1.77 g 
                 97 
                 49 
                 −4 to −12 
                 −4 
                 4.5 ml 
                 ML of KR-44 seed 
               
               
                 44A 
                   
                   
                   
                   
                   
                   
                   
                   
                 NH 3 / 
                 crystals one scoop 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 MeOH 
                 (99.7%) 
               
               
                   
               
             
          
           
               
                   
                   
                   
                   
                 Wt. 
                 % Purity 
                   
                   
                   
                   
                   
               
               
                   
                 Wt. of 
                   
                 % 
                 of crystals 
                 of 
                 Time of 
                 Temp. 
                 Seeding 
               
               
                 Expt. 
                 dia-A 
                 solvent 
                 solution 
                 (SS) 
                 crystals 
                 Reaction 
                 Profile 
                 Temp. 
               
               
                 No. 
                 (gms) 
                 system 
                 (w/w) 
                 (gms) 
                 (SS) 
                 (hrs) 
                 (° C.) 
                 (° C.) 
                 Base 
                 Remarks 
               
               
                   
               
               
                 KR-45 
                  20.0 g 
                 MeOH 
                 6 
                 1.52 
                 40.45 
                  53 
                 −10 to 
                 4 scoops 
                 4.5 ml NH 3 / 
                 Few crystals before 
               
               
                   
                   
                   
                   
                   
                   
                   
                 17° 
                 (99.7%)@ 
                 MeOH 
                 adding NH 3  and seed 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                 −15° C. 
                   
                 kept at −15° C. for 17 hrs 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 (.44 g crystals obtained 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 decanted. Then base/ 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 seed added with 5 hrs 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 crystals of 1:1 only 
               
               
                 KR-46 
                  10.0 g 
                 IPA 
                 19.8 
                 — 
                 — 
                  50 
                 15 to 10 
                   13 
                 3.5 ml NH 3 / 
                 KR-44 solid; no crystals 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 MeOH 
                 were obtained 
               
               
                 KR-47 
                 27.94 
                 MeOH 
                 32.72 
                 — 
                 — 
                  63 
                 −18 
                 −14 
                 2.5 ml NH 3 / 
                 To the ML of KR-42A 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 MeOH 
                 10 gms. Of KR 45 solid 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 added; no crystals 
               
               
                 KR-48 
                 26.21 
                 MeOH 
                 35.7 
                 — 
                 — 
                 142 
                 7 to −9 
                 −17 
                 2.5 ml NH 3 / 
                 ML of KR-43A; ML 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 MeOH 
                 gone bad; no crystals 
               
               
                 KR-49 
                 25.18 g 
                 Heptane 
                 33 
                 — 
                 — 
                  76 
                 RT to 
                 −18 
                 3 ml NH 3 / 
                 KR-44 solid; no crystals 
               
               
                   
                   
                 Toluene 
                   
                   
                   
                   
                 −18 
                   
                 MeOH 
                 clear solution 
               
               
                   
                   
                 MeOH 
               
               
                 KR-50 
                  10.0 g 
                 MeOH 
                 33 
                 — 
                 — 
                 120 hrs 
                 25 to 17 
                 — 
                 — 
                 KR-32, 33 solids Expt. To 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 find the appearance of 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 turbidity 
               
               
                 KR-51 
                  5.02 
                 MeOH/ 
                 33 
                 Gummy 
                 40.05 
                 110 
                 25 to 
                 — 
                 — 
                 Gummy bottom layer 
               
               
                   
                   
                 H 2 O 
                   
                 layer 
                   
                   
                 −10 
               
               
                   
               
             
          
           
               
                   
                   
                   
                   
                   
                   
                 Time 
                 Wt. of 
                   
                   
                   
               
               
                   
                 Wt. of 
                 % 
                   
                 Seeding 
                 Temp. 
                 of 
                 crystals 
                 % Purity of 
               
               
                 Expt. 
                 dia-A 
                 solution 
                 solvent 
                 temp 
                 Profile 
                 Reaction 
                 SS 
                 crystals 
               
               
                 No. 
                 (gms) 
                 (w/w) 
                 system 
                 (° C.) 
                 (° C.) 
                 (hrs) 
                 (gms) 
                 (SS) 
                 Base 
                 Remarks 
               
               
                   
               
               
                 KR- 
                 3.04 
                 35 
                 MeOH, 
                 15 
                 15 
                 23 
                 4.84 
                 43.87 
                 Methanolic 
                 Mixed together and 
               
               
                 52A 
                   
                   
                 H 2 O 
                   
                   
                   
                   
                   
                 ammonia 
                 filtered; ML 
               
               
                 KR-53 
                 3.01 
                 33 
                 MeOH, 
                 15 
                 15 
                 27 
                 4.84 
                 43.87 
                 Methanolic 
                 concentrated; Wt. 2.97 gms 
               
               
                   
                   
                   
                 H 2 O 
                   
                   
                   
                   
                   
                 ammonia 
               
               
                 KR-54 
                 2.057 
                 33 
                 MeOH, 
                 15 
                 15 
                 27 
                 1.9 
                 43.87 
                 Methanolic 
               
               
                   
                   
                   
                 H 2 O 
                   
                   
                   
                   
                   
                 ammonia 
               
               
                 KR-55 
                 79.53 
                 35 
                 Heptane, 
                 −15 
                 23 to 
                 120 
                 17.4 
                 38.28 
                 MeOH/NH 3   
               
               
                   
                   
                   
                 toluene, 
                   
                 −19 
                   
                   
                   
                 5 ml 
               
               
                   
                   
                   
                 methanol 
               
               
                 KR-56 
                 9.94 
                 33 
                 Methanol 
                 −10 
                 35 to 
                 36 
                 — 
                 48.68 
                 Ammonium 
                 Solid of KR-50 
               
               
                   
                   
                   
                   
                   
                 −19 
                   
                   
                   
                 acetate 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 0.054 gms 
               
               
                 KR-57 
                 56.47 
                 33 
                 Heptane, 
                 −13 
                 16 to 
                 67 
                 2.48 
                 35.38 
                 Methanolic 
                 — 
               
               
                   
                   
                   
                 methanol 
                   
                 −18 
                   
                   
                   
                 ammonia 
               
               
                   
                   
                   
                 toluene 
                   
                   
                   
                   
                   
                 6 ml 
               
               
                 KR-58 
                 53.99 
                 34 
                 Heptane, 
                 −14 to 
                 −12 to 
                 95 
                 — 
                 — 
                 — 
                 ML of KR-57; no 
               
               
                   
                   
                   
                 methanol, 
                 −18 
                 −18 
                   
                   
                   
                   
                 crystals 
               
               
                   
                   
                   
                 toluene 
               
               
                 KR-59 
                 6.62 
                 30 
                 Heptane, 
                 −18 
                 RT to 
                 50 
                 — 
                 — 
                 2 ml of 
                 KR-43 solid; no crystals 
               
               
                   
                   
                   
                 methanol, 
                   
                 −18 
                   
                   
                   
                 Methanolic 
               
               
                   
                   
                   
                 toluene 
                   
                   
                   
                   
                   
                 ammonia 
               
               
                   
               
             
          
           
               
                   
                   
                 Wt. of 
                   
                 Wt. 
                 % purity of 
                   
                 Temp. 
                   
               
               
                   
                   
                 diaA 
                 % solution 
                 of crystals 
                 crystals 
                 Time 
                 Profile 
               
               
                 Expt. No. 
                 BASE 
                 (gms) 
                 (w/w) 
                 (gms.) 
                 (SS) 
                 (hrs) 
                 (° C.) 
                 Remarks 
               
               
                   
               
               
                 KR-60 
                 S(−) α-methylbenzyl 
                 6.27 
                 12 
                 — 
                 40.9 
                 42 
                 −5 to −15 
                 Seed crystal at −5° C.; 
               
               
                   
                 Amine 
                   
                   
                   
                   
                   
                   
                 solvent MeOH 
               
               
                   
                 0.9 g ≈2 mol % 
               
               
                 KR-61 
                 T.B.A.B. 
                 5.56 
                 12 
                 6.90 
                 43.9 
                 42 
                 −5 to −15 
                 — 
               
               
                   
                 (0.12 g) 
               
               
                 KR-62 
                 R(+) α-methylbenzyl 
                 5.33 
                 12 
                 2.87 
                 52.5 
                 160 
                 −5 to −15 
                 Seed crystals at −5° C.; more 
               
               
                   
                 amine 0.08 g ≈2 mol % 
                   
                   
                   
                   
                   
                   
                 solids but 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                 changed 
               
               
                 KR-63 
                 TBAOH 0.08 gms 
                 6.22 
                 12 
                 3.38 
                 51.24 
                 165 
                 −5 to −15 
                 Seed crystal at6 −5° C. 
               
               
                   
                 ≈2 mol % 
               
               
                 KR-64 
                 2-2-OCH 3   
                 4.02 
                 12 
                 0.72 
                 43.3 
                 75 
                 −5 to −15 
               
               
                   
                 ethoxyethylamine, 
               
               
                   
                 2 mol % 0.07 gms 
               
               
                 KR-65 
                 Quinoline 2 mol % 
                 4.62 
                 12 
                 0.46 
                 43.2 
                 167 
                 −5 to −15 
                 Seed crystals at −5° C. 
               
               
                   
                 0.08 gms 
                   
                   
                   
                   
                   
                   
                 MeOH 
               
               
                 KR-66 
                 NNDMA 2 mol % 
                 5.51 
                 12 
                 0.45 
                 42.8 
                 137 
                 −5 to −15 
                 Seed crystals at −5° C. 
               
               
                   
                 0.05 gms 
                   
                   
                   
                   
                   
                   
                 MeOH 
               
               
                 KR-67 
                 TBASO 4  2 mol % 
                 6.53 
                 12 
                 3.2 
                 44.02 
                 137 
                 −5 to −15 
                 Seed crystals at −5° C. 
               
               
                   
                 0.12 gms 
                   
                   
                   
                   
                   
                   
                 MeOH 
               
               
                 KR-68 
                 R(+)Amine 2 mol %, 
                 5.16 
                 12 
                 2.48 
                 48.46 
                 115 
                 −5 to −20 
                 MeOH; seed crystals at −5° C. 
               
               
                   
                 0.03 
               
               
                 KR-69 
                 TBAOH 2 mol % 
                 5.14 
                 12 
                 0.81 
                 96.38 
                 115 
                 −5 −17 
                 MeOH; seed crystals at −5° C. 
               
               
                   
                 0.06 gms 
               
               
                   
               
             
          
           
               
                   
                   
                   
                 % solution 
                   
                 % purity of 
                   
                 Temp. 
                   
               
               
                   
                   
                 Wt. of dia A 
                 (w/w) 
                 Wt. of crystals 
                 crystals 
                   
                 Profile 
               
               
                 Expt. No. 
                 BASE 
                 (gms) 
                 in IPA 
                 (gms.) 
                 (SS) 
                 Time (hrs) 
                 (° C.) 
                 Remarks 
               
               
                   
               
               
                 KR-70 
                 R + Amine 
                 5.20 
                 12 
                 — 
                 — 
                 140 
                 −5 to −19 
                 Gummy to the bottom. At RT 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                 two layers. seed 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                 crystals at −5° C. 
               
               
                 KR-71 
                 TBAOH 
                 5.15 
                 12 
                 — 
                 — 
                 140 
                   
                 Gummy to the bottom; at 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                 −5° C. at two layers conc.; 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                 seed crystals at −5° C. 
               
               
                   
               
             
          
           
               
                   
                   
                   
                   
                   
                 % 
                   
                   
                   
                   
                   
               
               
                   
                 Wt. 
                   
                   
                 Wt. of 
                 Purity 
                 Time 
               
               
                   
                 of 
                   
                 % 
                 crystals 
                 of 
                 of 
                 Temp. 
                 Seeding 
               
               
                 Expt. 
                 dia-A 
                 solvent 
                 solution 
                 (SS) 
                 crystals 
                 Reaction 
                 Profile 
                 Temp. 
               
               
                 No. 
                 (gms) 
                 system 
                 (w/w) 
                 (in gms) 
                 (SS) 
                 (hrs) 
                 (° C.) 
                 (° C.) 
                 Base 
                 Remarks 
               
               
                   
               
               
                 KR-72 
                 5.7 
                 toluene 
                 12 
                 No crystals 
                 — 
                 160 hrs 
                 6 to −20 
                 −3.5 
                 TBAOH 
                 No crystals, seed 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 crystal as it contain 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 TBAOH from 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 previous expt. 
               
               
                 KR-73 
                 20.9 
                 MeOH 
                 12 
                 No crystals 
                 — 
                 140 hrs 
                 −5 to 
                 −5 
                 2.9 g 
                 SAF-20 material 
               
               
                   
                   
                   
                   
                   
                   
                   
                 −20 
                   
                 TBAOH 
                 reaction material 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 decomposed 
               
               
                 KR-74 
                 5.22 
                 MeOH 
                 12 
                 No crystals 
                 — 
                 140 hrs 
                 +5 to 
                 −3 
                 DBN 2 mol % 
                 Material 
               
               
                   
                   
                   
                   
                   
                   
                   
                 −20 
                   
                 0.08 g 
                 decomposed 
               
               
                 KR-75 
                 9.79 
                 MeOH 
                 12 
                 Crystal 1:1 
                 41.49 
                 140 hrs 
                 5 to −2 
                 −3.5 
                 TEA 9 mol % 
                 At RT after 24 hrs 
               
               
                   
                   
                   
                   
                 at RT 
                   
                   
                   
                   
                 0.2 g 
                 crystal dissolved 
               
               
                   
                   
                   
                   
                 dissolved 
                   
                   
                   
                   
                   
                 composition 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 ≈1:1 NMR shows 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 decomposition 
               
               
                 KR-76 
                 5.22 
                 toluene 
                 33 
                 No crystals 
                 — 
                 142 hrs 
                 −5 to 
                 −15 
                 NH 3 /MeOH 
                 Added IPA after 
               
               
                   
                   
                   
                   
                   
                   
                   
                 −20° C. 
                   
                 1 ml 
                 120 hrs 
               
               
                 KR-77 
                 4.99 
                 Heptane:toluene 
                 29.4 
                 2 layers 
                 — 
                 168 
                 −5 to 
                 −5 
                 0.5 ml, 6% 
               
               
                   
                   
                 73:26 
                   
                   
                   
                   
                 −20 
                   
                 MeOH/NH 3   
               
               
                 KR-78 
                 5.02 
                 Toluene + 
                 27.8 
                 2 layers 
                 — 
                 168 
                 −5 to 
                 −5 
                 0.5 ml, 6% 
                 Stepwise cooling −5 
               
               
                   
                   
                 isopropanol 
                   
                   
                   
                   
                 −20 
                   
                 MeOH/NH 3   
               
               
                   
                   
                 32 + 67 
               
               
                 KR-79 
                 5.06 
                 Heptane 
                 29.8 
                 2 layers 
                 Two 
                 164 
                 −5 to 10 
                 −5 
                 0.5 ml, 6% 
                 Stepwise cooling 
               
               
                   
                   
                 Ethylacetate 
                   
                   
                 layers 
                   
                   
                   
                 MeOH/NH 3   
               
               
                   
                   
                 Toluene in 
               
               
                   
                   
                 the ratio 
               
               
                   
                   
                 74:10:15 
               
               
                   
               
             
          
           
               
                   
                   
                   
                   
                   
                 Wt. of 
                   
                   
                   
                   
               
               
                   
                   
                 Wt. of 
                   
                   
                 crystals 
                 % purity 
                   
                 Temp. 
               
               
                   
                   
                 dia A 
                 % solution 
                 Solvent 
                 (SS) 
                 of crystals 
                   
                 profile 
               
               
                 Expt. No. 
                 BASE 
                 (gms) 
                 (w/w) 
                 system 
                 (gms) 
                 (SS) 
                 Time (hrs) 
                 (° C.) 
                 Remarks 
               
               
                   
               
               
                 KR-80 
                 4 ml of 
                 20.02 
                 33.25 
                 MeOH 
                 No 
                 — 
                 17 
                 7 to −5 
                 Julobo failure at 33° C. 
               
               
                   
                 MeOH/NH 3  6% 
                   
                   
                   
                 crystals 
                   
                   
                   
                 over high conc. gave for 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 NMR aldehyde is 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 present. Seed crystal at 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 7° C. 
               
               
                 KR-81 
                 1.0 ml 
                 4.99 
                 12.15 
                 MeOH 
                 0.33 
                 89 
                 120 
                 −5 to −19 
                 Stepwise cooling very 
               
               
                   
                 NH 3 /MeOH 
                   
                   
                   
                   
                   
                   
                   
                 few crystal indicating 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 transformation kept 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 under stirring for 6 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 days; seed crystals at −5° C. 
               
               
                 KR-82 
                 4.0 ml of 6% 
                 20.02 
                 33.00 
                 MeOH 
                 9.94 
                 41 
                 96 
                 −5 to −19 
                 Stepwise cooling hard 
               
               
                   
                 NH 3 /MeOH 
                   
                   
                   
                   
                   
                   
                   
                 mass filtered; seed 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 crystals at −5° C. 
               
               
                 KR-83 
                 2.0 ml of 6% 
                 8.89 
                 11.94 
                 MeOH 
                 1.7 
                 97.2 
                 ≈40 
                 −18 to −20 
                 Seed crystal at −18° C.; 
               
               
                   
                 NH 3   
                   
                   
                   
                   
                   
                   
                   
                 ML of KR-82 
               
               
                 Kr-84 
                 2.0 ml 
                 5.0 
                 12.0 
                 MeOH 
                 .75 
                 57.89 
                 60 
                 −15 for 3 
                 Curdy not settling 
               
               
                   
                 NH 3 /MeOH 
                   
                   
                   
                   
                   
                   
                 days 
                 filtered seed crystals at 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                 −18 for 24 hr 
                 −15° C. 
               
               
                 KR-85 
                 2.0 ml 
                 5.03 
                 17.4 
                 MeOH 
                 1.28 
                 92.9 
                 91 
                 −15 to −18 
                 Expt. without stirring; 
               
               
                   
                 MeOH/NH 3   
                   
                   
                   
                   
                   
                   
                   
                 seed crystal at −15° C. 
               
               
                 KR-86 
                 2.0 ml of 6% 
                 5.05 
                 17.66 
                 MeOH 
                 2.18 
                 40.0 
                 22 
                 −15 
                 Expt. Without stirring; 
               
               
                   
                 NH 3 /MeOH 
                   
                   
                   
                   
                   
                   
                   
                 seed crystal at −15° C. 
               
               
                   
               
             
          
           
               
                   
                   
                   
                   
                   
                 Wt. of 
                   
                   
                   
                   
               
               
                   
                   
                 Wt. of 
                   
                   
                 crystals 
                 % purity 
                   
                 Temp. 
               
               
                 Expt. 
                   
                 dia A 
                 % solution 
                 Solvent 
                 (SS) 
                 of crystals 
                 Time 
                 profile 
               
               
                 No. 
                 BASE 
                 (gms) 
                 (w/w) 
                 system 
                 (gms) 
                 (SS) 
                 (hrs) 
                 (° C.) 
                 Remarks 
               
               
                   
               
               
                 KR-87 
                 2 ml of 6% 
                 8.0 
                 16.82 
                 MeOH 
                 5.61 
                 40.8 
                 50 
                 5 to −15 
                 Was used after mixing ML of 
               
               
                   
                 NH 3 /MeOH 
                   
                   
                   
                   
                   
                   
                   
                 88+ see expt KR-87 dt. 2.7.97; 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 seed crystal at 5° C.; added 0.5 ml 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 glacial CH 3 COOH 
               
               
                 KR-88 
                 2.0 ml of 6% 
                 5.05 
                 12.02 
                 MeOH 
                 0.84 
                 89.92 
                 120 
                 −5 to −15 
                 Mixed with KR-87 Ml; Expt. 
               
               
                   
                 NH 3 /MeOH 
                   
                   
                   
                   
                   
                   
                   
                 Without stirring; seed crystals 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 at −15° C. 
               
               
                 KR-89 
                 2.0 
                   
                 18.11 
                 MeOH 
                 2.34 
                 44.06 
                 72 
                 −15 
                 Expt. Without stirring; seed 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 crystals at −15° C. 
               
               
                 KR-90 
                 2.0 ml 
                 9.61 
                 21.02 
                 MeOH 
                 0.08 
                 — 
                 52 
                 −10 to 
                 Changed to stirring on 9.7.97; 
               
               
                   
                 NH 3 /MeOH 6% 
                   
                   
                   
                   
                   
                   
                 −15 
                 ML KR 88 + 89 87; seed 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 crystals at −15° C. 
               
               
                 KR-91 
                 2.0 ml 
                 5.05 
                 18.1 
                 MeOH 
                 2.65 
                 38.99 
                 24 
                 −15 
                 Std at 156.00 hrs at 18.0 
               
               
                   
                 NH 3 /MeOH 
                   
                   
                   
                   
                   
                   
                   
                 maximum than usually seen; 
               
               
                   
                 6% w/w 
                   
                   
                   
                   
                   
                   
                   
                 seed crystals at −15° C. 
               
               
                 KR-92 
                 10 ml 
                 20.75 
                 18.09 
                 MeOH 
                 2.43 
                 94.5 
                 112 
                 −8 
                 Inj of ML repeated as pure 
               
               
                   
                 NH 3 /MeOH 
                   
                   
                   
                   
                   
                   
                   
                 sample 94% crystals 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 contamination suspected; 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 solid of KR 76 − 79; seed 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 crystal at −10° C.; 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 ML = 116.08 gms 
               
               
                 KR-93 
                 10 ml 
                 23.25 g 
                 19.26 
                 MeOH 
                 1.16 
                 97.6 
                 48 
                 −8.6 
                 2 ml of ACOH was added; 
               
               
                   
                 NH 3 /MeOH 6% 
                   
                   
                   
                   
                   
                   
                   
                 seed crystals at −8° C.; ML of 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 KR-92 + 5.0 g of liq. Dia-A 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 used in this expt. 
               
               
                 KR-93A 
                 9 ml 
                 22.09 
                 17.05 
                 MeOH 
                 No 
                 — 
                 80 
                 −8.6 
                 No crystal conc. to 33% 
               
               
                   
                 NH 3 /MeOH 6% 
                   
                   
                   
                 crystals 
                   
                   
                   
                 spoiled while concentrating; 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 seed crystal at −8° C. 
               
               
                   
               
             
          
           
               
                   
                   
                   
                   
                   
                   
                   
                 Wt. of 
                 % Purity 
                   
                   
               
               
                   
                   
                 % 
                   
                 Seeding 
                 Temp. 
                   
                 crystals 
                 of 
               
               
                 Expt. 
                 Wt. of 
                 solution 
                 Solvent 
                 Temp. 
                 profile 
                 Time 
                 (SS) 
                 crystals 
               
               
                 No. 
                 dia-A 
                 (w/w) 
                 system 
                 (° C.) 
                 (° C.) 
                 (hrs) 
                 (gms) 
                 (SS) 
                 BASE 
                 Remarks 
               
               
                   
               
               
                 KR-94 
                 4.96 
                 30 
                 MeOH 
                 10 
                 10 
                 24 
                 4.83 
                 42.8 
                 — 
                 KR-82, 91, 68 solids. Seed 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 crystal present 
               
               
                 KR-95 
                 4.98 
                 21% 
                 MeOH 
                 10 
                 10 
                 24 
                 2.78 
                 38.2 
                 — 
                 KR-82, 88, 91, 87 solids. Seed 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 crystal present 
               
               
                 KR-96 
                 4.7 
                 10.38 
                 MeOH 
                 10 
                 10−0 
                 113 
                 2.9 
                 38 
                 — 
                 KR-82, 68, 91, 87 solids. 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 Crystal present at 5° C. 
               
               
                 KR-97 
                 5.01 
                 15.7 
                 MeOH 
                 10 
                 10 
                 24 
                 2.2 
                 37.8 
                 — 
                 KR-82, 68, 91, 87 solids 
               
               
                 KR-98 
                 5.08 
                 25 
                 MeOH 
                 10 
                 10 
                 24 
                 1.34 
                 — 
                 — 
                 SAF-21 material 
               
               
                 KR-99 
                 4.99 
                 20 
                 MeOH 
                 10 
                 10 
                 24 
                 1.47 
                 38 
                 — 
                 SAF-21 material 
               
               
                 KR-100 
                 5.00 
                 10 
                 MeOH 
                 5 
                 10 to −5 
                 50 
                 1.08 
                 39.25 
                 — 
                 SAF-21 material 
               
               
                 KR-101 
                 4.99 
                 15 
                 MeOH 
                 10 
                 10 
                 24 
                 0.8 
                 42.94 
                 — 
                 SAF-21 material 
               
               
                 KR-102 
                 4.94 
                 10 
                 MeOH 
                 7 
                 8 to −8 
                 120 
                 1.30 
                 36.68 
                 2 ml NH 3 / 
                 SAF-21 material 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 MeOH 
               
               
                 KR-103 
                 4.95 
                 10 
                 MeOH 
                 7 
                 8 to −2 
                 46 
                 1.13 
                 41.01 
                 — 
                 SAF-21 material 
               
               
                 KR-104 
                 4.19 
                 13.7 
                 MeOH 
                 8 
                 8 to −12 
                 46 
                 1.13 
                 42.81 
                 — 
                 ML of KR-101 
               
               
                 KR-105 
                 18.64 
                 12 
                 MeOH 
                 −8 
                 0 to −18 
                 138 
                 3.76 
                 72.2 
                 8 ml NH 3 / 
                 KR-91, 98, 99, 100, 103, 104 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 MeOH 
                 MLs, 
               
               
                 KR-106 
                 5 
                 25 
                 Heptane/ 
                 28 
                 10 
                 88 
                 1.98 
                 42.88 
                 — 
                 KR-60, 61 solids 
               
               
                   
                   
                   
                 toluene 
               
               
                 KR-107 
                 13.5 
                 32 
                 MeOH 
                 0 
                 0 to −10 
                 138 
                 No 
                 — 
                 2 ml NH 3 / 
                 ML of KR-105; neutralized 
               
               
                   
                   
                   
                   
                   
                   
                   
                 crystals 
                   
                 MeOH 
                 with ACOH concentrated 
               
               
                 KR-108 
                 39.39 
                 33 
                 MeOH 
                 5 
                 5 to −15 
                 240 
                 No 
                 — 
                 10 ml of 
                 ML of KR-107 + KR 55, 94 − 97 
               
               
                   
                   
                   
                   
                   
                   
                   
                 crystals 
                   
                 NH 3 /MeOH 
                 solids. 
               
               
                 KR-109 
                 12.12 
                 35.11 
                 MeOH 
                 25 
                 25 to 10 
                 18 
                 — 
                 — 
                   
                 0.13 MPBA added; solid 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 Aα(1:1) Restd. As 109A 
               
               
                   
               
             
          
           
               
                   
                   
                   
                   
                   
                   
                   
                 Wt. of 
                 % Purity 
                   
               
               
                   
                   
                 % 
                   
                 Seeding 
                 Temp. 
                   
                 crystals 
                 of 
               
               
                 Expt. 
                 Wt. of 
                 solution 
                 Solvent 
                 Temp. 
                 profile 
                 Time 
                 (SS) 
                 crystals 
               
               
                 No. 
                 dia-A 
                 (w/w) 
                 system 
                 (° C.) 
                 (° C.) 
                 (hrs) 
                 (gms) 
                 (SS) 
                 Remarks 
               
               
                   
               
               
                 KR- 
                 12.11 
                 33 
                 MeOH 
                 10 
                 10 
                 27 
                 — 
                 47.2 
                 ML of KR-109; a crystal 
               
               
                 109A 
                   
                   
                   
                   
                   
                   
                   
                   
                 tested and made uniform 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 solution 50 μl MPBA added 
               
               
                 KR- 
                 12.11 
                 33 
                 MeOH 
                 10 
                 10 
                 20 
                 — 
                 47.2 
                 ML of KR-109A; a crystal 
               
               
                 109B 
                   
                   
                   
                   
                   
                   
                   
                   
                 tested and made uniform 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 solution 150 μl MPBA added 
               
               
                 KR- 
                 12.11 
                 33 
                 MeOH 
                 10 
                 10 
                 40 
                 — 
                 — 
                 ML of KR-109B 
               
               
                 109C 
               
               
                 KR-110 
                 12.11 
                 33 
                 MeOH 
                 −15 
                 10 to −15 
                 75 
                 No crystals 
                 — 
                 ML of KR-109C, 1 ml 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 NH 3 /MeOH 2 ml of KR-108 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 mixed with KR-109C 
               
               
                 KR-111 
                 32.22 
                 12 
                 MeOH 
                 −5 
                 −5 to −15 
                 120 
                 3.70 
                 96.5 
                 ML of KR- 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 65, 66, 67, 95, 96, 97, 5 ml 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 NH 3 /MeOH 
               
               
                 KR-112 
                 19.89 
                 12 
                 MeOH 
                 −5 
                 −5 to −15 
                 260 
                 No crystals 
                 — 
                 3 ml NH 3 /MeOH mixed 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 M.L&#39;s taken for experiment 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 after concentration. 
               
               
                 KR-113 
                 7.88 
                 12 
                 MeOH 
                 −5 
                 −5 to −15 
                 118 
                 No crystals 
                 — 
                 Mixed M.L&#39;s; 2 ml 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 NH 3 /MeOH 
               
               
                 KR-114 
                 5.31 
                 27.4 
                 Heptane/toluene 
                 10 
                 10 
                 66 
                 2.84 
                 97.19 
                 Old samples of KR-36, two layers 
               
               
                 KR-115 
                 3.05 
                 12.03 
                 MeOH 
                 −15 
                 −15 
                 114 
                 1.05 
                 43.25 
                 KR-111 solid melted. 2 ml 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 NH 3 /MeOH 
               
               
                 KR-116 
                 38.15 
                 12 
                 MeOH 
                 +5 
                 5 to 
                 92 
                 1.2 
                 44.2 
                 SAF-22 material, 16 ml 
               
               
                   
                   
                   
                   
                   
                 −14 
                   
                   
                   
                 NH 3 /MeOH 
               
               
                   
               
             
          
           
               
                   
                   
                   
                   
                   
                   
                   
                 Wt. 
                 % Purity 
                   
               
               
                   
                 Wt. of 
                 % 
                   
                 Seeding 
                 Temp. 
                   
                 of crystals 
                 of 
               
               
                   
                 dia-A 
                 solution 
                 Solvent 
                 Temp. 
                 profile 
                 Time 
                 (SS) 
                 crystals 
               
               
                 Expt. No. 
                 (gms) 
                 (w/w) 
                 system 
                 (° C.) 
                 (° C.) 
                 (hrs) 
                 (gms) 
                 (SS) 
                 Remarks 
               
               
                   
               
               
                 KR-117 
                 37.92 
                 33 
                 MeOH 
                 1 
                 19 to 
                 110 
                 No crystals 
                 — 
                 SAF-22 + KR116; 16 ml 
               
               
                   
                   
                   
                   
                   
                 −14 
                   
                   
                   
                 NH 3 /MeOH 
               
               
                 KR-118 
                 32.18 
                 33 
                 MeOH 
                 −14 
                 8 to −14 
                 94 
                 14.0 
                 43.5 
                 SAF-24, 12 ml N 3 /MeOH 
               
               
                 KR-119 
                 18 
                 21.4 
                 MeOH 
                 −14 
                 −14 
                 140 
                 No crystals 
                 — 
                 ML of KR-118, 65 ml 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 NH 3 /MeOH 
               
               
                 KR-120 
                 9 
                 33 
                 TEA 
                 −14 
                 −14 
                 140 
                 — 
                 — 
                 No crystals 
               
               
                 KR-121 
                 155 
                 32 
                 MeOH 
                 −5 
                 −14 
                 112 
                 92.86 
                 46.84 
                 SAF-27 
               
               
                 KR-122 
                 63 
                 20 
                 MeOH 
                 −14 
                 −14 
                 46 
                 33.8 
                 48.24 
                 ML of KR-121 
               
               
                 KR-123 
                 188 
                 33 
                 MeOH 
                 10 
                 10 
                 280 
                 159 
                 46.58 
                 SAF-27 material 
               
               
                 KR-124 
                 334 
                 33 
                 MeOH 
                 −14 
                 −14 
                 285 
                 270.9 
                 48.25 
                 Pilot plant batch 
               
               
                 KR-125 
                 220 
                 33 
                 MeOH 
                 10 
                 10 
                 80 
                 140.8 
                 47.8 
                 No data, SAF-28, Pilot plant batch 
               
               
                 KR-126 
                 124 
                 30 
                 MeOH 
                 −6 
                 0 to −14 
                 168 
                 202.0 
                 42.6 
                 MLs of KR-122 to 124 
               
               
                 KR-127 
                 18.17 
                 12 
                 MeOH 
                 10 
                 10 to −14 
                 66 
                 6.61 
                 44.1 
                 ML of KR-125 
               
               
                 KR-128 
                 11.56 
                 8 
                 MeOH 
                 0 
                 0 to −14 
                 202 
                 No crystals 
                 — 
                 ML of 127 
               
               
                 KR-129 
                 10.10 
                 33 
                 IPA 
                 10 
                 10 to −17 
                 20 
                 No crystals 
                 — 
                 KR-125 solid 
               
               
                 KR-130 
                 1152 
                 36 
                 MeOH 
                 −5 
                 −5 
                 — 
                 651.63 
                 42.4 
               
               
                 KR-131 
                 10.04 
                 22.84 
                 Isobutanol 
                 0 
                 5 to −5 
                 167 
                 No crystals 
                 — 
                 KR-124 solids 
               
               
                   
                   
                   
                 toluene 
               
               
                 KR-132 
                 7.06 
                 33 
                 T.Butanol TEA 
                 1 
                 −1 
                 90 
                 — 
                 — 
                 KR-124 solids. At RT 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 crystals dissolved 
               
               
                 KR- 
                 9.98 
                 15.2 
                 Heptane TEA 
                 4 
                 2 to −10 
                 138 
                 — 
                 — 
                 KR-124 solids; A crystal 
               
               
                 132A 
                   
                   
                   
                   
                   
                   
                   
                   
                 sowed 40.6%; very few 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 crystals not sep. 
               
               
                   
               
             
          
           
               
                   
                   
                   
                   
                   
                   
                   
                   
                 % 
                   
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                 Purity 
               
               
                   
                   
                 % 
                   
                 S&#39;eeding 
                 Temp. 
                   
                 Wt. 
                 of 
               
               
                   
                 Wt. of 
                 solution 
                 Solvent 
                 Temp. 
                 profile 
                 Time 
                 of crystals 
                 crystals 
               
               
                 Expt. No. 
                 dia-A 
                 (w/w) 
                 system 
                 (° C.) 
                 (° C.) 
                 (in hrs) 
                 (SS) 
                 (SS) 
                 Remarks 
               
               
                   
               
               
                 KR-133 
                 9.98 
                 20 
                 Heptane 
                 −10 
                 −10 
                 95 
                 No 
                 — 
                 KR-132 A ML 
               
               
                   
                   
                   
                 TEA 
                   
                   
                   
                 crystals 
               
               
                 KR-134 
                 5.08 
                 33 
                 Heptane 
                 −11 
                 −11 
                 80 
                 — 
                 40.6 
                 A cryst showed enricment, during 
               
               
                   
                   
                   
                 TEA 
                   
                   
                   
                   
                   
                 sampling process more crystals 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 appeared (1:1) 
               
               
                 KR-135 
                 5 
                 32 
                 Heptane 
                 −5 
                 −5 
                 90 
                 0.15 
                 86.8 
               
               
                   
                   
                   
                 TEA 
               
               
                 KR-135A 
                 4.85 
                 33 
                 Heptane 
                 −5 
                 −4 to −13 
                 240 
                 2.57 
                 44 
                 ML of KR-135 
               
               
                   
                   
                   
                 TEA 
               
               
                 KR-136 
                 8 
                 40 
                 Heptane 
                 −5 
                 −5 
                 90 
                 0.11 
                 77.2 
               
               
                   
                   
                   
                 TEA 
               
               
                 KR-136A 
                 7.89 
                 40 
                 Heptane 
                 −5 
                 −5 to −13 
                 240 
                 2.85 
                 54 
                 ML of KR-136 
               
               
                   
                   
                   
                 TEA 
               
               
                 KR-137 
                 120 
                 40 
                 Heptane 
                 −4 
                 −4 
                 144 
                 34.0 
                 40.9 
                 KR-124 crystals 
               
               
                   
                   
                   
                 TEA 
               
               
                 KR-138 
                 100 
                 40 
                 Heptane 
                 −6 
                 0 to −6 
                 163 
                 27.10 
                 43.2 
                 Hep:TEA 1:1, crystals of KR-124 
               
               
                   
                   
                   
                 TEA 
                   
                   
                   
                   
                   
                   
               
               
                 KR-139 
                 80 
                 33 
                 Heptane 
                 4 
                 4 
                 72 
                 No 
                 — 
                 ML of KR-137 
               
               
                   
                   
                   
                 TEA 
                   
                   
                   
                 crystals 
               
               
                 KR-140 
                 5.04 
                 24 
                 Heptane 
                 4 
                 4 
                 168 
                 0.85 
                 28.2 
                 more decomposed products 
               
               
                   
                   
                   
                 I.P.amine 
               
               
                 KR-141 
                 4.0 
                 4.0 
                 Heptane 
                 4 
                 4 to −5 
                 192 
                 No 
                 — 
                 Layer separation observed 
               
               
                   
                   
                   
                 (S)-α-methyl 
                   
                   
                   
                 crystals 
               
               
                   
                   
                   
                 benzylamine 
               
               
                   
               
             
          
           
               
                   
                   
                   
                   
                   
                   
                   
                 Wt. 
                   
                   
               
               
                   
                   
                   
                   
                   
                   
                   
                 of 
               
               
                   
                 Wt. of 
                   
                   
                 Seeding 
                 Temp. 
                   
                 crystals 
                 % Purity 
               
               
                   
                 dia-A 
                 % solution 
                 Solvent 
                 Temp. 
                 profile 
                 Time 
                 (SS) 
                 of crystals 
               
               
                 Expt. No. 
                 (gms) 
                 (w/w) 
                 system 
                 (° C.) 
                 (° C.) 
                 (hrs) 
                 (gms) 
                 (SS) 
                 Remarks 
               
               
                   
               
               
                 KR-142 
                 12.05 
                 39 
                 TEA, Toluene, 
                 −1 
                 2 to −1 
                 63 
                 No 
                 — 
                 Tol:TEA:Hep = 1:2:3 ratio 
               
               
                   
                   
                   
                 Heptane 
                   
                   
                   
                 crystals 
               
               
                 KR-143 
                 12.05 
                 40 
                 TEA, Hexane 
                 −1 
                 2 to −3 
                 63 
                 3.25 
                 45.6 
               
               
                 KR-144 
                 5.0 
                 20 
                 MeOH 
                 4 
                 4 
                 96 
                 1.0 
                 51.27 
                 Isopropylamine 100 μl added 
               
               
                 KR-145 
                 4.01 
                 56 
                 Diisopropylamine 
                 4 
                 4 
                 120 
                 No 
                 — 
                 Clear solution. No crystals 
               
               
                   
                   
                   
                   
                   
                   
                   
                 crystals 
               
               
                 KR-146 
                 40.21 
                 32.8 
                 Heptane 
                 4 
                 4 
                 24 
                 No 
                 — 
                 M:He:T (28:47:65) KR-130 
               
               
                   
                   
                   
                 Toluene 
                   
                   
                   
                 crystals 
                   
                 compound two layers separated 
               
               
                   
                   
                   
                 MeOH 
               
               
                 KR-147 
                 1.5278 
                 10 
                 MeOH 
                 −1.9 
                 0 to −5 
                 280 
                 0.5 
                 98 
                 Two layers separated No data, 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 seed crystals Wt. 0.37/gr. 
               
               
                 KR-147A 
                 1.0 
                 16 
                 MeOH 
                 −10 
                 −10 
                 144 
                 0.1662 
                 97.7 
                 Crystals: 0.1662 M.L. of 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 Aα = 20% of 147 gm 
               
               
                 KR-148 
                 31.19 
                 40.16 
                 IPA 
                 0 
                 0 to −10 
                 158 
                 27.00 
                 44 
                 Cryst: 27.0, TEA: 2 ml 
               
               
                 KR-149 
                 2.5 
                 10.4 
                 MeOH 
                 0 
                 0 to −8 
                 168 
                 1.43 
                 69 
                 Cryst: 1.43, 20% SS enriched 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 solution 
               
               
                 KR-150 
                 10.0 
                 8.0 
                 MeOH 
                 0 
                 0 to −8 
                 144 
                 6.43 
                 46.31 
                 Cryst: 6.43 gr, S.M. heated for 8 hrs 
               
               
                 KR-151 
                 5.4 
                 10.8 
                 MeOH 
                 2 
                 5 to −6 
                 150 
                 1.47 
                 95 
                 Stirring, Aα = 20%, Cryst. 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 Redissolved, restored as 151A 
               
               
                 KR-152 
                 7.2 
                 8 
                 MeOH 
                 2 
                 5 to −3 
                 144 
                 3.12 
                 35 
                 Cryst. After 48 hrs + 2° C. (24 hrs). 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 Redissolved contd. Cryst: 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 3.1 A = 20% 
               
               
                   
               
             
          
           
               
                   
                   
                   
                   
                   
                   
                   
                 Wt. 
                   
                   
               
               
                   
                   
                   
                   
                   
                   
                   
                 of 
               
               
                   
                 Wt. of 
                   
                   
                 Seeding 
                 Temp. 
                   
                 crystals 
                 % Purity 
               
               
                   
                 dia-A 
                 % solution 
                 Solvent 
                 Temp. 
                 profile 
                 Time 
                 (SS) 
                 of crystals 
               
               
                 Expt. No. 
                 (gms) 
                 (w/w) 
                 system 
                 (° C.) 
                 (° C.) 
                 (hrs) 
                 (gms) 
                 (SS) 
                 Remarks 
               
               
                   
               
               
                 KR-153 
                 10.38 
                 10 
                 MeOH 
                 2 
                 5 to −2 
                 135 
                 5.71 
                 55.7 
                 Crystal appeared, redissolved 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 and started as 153A, Aα = 20% 
               
               
                 KR-154 
                 2.53 
                 8 
                 IPA 
                 2 
                 5 to −10 
                 330 
                 1.78 
                 57.5 
                 Crystal: 1.79 Aα = 20% 
               
               
                 Kr-155 
                 7.7 
                 10 
                 MeOH 
                 2 
                 5 to −6 
                 170 
                 4.40 
                 60.46 
                 Cryst: 3.46, Aα = 20%, ML of 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 151A refluxed, added fresh 2.0 gr 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 1:1 
               
               
                 KR-156 
                 2.57 
                 8.6 
                 IPA 
                 0 
                 5 to −4 
                 164 
                 1.35 
                 52.5 
                 Aα = 20% 
               
               
                 KR-157 
                 1.99 
                 8 
                 IPA 
                 0 
                 2 to −4 
                 96 
                 1.08 
                 45.9 
               
               
                 KR-158 
                 5.63 
                 33 
                 Heptane 
                 −8 
                 −8 
                 150 
                 1.55 
                 55.2 
                 KR-153 A Cryst, M.L. 
               
               
                   
                   
                   
                 Toluene 
                   
                   
                   
                   
                   
                 Wt: 11.53 
               
               
                 KR-159 
                 5.85 
                 8 
                 MeOH 
                 2 
                 5 to 0 
                 168 
                 1.8 
                 52.7 
               
               
                 &amp; 159A 
               
               
                 KR-160 
                 2.7 
                 10 
                 MeOH 
                 2 
                 5 to −3 
                 142 
                 1.67 
                 70.25 
                 M.L. taken for 160. A expt. 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 Aα = 20% 
               
               
                 KR-160A 
                 1.1 
                 4.4 
                 MeOH 
                 −6 
                 −3 to −10 
                 170 
                 0.61 
                 49.25 
                 Seed crystal dissolved, added 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 fresh seed crystal; changed to −10° C. 
               
               
                 KR-161 
                 3.60 
                 8 
                 MeOH 
                 2 
                 5 to −4 
                 140 
                 1.07 
                 96.90 
                 M.L. taken for 161A expt. 
               
               
                 KR-161A 
                 2.53 
                 9 
                 MeOH 
                 −6 
                 −6 to −10 
                 210 
                 0.47 
                 94.07 
                 ML of KR 160 
               
               
                 KR-162 
                 2.0 
                 8 
                 n- 
                 2 
                 5 to −8 
                 220 
                 No 
                 — 
                 Kept in the fridge. 
               
               
                   
                   
                   
                 propanol 
                   
                   
                   
                 crystals 
               
               
                 KR-163 
                 2.0 
                 6 
                 Butanol 
                 −2 
                 0 to −10 
                 260 
                 1.5 
                 45.59 
               
               
                 KR-164 
                 2.02 
                 10 
                 Butanol 
                 5 
                 5 to −10 
                 70 
                 0.82 
                 49.23 
                 Julabo problem. Kept n the fridge. 
               
               
                 KR-165 
                 5.03 
                 15 
                 Butanol 
                 5 
                 5 to −10 
                 70 
                 1.08 
                 42.3 
                 Kept in fridge for 2 days 
               
               
                 KR-166 
                 9.368 
                 30 
                 MeOH 
                 −10 
                 −10 to −15 
                 262 
                 10 
                 44.17 
                 Julabo problem 
               
               
                   
               
             
          
           
               
                   
                   
                   
                   
                   
                   
                   
                 Wt. of 
                 % Purity 
                   
               
               
                   
                 Wt. of 
                 % 
                   
                   
                   
                   
                 crystals 
                 of 
               
               
                   
                 dia-A 
                 solution 
                 Solvent 
                 Seeding 
                 Temp. profile 
                 Time 
                 (SS) 
                 crystals 
               
               
                 Expt. No. 
                 (gms) 
                 (w/w) 
                 system 
                 (° C.) 
                 (° C.) 
                 (hrs) 
                 (gms) 
                 (SS) 
                 Remarks 
               
               
                   
               
               
                 KR-167 
                 2.01 
                 10 
                 MeOH.BuOH 
                 0 
                 5 to −10 
                 260 
                 0.6 
                 48.52 
                 BuOH:MeOH is 1:1 
               
               
                 KR-168 
                 2.01 
                 11 
                 MeOH 
                 0 
                 5 to −6 
                 142 
                 0.81 
                 46.5 
                 1% water 
               
               
                 KR-169 
                 11.53 
                 35 
                 Heptane/ 
                 −2 
                 0 to −10 
                 214 
                 7.86 
                 46.1 
                 Hep:TEA 55:45; ML deteriation 
               
               
                   
                   
                   
                 TEA 
                   
                   
                   
                   
                   
                 observed 
               
               
                 KR-170 
                 10.02 
                 33 
                 Heptane/ 
                 −2 
                 0 to −6 
                 96 
                 9.18 
                 46.3 
                 HeP:TEA = 60:40 
               
               
                   
                   
                   
                 TEA 
               
               
                 KR-171 
                 10.02 
                 33 
                 Heptane/ 
                 −6 
                 −6 to −10 
                 121 
                 4.74 
                 48.2 
                 Hep:TEA = 1:1 
               
               
                   
                   
                   
                 TEA 
               
               
                 KR-172 
                 10.10 
                 36 
                 Heptane/ 
                 0 
                 0 to −5 
                 166 
                 6.3 
                 46.1 
                 Hep:T:TEA = 10:2:8 
               
               
                   
                   
                   
                 TEA 
               
               
                   
                   
                   
                 Toluene 
               
               
                   
               
             
          
           
               
                   
                   
                   
                   
                   
                   
                   
                 Wt. of 
                 % Purity 
                   
               
               
                   
                 Wt. of 
                 % 
                   
                 Seeding 
                   
                   
                 crystals 
                 of 
               
               
                   
                 dia-A 
                 solution 
                 Solvent 
                 Temp. 
                 Temp. profile 
                   
                 (SS) 
                 crystals 
               
               
                 Expt. No. 
                 (gms) 
                 (w/w) 
                 system 
                 (° C.) 
                 (° C.) 
                 Time (hrs) 
                 (gms) 
                 (SS) 
                 Remarks 
               
               
                   
               
               
                 KR-173 
                 9.9 
                 32 
                 TEA/Heptane 
                 0 
                 0 to −5 
                 166 
                 7.03 
                 45.59 
                 HeP:TEA = 5.2:15.4; 
               
               
                 KR-174 
                 9.99 
                 13.19 
                 MeOH 
                 0 
                 +19 to −10 
                 120 
                 1.01 
                 95.05 
               
               
                 KR-175 
                 5.02 
                 13.63 
                 MeOH 
                 1 
                 5 to −10 
                 122 
                 0.54 
                 93.57 
                 Refluxed for 1 hr, filtered 
               
               
                 KR-176 
                 4.99 
                 10.31 
                 MeOH 
                 0 
                 3 to −15 
                 125 
                 0.54 
                 92.56 
                 Refluxed, filtered 
               
               
                 KR-177 
                 10.03 
                 10.15 
                 MeOH 
                 0 
                 3 to −15 
                 125 
                 1.36 
                 93.44 
                 Refluxed, filtered 
               
               
                 KR-178 
                 10.09 
                 13 
                 MeOH 
                 0 
                 5 to −10 
                 53 
                 2.70 
                 95 
                 Refluxed for 1 hr 
               
               
                 KR-179 
                 9.98 
                 13.26 
                 MeOH 
                 0 
                 5 to −10 
                 126 
                 1.70 
                 92.45 
                 Refluxed for 1 hr, 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 filtered 
               
               
                 KR-180 
                 15.0 
                 13 
                 MeOH 
                 0 
                 5 to −10 
                 126 
                 2.42 
                 94.8 
                 Refluxed for 1 hr, 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 filtered 
               
               
                 KR-181 
                 36.33 
                 13 
                 MeOH 
                 0 
                 5 to −10 
                 68 
                 13.31 
                 96.5 
                 Refluxed for 1 hr, 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 filtered 
               
               
                 KR-182 
                 33.8 
                 13 
                 MeOH 
                 0 
                 5 to −10 
                 97 
                 4.8 
                 99 
                 ML of 174-178 
               
               
                 KR-183 
                 10.09 
                 13.5 
                 MeOH 
                 0 
                 5 to −10 
                 45 
                 1.6 
                 49.3 
                 All old samples mixed 
               
               
                 KR-184 
                 10 
                 13 
                 MeOH 
                 0 
                 5 to −10 
                 100 
                 1.62 
                 96.45 
                 All old samples mixed 
               
               
                 KR-185 
                 15.17 
                 13 
                 MeOH 
                 0 
                 5 to −10 
                 110 
                 2.76 
                 98 
                 All old sample mixed 
               
               
                 KR-186 
                 100 
                 13 
                 MeOH 
                 1 
                 5 to −2 
                 17 
                 54.36 
                 47.3 
                 Refluxed for 1 hr, 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 filtered 
               
               
                 KR-187 
                 100 
                 13 
                 MeOH 
                 0 
                 5 to −2 
                 90 
                 68 
                 47.01 
                 Refluxed for 1 hr, 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 filtered 
               
               
                 KR-188 
                 54.45 
                 13 
                 MeOH 
                 0 
                 5 to −2 
                 24 
                 37.67 
                 45.21 
                 Moisture in MeOH 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 1.294 
               
               
                 KR-189 
                 50.10 
                 13 
                 MeOH 
                 −2 
                 5 to −7 
                 50 
                 25.38 
               
               
                 KR-190 
                 40.02 
                 10 
                 MeOH 
                 −2 
                 5 to −6 
                 44 
                 32.77 
                 44.55 
               
               
                   
               
             
          
           
               
                   
                   
                   
                   
                   
                   
                   
                 Wt. of 
                 % Purity 
                   
               
               
                   
                 Wt. of 
                 % 
                   
                 Seeding 
                   
                   
                 crystals 
                 of 
               
               
                   
                 dia-A 
                 solution 
                 Solvent 
                 Temp. 
                 Temp. profile 
                 Time 
                 (SS) 
                 crystals 
               
               
                 Expt. No. 
                 (gms) 
                 (w/w) 
                 system 
                 (° C.) 
                 (° C.) 
                 (hrs) 
                 (gms) 
                 (SS) 
                 Remarks 
               
               
                   
               
               
                 KR-191 
                 25 
                 13 
                 MeOH 
                 +5 
                 10 to 3 
                 24 
                 19.22 
                 41.58 
                 Moisture MeOH 0.278 
               
               
                 KR-192 
                 10.04 
                 13 
                 MeOH 
                 −1 
                 5 to −2 
                 24 
                 6.38 
                 45.67 
                 MeOH distilled over Na 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 KR-10, 138, 146 material 
               
               
                 KR-193 
                 10.06 
                 14.36 
                 MeOH 
                 — 
                 0 to −10 
                 48 
                 6.09 
                 46.8 
                 No seed crystal added, 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 crystals started at −1° C.; 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 No stirring 
               
               
                 KR-194 
                 10.01 
                 13 
                 MeOH 
                 −1 
                 5 to −10 
                 48 
                 5.36 
                 44.7 
               
               
                 KR-195 
                 10.08 
                 13.5 
                 IPA/Hexane 
                 1 
                 5 to −10 
                 142 
                 6.43 
                 44.9 
                 IPA:Hexane 45:55 
               
               
                 KR-196 
                 10 
                 13.6 
                 IPA 
                 3 
                 5 to −10 
                 142 
                 7.71 
                 45.6 
               
               
                 KR-197 
                 9.08 
                 8.22 
                 IPA 
                 — 
                 20 to 3 
                 26 
                 4.80 
                 46.5 
                 No seed added 
               
               
                 KR-198 
                 87.78 
                 13 
                 MeOH 
                 −1 
                 5 to −15 
                 139 
                 11.60 
                 97 
                 ML of KR 181-185 mixed. Conc. 
               
               
                 KR-199 
                 40.15 
                 25 
                 Heptane/TEA 
                 −3 
                 5 to −17 
                 67 
                 6.88 
                 41.23 
               
               
                 KR-200 
                 42.83 
                 13 
                 MeOH 
                 — 
                 5 to −1 
                 30 
                 8.12 
                 47.4 
                 No seed crystal 
               
               
                 KR-201 
                 40.06 
                 13 
                 MeOH 
                 0 
                 15 to 0 
                 24 
                 10.24 
                 47.58 
                 No data 
               
               
                 KR-202 
                 20.09 
                 13 
                 MeOH 
                 0 
                 5 to 0 
                 80 
                 — 
                 — 
                 3.92 ACOH added at 2° C. 
               
               
                 KR-203 
                 18.7 
                 13 
                 MeOH 
                 0 
                 5 to −5 
                 30 
                 11.13 
                 46.92 
                 2.98 gr ACOH added 
               
               
                 KR-204 
                 17.69 
                   
                 MeOH 
                 −2 
                 5 to −4 
                 98 
                 7.84 
                 44.5 
                 Methyl ester added (0.1 gr) 
               
               
                 KR-205 
                 17.68 
                 13 
                 MeOH 
                 0 
                 5 to −6 
                 98 
                 0.45 
                 45.73 
                 Without methylester 
               
               
                 KR-206 
                 10.02 
                 13.5 
                 MeOH 
                 −2 
                 4 to −7 
                 42 
                 5.63 
                 45.23 
                 ML added 1.5 
               
               
                 KR-207 
                 10.02 
                 13.3 
                 MeOH 
                 −2 
                 5 to −7 
                 42 
                 6.6 
                 44.77 
                 ML added 0.5 gr. 
               
               
                 KR-208 
                 13.3 
                 13 
                 MeOH 
                 −6 
                 5 to −7 
                 42 
                 6.06 
                 44.93 
                 ML added 0.5 gr 
               
               
                 KR-209 
                 10.01 
                 13.8 
                 MeOH 
                 −2 
                 5 to −7 
                 42 
                 4.76 
                 45.12 
                 Without ML addition 
               
               
                   
               
             
          
           
               
                   
                   
                   
                   
                 Seeding 
                 Temp. 
                   
                 Wt. of 
                 % Purity of 
                   
               
               
                   
                 Wt. of dia-A 
                 % solution 
                 Solvent 
                 Temp. 
                 profile 
                   
                 crystals 
                 crystals 
               
               
                 Expt. No. 
                 (gms) 
                 w/w 
                 system 
                 (° C.) 
                 (° C.) 
                 Time (hrs) 
                 (gms) 
                 (SS) 
                 Remarks 
               
               
                   
               
               
                 KR-210 
                 10 
                 13 
                 MeOH 
                 −1 
                 2 to −10 
                 76 
                 7.49 
                 46.89 
                 Less seed crystals 2-3 at −6. 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 After 1 hr of seeding 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 crystal growth formed. 
               
               
                 KR-211 
                 10.04 
                 13 
                 MeOH 
                 −1 
                 22 to −10 
                 76 
                 7.2 
                 45.91 
                 Less seed crystal. 
               
               
                 KR-212 
                 11.75 
                 13 
                 MeOH 
                 −1 
                 23 to −9 
                 76 
                 5.63 
                 43.71 
                 KR 206 to 208 MLs 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 mixed 
               
               
                 KR-213 
                 65.70 
                 30 
                 MeOH 
                 −8 
                 82 to −15 
                 120 
                 20.05 
                 45.21 
                 ML of KR-198 gummy 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 material 
               
               
                 KR-214 
                 10.04 
                 10 
                 MeOH 
                 2 
                 22 to −15 
                 120 
                 No 
                 — 
                 MLs of KR 186-194 
               
               
                   
                   
                   
                   
                   
                   
                   
                 crystals 
                   
                 mixed, conc. Iron cryst. 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 Added (100 mg) 
               
               
                 KR-214A 
                 10.4 
                 10 
                 MeOH 
                 −9 
                 25 to −10 
                 57 
                 2.89 
                 43.26 
                 ML of 214 
               
               
                 KR-215 
                 10.07 g 
                 13 
                 MeOH 
                 — 
                 20 to 5 
                 24 
                 — 
                 — 
                 Melted at 90° and added 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 Iron rust crystals 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 dissolved at R.T. No 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 seed crystal 
               
               
                 KR-215A 
                 10.07 
                 14 
                 MeOH 
                 −9 
                 21 to −10 
                 54 
                 0.29 
                 43.64 
                 ML of KR-215 
               
               
                 KR-216 
                 9.98 
                 13.27 
                 MeOH 
                 4 
                 20 to −2 
                 24 
                 4.23 
                 43.27 
                 Charcoal added (400 mg) 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 refluxed and filtered 
               
               
                 KR-217 
                 30 
                 13.7 
                 MeOH 
                 −4 
                 11 to −2 
                 68 
                 — 
                 — 
                 Turbidity at 0° C. filtered, 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 crystals at RT dissolved 
               
               
                 KR-217A 
                 30 
                 13.9 
                 MeOH 
                 −10 
                 −10 
                 24 
                 12.98 
                 43.05 
                 ML of KR 217 
               
               
                 KR-218 
                 10 
                 14 
                 MeOH 
                 −10 
                 −10 
                 68 
                 6.79 
                 44.27 
                 ML of 215A 
               
               
                 KR-219 
                 30 
                 13 
                 MeOH 
                 1 
                 12 to −5 
                 28 
                 5.11 
                 42.57 
                 Melted at 100° C. for 2 hrs 
               
               
                   
               
             
          
           
               
                   
                   
                   
                   
                 Seeding 
                 Temp. 
                   
                 Wt. of 
                 % Purity of 
                   
               
               
                   
                 Wt. of dia-A 
                 % solution 
                 Solvent 
                 Temp. 
                 profile 
                   
                 crystals 
                 crystals 
               
               
                 Expt. No. 
                 (gms) 
                 w/w 
                 system 
                 (° C.) 
                 (° C.) 
                 Time (hrs) 
                 (gms) 
                 (SS) 
                 Remarks 
               
               
                   
               
               
                 KR-220 
                 16.53 
                 9 
                 MeOH 
                 −5 
                 −3 to −9 
                 26 
                 1.34 
                 70.32 
                 KR-217A ML 
               
               
                 KR-221 
                 15.05 
                 13 
                 MeOH 
                 1 
                 12 to −5 
                 30 
                 0.61 
                 43.62 
                 Iron rust 100 mg solid 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 dissolved at R.T. 
               
               
                 KR-222 
                 15.13 
                 8 
                 MeOH 
                 0 
                 5 to −5 
                 90 
                 2.04 
                 98.76 
                 ML of KR-220, slurry 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 addition 
               
               
                 KR-223 
                 24.89 
                 12 
                 MeOH 
                 0° C. 
                 5 to 0 
                 90 
                 11.33 
                 45.43 
                 Slurry addition 
               
               
                 KR-224 
                 650 mg 
                 19.8 
                 MeOH 
                 −1 
                 0 to −2 
                 24 
                 — 
                 — 
                 Crystals were used as 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 seed crystals for KR-222 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 and KR-223; 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 crystallization of Aα 
               
               
                 KR-225 
                 13.09 
                 13.0 
                 MeOH 
                 −3.6 
                 −3 to −15 
                 60 
                 — 
                 38.27 
                 ML of KR-222. ACOH 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 added equilibrate at 100° 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 for 1 hr. gummy 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 material not weighed 
               
               
                 KR-226 
                 10.02 
                 21.08 
                 Heptane/TEA 
                 4 
                 +21 to −4 
                 168 
                 — 
                 — 
                 Heptane:TEA 1:1 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 crystals observed at Low 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 temp. dissolved at R.T. 
               
               
                   
               
             
          
           
               
                   
                   
                   
                   
                 Seeding 
                 Temp. 
                   
                 Wt. of  
                 % Purity of 
                   
               
               
                   
                 Wt. of dia-A 
                 % solution 
                 Solvent 
                 Temp. 
                 profile 
                   
                 crystals 
                 crystals 
               
               
                 Expt. No. 
                 (gms) 
                 w/w 
                 system 
                 (° C.) 
                 (° C.) 
                 Time (hrs) 
                 (gms) 
                 (SS) 
                 Remarks 
               
               
                   
               
               
                 KR-227 
                 19.53 
                 10 
                 MeOH 
                 5 
                 5 
                 115 
                 2.85 
                 34.5 
                 0.5 gr ACOH added. 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 Equilibrated at 65° C. for 1 hr 
               
               
                 KR-228 
                 15.57 
                 13 
                 MeOH 
                 −4 
                 2 to −4 
                 92 
                 2.48 
                 42.5 
                 ML&#39;s mixed conc. 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 equilibrated for 1 hr 
               
               
                 KR-229 
                 16.0 
                 9 
                 MeOH 
                 −3 
                 0 to −3 
                 46 
                 2.77 
                 42.07 
                 ML of KR 237. 0.5 gr 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 ACOH added 
               
               
                 KR-230 
                 10.08 
                 13 
                 MeOH 
                 7 
                 7 to 8 
                 48 
                 — 
                 — 
                 Iron rust added. 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 Crystals observed 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 dissolved at R.T. (1) 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 Solution equilibrated 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 for 2 hr. at 65° C. 
               
               
                 KR-231 
                 13.0 
                 12.5 
                 MeOH 
                 — 
                 — 
                 — 
                 — 
                 — 
                 Equilibrated at 120° C. 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 for 6 hr. 
               
               
                 KR-232 
                 15.04 
                 13.6 
                 MeOH 
                 10 
                 10 to −13 
                 185 
                 2.78 
                 96 
                 Solid equilibrated at 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 120° C. for 2 hrs. 
               
               
                 KR-233 
                 13 
                 13 
                 MeOH 
                 10 
                 10 to −8 
                 150 
                 2.13 
                 94.7 
                 Equilibrated at 120° C. 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 for 2 hrs. Iron rust 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 added. 
               
               
                 KR-234 
                 30 
                 13 
                 MeOH 
                 5 
                 5 to −2 
                 4.6 
                 11.21 
                 43.36 
                 Equilibrated at 110° C. 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 for 1½ hrs. 
               
               
                 KR-235 
                 60 
                 13 
                 MeOH 
                 7 
                 10 to 4 
                 96 
                 1.67 
                 98.2 
                 Equilibrate 120° C., 2 hrs. 
               
               
                   
               
             
          
           
               
                   
                   
                 % 
                   
                   
                 Seeding 
                 Wt. of 
                 % Purity of 
                   
                   
               
               
                   
                 Wt. of dia-A 
                 solution 
                 Solvent 
                 Temp. profile 
                 Temp. 
                 crystals 
                 crystals 
                   
               
               
                 Expt. No. 
                 (gms) 
                 (w/w) 
                 system 
                 (° C.) 
                 (° C.) 
                 (SS) (gms) 
                 (SS) 
                 Time (hrs) 
                 Remarks 
               
               
                   
               
               
                 KR-236 
                 30 
                 10 
                 IPA 
                 +2 to +3 
                 +3 
                 12.1 
                 42.68 
                 22 
                 Mixed sample 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 equilibrate at 120° for 2 hrs 
               
               
                 KR-237 
                 13 
                 13 
                 MeOH 
                 −15 
                 −15 
                 0.73 
                 94 
                 48 
                 ML of 232 
               
               
                 KR-238 
                 15.1 
                 13 
                 IBA 
                 3 
                 3 
                 20.54 
                 39.7 
                 144 
                 — 
               
               
                 KR-239 
                 99 
                 13 
                 MeOH 
                 +10 to +4 
                 9 
                 50.5 
                 52 
                 96 
                 Equilibrated at 120° for 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 4 hrs 
               
               
                 KR-240 
                 10 
                 13 
                 MeOH 
                 8 to 10 
                 9 
                 1.96 
                 39 
                 9 
                 Melt sample + PEA 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 added 
               
               
                 KR-241 
                 9.9 
                 13 
                 MeOH 
                 +10 
                 10 
                 &lt;100 
                 32.78 
                 94 
                 1 ml NH 3 /MeOH 
               
               
                 KR-242 
                 10 
                 13 
                 MeOH 
                 +10 
                 10 
                 .95 
                 44 
                 94 
                 Quinidine at 6° C. added 
               
               
                 KR-243 
                 10 
                 12.8 
                 MeOH 
                 +18 to +3 
                 14 
                 3.46 
                 47.02 
                 96 
                 ACOH added. 0.33 gr 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 S.M melted 
               
               
                   
               
             
          
           
               
                   
                 Wt. of 
                 % 
                   
                 Temp. 
                 Seeding 
                 Wt. of crystals 
                 % Purity of 
                   
                   
               
               
                   
                 dia-A 
                 solution 
                 Solvent 
                 profile 
                 Temp. 
                 (SS) 
                 crystals 
                 Time 
               
               
                 Expt. No. 
                 (gms) 
                 (w/w) 
                 system 
                 (° C.) 
                 (° C.) 
                 (gms) 
                 (SS) 
                 (hrs) 
                 Remarks 
               
               
                   
               
               
                 KR-244 
                  99.5 
                 13 
                 MeOH 
                 18 to −7 
                 8 
                 1.39 
                 94 
                 140 
                 Melt of RUN-I from Pilot 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 plant expt. 
               
               
                 KR-245 
                 92.85 
                 13 
                 MeOH 
                 +6 to −12 
                 7 
                 — 
                 — 
                 122 
                 Run I material without 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 melting. No crystals, conc. 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 to 17% and std. As KR-248 
               
               
                 KR-246 
                  21.2 g 
                 26 
                 MeOH 
                 +20 to 
                 15 
                 1.65 
                 57.4 
                 24 
                 KR-239 material 
               
               
                   
                   
                   
                   
                 +12 
               
               
                 KR-246A 
                 19.35 
                 25 
                 MeOH 
                 +12 
                 12 
                 14.23 
                 45.30 
                 24 
                 ML of KR-246 
               
               
                 KR247 
                  93.6 
                 19.8 
                 MeOH/ 
                 +6 to −13 
                 5 
                 9.54 
                 97.5 
                 188 
                 ML Conc to 19.8% 140 g 
               
               
                   
                   
                   
                 Heptane 
                   
                   
                   
                   
                   
                 Heptane added 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 ML of KR-244 
               
               
                 KR-248 
                 92.85 g 
                 22% 
                 MeOH 
                 +6 to −12 
                 5 
                 6.06 
                 95.4 
                 122 
                 Heptane 140 g added 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 ML of KR-245 
               
               
                 KR-249 
                 20.08 
                 22% 
                 HTM 
                 +20 to 
                 0 
                 2.20 
                 96.3 
                 47 
                 KR-250; 251; 252 
               
               
                   
                   
                   
                   
                 −6 
               
               
                 KR-250 
                  20.0 
                 — 
                 — 
                 — 
                 — 
                 — 
                 — 
                 — 
                 Melting of 1:1 mat. at 120° C., 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 140° C., 160° C., 180° C., 200° C. 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 for 2 hrs 
               
               
                 KR-251 
                  0.51 g 
                 9 
                 Heptane 
                 +10 to −14 
                 −6 
                 No 
                 — 
                 96 
                 Kept in deep fridge; 
               
               
                   
                   
                   
                 THF 
                   
                   
                 crystals 
                   
                   
                 THF:Hep (10:90) 
               
               
                 KR252 
                  0.51 
                 9 
                 Heptane 
                 +10 to −14 
                 −6 
                 No 
                 — 
                 — 
                 Kept with deep freezer in 
               
               
                   
                   
                   
                 THF 
                   
                   
                 crystals 
                   
                   
                 THF:Hep (10:98) 
               
               
                 KR-253 
                  22.7 
                 22 
                 MeOH 
                 +14 to −2 
                 0 
                 20.25 
                 44.3 
                 138 
                 Crystals are gummy nature 
               
               
                   
                   
                   
                 Heptane 
               
               
                   
                   
                   
                 Toluene 
               
               
                   
               
             
          
           
               
                   
                   
                   
                   
                   
                   
                 Wt. of 
                 % Purity 
                   
                   
               
               
                   
                   
                 % 
                   
                 Temp. 
                 Seeding 
                 crystals 
                 of 
               
               
                   
                 Wt. of dia-A 
                 solution 
                 Solvent 
                 profile 
                 Temp. 
                 (SS) 
                 crystals 
                 Time 
               
               
                 Expt. No. 
                 (gms) 
                 (w/w) 
                 system 
                 (° C.) 
                 (° C.) 
                 (gms) 
                 (SS) 
                 (hrs) 
                 Remarks 
               
               
                   
               
               
                 KR-254 
                 20 
                 22.07 
                 HTM 
                 +20 to −1 
                 5 
                 — 
                 — 
                 50 
                 Gummy solid, dissolved at 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 R.T. 
               
               
                 KR-255 
                 29.94 
                 23.07 
                 MeOH + 
                 +8 to −16 
                 0 
                 4.5 
                 44.52 
                 150 
                 MeOH:Toluene 80:20 
               
               
                   
                   
                   
                 Tol 
                   
                   
                   
                   
                   
                 KR-239 melted 
               
               
                 KR-256 
                 25 
                 20.18 
                 Tol + IPA 
                 +8 to −1 
                 −7 
                 No 
                 — 
                 150 
                 Seed crystal present. 
               
               
                   
                   
                   
                   
                   
                   
                 crystals 
                   
                   
                 Toluene:IPA 33:67, No 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 crystals 
               
               
                 KR-257 
                 20 
                 11 
                 MeOH: 
                 23 to −7 
                 3 
                 7.76 
                 43.29 
                 70 
                 Crystal dissolved before −5° C.; 
               
               
                   
                   
                   
                 Toluene 
                   
                   
                   
                   
                   
                 present after −5° C. addn. 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 12.16 g KR added at −10° C. 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 and expt. Contd. MeOH:Tol 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 63:3.7 
               
               
                 KR-258 
                 20 
                 11.83 
                 MeOH: 
                 23 to −6 
                 9 
                 8.19 
                 43.7 
                 70 
                 KR-239 melt, MeOH:tol 
               
               
                   
                   
                   
                 Toluene 
                   
                   
                   
                   
                   
                 151:3.75 
               
               
                 KR-259 
                 17.36 
                 16.2 
                 MeOH: 
                 +20 to +2 
                 14 
                 7.05 
                 43.3 
                 46 
                 MeOH:Toluene 87:3.2 
               
               
                   
                   
                   
                 Toluene 
               
               
                 KR-260 
                 20.00 
                 11.5 
                 Toluene/ 
                 15 to −6 
                 9 
                 90 
                 No 
                 35.39 
                 S.M. melted at 120° C. for 3 hrs. 
               
               
                   
                   
                   
                 MeOH 
                   
                   
                   
                 crystals 
                   
                 NH 3 /.MeOH added, 2 ml; 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 Tol. 3% 
               
               
                 KR-261 
                 20.04 
                 11.5 
                 Toluene/ 
                 15 to −6 
                 9 
                 90 
                 0.52 
                 41.00 
                 Melted at 120° C. for 3 hrs; 
               
               
                   
                   
                   
                 MeOH 
                   
                   
                   
                   
                   
                 Tol 3%; Blank no ammonia 
               
               
                 KR-262 
                 20 
                 11.5 
                 Toluene/ 
                 15 to −6 
                 9 
                 90 
                 6.7 
                 42.27 
                 1 ml MeOH/NH 3  added at −5° C.; 
               
               
                   
                   
                   
                 MeOH 
                   
                   
                   
                   
                   
                 Tol. 3% 
               
               
                 KR-263 
                 9.09 
                 15 
                 Heptane/ 
                 +10 to 
                 −12 
                 142 
                 — 
                 — 
                 Added one drop of TEA at −14° C. 
               
               
                   
                   
                   
                 THF 
                 −14 
                   
                   
                   
                   
                 Crystals appeared but 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 dissolved while filtering 
               
               
                   
               
             
          
           
               
                   
                   
                   
                   
                   
                   
                   
                 % 
                   
                   
               
               
                   
                   
                   
                   
                   
                   
                 Wt. of 
                 Purity 
               
               
                   
                   
                 % 
                   
                 Seeding 
                   
                 crystals 
                 of 
               
               
                   
                 Wt. of dia-A 
                 solution 
                 Solvent 
                 Temp. 
                 Temp. profile 
                 (SS) 
                 crystals 
               
               
                 Expt. No. 
                 (gms) 
                 (w/w) 
                 system 
                 (° C.) 
                 (° C.) 
                 (gms) 
                 (SS) 
                 Time (hrs) 
                 Remarks 
               
               
                   
               
               
                 KR-264 
                 20 
                 12 
                 MeOH/ 
                 −6 to −9 
                 −6 
                 42 
                 7.7 
                 46.23 
                 KR-260 melted; Benzene 
               
               
                   
                   
                   
                 Benzene 
                   
                   
                   
                   
                   
                 2.5% 
               
               
                 KR-265 
                 19.96 
                 12 
                 MeOH/ 
                 −6 
                 −6 to 9 
                 42 
                 1.98 
                 43.02 
                 Benzene 10% 
               
               
                   
                   
                   
                 Benzene 
               
               
                 KR-266 
                 20.08 
                 12.5 
                 MeOH 
                 −5 
                 −1 to −17 
                 118 
                 No 
                 — 
                 ML of KR 247, 3 ml 
               
               
                   
                   
                   
                   
                   
                   
                   
                 crystals 
                   
                 NH 3 /MeOH added 
               
               
                 KR-267 
                 150.06 
                 12 
                 MeOH 
                 8 
                 20 to 2 
                 94 
                 15.65 
                 98 
                 S.M. melted 
               
               
                 KR-268 
                 20.12 
                 15 
                 Heptane/ 
                 2 
                 16 to 2 
                 46 
                 5.63 
                 44.34 
                 2% THF, at R T crystals 
               
               
                   
                   
                   
                 THF 
                   
                   
                   
                   
                   
                 liquid became 
               
               
                 KR-267 
                 150.06 
                 12 
                 MeOH 
                 8 
                 20 to 2 
                 94 
                 15.65 
                 98 
                 S.M. melted 
               
               
                 KR-268 
                 20.12 
                 15 
                 Heptane/ 
                 2 
                 16 to 2 
                 46 
                 5.63 
                 44.34 
                 2% THF, at R T crystals 
               
               
                   
                   
                   
                 THF 
                   
                   
                   
                   
                   
                 became liquid 
               
               
                 KR-269 
                 19.96 
                 15 
                 Heptane/ 
                 2 
                 15 to −2 
                 46 
                 1.96 
                 43.97 
                 4% THF 
               
               
                   
                   
                   
                 THF 
               
               
                 KR-270 
                 5.12 
                 25 
                 Diglyme/ 
                 0 
                 0 
                 24 
                 — 
                 — 
                 Melted sample used for expt. 
               
               
                   
                   
                   
                 Heptane 
                   
                   
                   
                   
                   
                 No crystals; Diglyme 10% 
               
               
                 KR-271 
                 20.41 
                 13.5 
                 THF/ 
                 8 
                 15 to −4 
                 92 
                 45.91 
                 45.91 
                 6% THF 
               
               
                   
                   
                   
                 Heptane 
               
               
                 KR-272 
                 125.71 
                 22 
                 MeOH 
                 7 
                 13 to −3 
                 28 
                 — 
                 41.05 
                 ML of KR-267 Crystals 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 mixed with ML and kept 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 again for crystallization (KR- 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 273). 
               
               
                 KR-273 
                 125.7 
                 22.42 
                 MeOH 
                 8 
                 +11 to −6 
                 50 
                 20.16 
                 95.01 
                 I 
               
               
                 KR-274 
                 112.85 
                 22.12 
                 MeOH 
                 8 
                 11 to −4 
                 120 
                 3.52 
                 87.02 
                 ML of KR-273-II 
               
               
                 KR-275 
                 50.06 
                 34.9 
                 MeOH 
                 19 
                 19 to 8 
                 65 
                 — 
                 — 
                 No crystals, oily layer 
               
               
                 KR-276 
                 107.64 
                 22.15 
                 MeOH 
                 8 
                 20 to +3 
                 124 
                 11.20 
                 97.63 
                 ML of 274 concentrated and 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 equilibrated-III 
               
               
                   
               
             
          
           
               
                   
                   
                   
                   
                   
                   
                   
                   
                 % 
                   
               
               
                   
                   
                   
                   
                   
                   
                   
                 Wt. of 
                 Purity 
               
               
                   
                 Wt. of 
                 % 
                   
                 Seeding 
                 Temp. 
                   
                 crystals 
                 of 
               
               
                   
                 dia-A 
                 solution 
                 Solvent 
                 Temp. 
                 Profile 
                   
                 (SS) 
                 crystals 
               
               
                 Expt. No. 
                 (gms) 
                 (w/w) 
                 system 
                 (° C.) 
                 (° C.) 
                 Time (hrs) 
                 (gms) 
                 (SS) 
                 Remarks 
               
               
                   
               
               
                 KR-277 
                 175.64 
                 32.06 
                 MeOH 
                 7 
                 20 to 5 
                 30 
                 — 
                 — 
                 Julabo started heating. 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 Reaction stopped. No 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 crystals; solution conc. 
               
               
                 KR-278 
                 88.37 
                 22.34 
                 MeOH 
                 8 
                 18 to 
                 240 
                 5.0 
                 95.13 
                 ML of KR-276-IV 
               
               
                   
                   
                   
                   
                   
                 −15 
               
               
                 KR-279 
                 155.96 
                 25.35 
                 MeOH 
                 4 
                 +20 to 
                 260 
                 — 
                 — 
                 No crystals. ML of KR-277 
               
               
                   
                   
                   
                   
                   
                 −19 
               
               
                 KR-280 
                 82.05 
                 29.88 
                 MeOH 
                 5 
                 15 to −10 
                 137 
                 1.93 
                 91.56 
                 ML of 278 equilibrated-V 
               
               
                 KR-281 
                 150.42 
                 23 
                 MeOH 
                 10 
                 16 to +4 
                 74 
                 18.57 
                 96.64 
                 Fresh dil-A equilibrated 
               
               
                 KR-282 
                 130.87 
                 21.73 
                 MeOH 
                 10 
                 15 to +5 
                 97 
                 18.89 
                 98.04 
                 Recycle-I KR-281 ML 
               
               
                 KR-283 
                 110.18 
                 22.06 
                 MeOH 
                 10 
                 20 to 0 
                 192 
                 10.97 
                 95.3 
                 Recylce-II, KR-282 ML 
               
               
                 KR-284 
                 75.34 
                 23.05 
                 MeOH 
                 0 
                 0 to −16 
                 98 
                 0.64 
                 91.6 
                 ML of KR-280, 5 th  cycle-VI 
               
               
                 KR-285 
                 97.8 
                 22.06 
                 MeOH 
                 10 
                 15 to −6 
                 75 
                 2.48 
                 88.6 
                 ML of KR-283, recycle-III 
               
               
                 KR-286 
                 40.0 
                 22.4 
                 MeOH 
                 9 
                 20 to −5 
                 76 
                 8.36 
                 91.52 
                 KF 0.122 added. Solids 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 from carboy equilibrated 
               
               
                 KR-287 
                 40.02 
                 33.13 
                 N,N- 
                 9 
                 20 to −15 
                 360 
                 — 
                 — 
                 No crystals. Heptane added 
               
               
                   
                   
                   
                 diethylaniline 
                   
                   
                   
                   
                   
                 in between (50 g) N, NDEA 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 33% 
               
               
                 KR-288 
                 31.15 
                 25.3 
                 MeOH 
                 10 
                 15 to 
                 260 
                 No 
                 — 
                 KF added 100 mg at 9° C. 
               
               
                   
                   
                   
                   
                   
                 −12 
                   
                 crystals 
                   
                 First time crystals formed. 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 Dissolved while filtering. 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 Restarted no crystals. 
               
               
                 KR-289 
                 40.02 
                 26.32 
                 Heptane/ 
                 6 
                 10 to −10 
                 98 
                 2.54 
                 81.35 
                 Hexane added at 3° C. run- 
               
               
                   
                   
                   
                 Hexane, 
                   
                   
                   
                   
                   
                 III material; N,N-DEA 25% Heptane 
               
               
                   
                   
                   
                 N,N-DEA 
                   
                   
                   
                   
                   
                 58% 
               
               
                   
               
             
          
           
               
                   
                   
                   
                   
                   
                   
                   
                 Wt. of 
                   
                   
               
               
                   
                 Wt. of 
                 % 
                   
                 Seeding 
                 Temp. 
                   
                 crystals 
                 % Purity 
               
               
                   
                 dia-A 
                 solution 
                 Solvent 
                 Temp. 
                 Profile 
                   
                 (SS) 
                 of crystals 
               
               
                 Expt. No. 
                 (gms) 
                 (w/w) 
                 system 
                 (° C.) 
                 (° C.) 
                 Time (hrs) 
                 (gms) 
                 (SS) 
                 Remarks 
               
               
                   
               
               
                 KR-290 
                 48.88 
                 27.3 
                 Heptane, 
                 7 
                 10 to −11 
                 205 
                 24.6 
                 49.07 
                 Run-III material 
               
               
                   
                   
                   
                 Hexane, 
                   
                   
                   
                   
                   
                 N,N-DEA 13.3%; Hep 64.5% 
               
               
                   
                   
                   
                 N,N- 
               
               
                   
                   
                   
                 diethylaniline 
               
               
                 KR-291 
                 94.4 
                 25.15 
                 MeOH 
                 7 
                 13 to −7 
                 100 
                 3.2 
                 94.24 
                 ML of KR-285 
               
               
                 KR-292 
                 88.46 
                 24.62 
                 MeOH 
                 7 
                 10 to −10 
                 120 
                 23.96 
                 60.3 
                 Two layers formed, lower layer 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 became semisolid. ML of KR-291 
               
               
                 KR-293 
                 73.64 
                 42.36 
                 MeOH 
                 7 
                 10 to −10 
                 120 
                 — 
                 — 
                 Solids melted after filtration. (1) 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 ML of KR-284 
               
               
                 KR-294 
                 45.5 
                 36.6 
                 N,N,- 
                 7 
                 10 to −11 
                 116 
                 — 
                 — 
                 Solution became two layers, lower 
               
               
                   
                   
                   
                 DEA 
                   
                   
                   
                   
                   
                 layer became little thick. 
               
               
                   
                   
                   
                 heptane, 
                   
                   
                   
                   
                   
                 Mixed with KR-287 material 
               
               
                   
                   
                   
                 hexane 
                   
                   
                   
                   
                   
                 N,NDEA 15.3% Hep 62% 
               
               
                 KR-295 
                 132.6 
                 26.11 
                 MeOH 
                 7 
                 10 to −10 
                 166 
                 20.02 
                 96.44 
                 SAF-29 material which was 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 equilibrated 
               
               
                 KR-296 
                 109.22 
                 26.88 
                 MeOH 
                 7 
                 10 to −12 
                 142 
                 — 
                 — 
                 After 70 hrs made 33% solution, 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 after making 33% black gummy 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 mass formed as lower layer. 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 Concentrated; no crystals 
               
               
                 KR-297 
                 200.13 
                 25.05 
                 MeOH 
                 7 
                 11 to −5 
                 42 
                 70.5 
                 48.73 
                 Gummy material in bottom layer 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 pilot plant, RUN-I material 
               
               
                 KR-298 
                 148.05 
                 23.95 
                 MeOH 
                 7 
                 20 to −5 
                 70 
                 37.52 
                 90.7 
                 Run - III material equilibrated 
               
               
                   
               
             
          
           
               
                   
                   
                   
                   
                   
                   
                   
                   
                 % 
                   
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                 Purity 
               
               
                   
                 Wt. of 
                 % 
                   
                 Seeding 
                 Temp. 
                   
                 Wt. of crystals 
                 of 
               
               
                   
                 dia-A 
                 solution 
                 Solvent 
                 Temp. 
                 Profile 
                   
                 (SS) 
                 crystals 
               
               
                 Expt. No. 
                 (gms) 
                 (w/w) 
                 system 
                 (° C.) 
                 (° C.) 
                 Time (hrs) 
                 (gms) 
                 (SS) 
                 Remarks 
               
               
                   
               
               
                 KR-299 
                 105.38 
                 21.08 
                 MeOH 
                 7 
                 10 to −1 
                 180 
                 — 
                 — 
                 No crystals. ML of KR-298 
               
               
                 KR-300 
                 147.68 
                 22.67 
                 MeOH 
                 7 
                 11 to 5 
                 78 
                 26.69 
                 94.48 
               
               
                 KR-301 
                 279.57 
                 29.98 
                 MeOH 
                 15 
                 20 to 5 
                 102 
                 49.44 
                 95.67 
                 SAF-30 equilibrated material 
               
               
                 KR-302 
                 20.06 
                 23.9 
                 IPA 
                 13 
                 15 to 12 
                 54 
                 16.32 
                 44.5 
                 Old material recovered in KR 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 expts. 
               
               
                 KR-303 
                 115.31 
                 24.26 
                 MeOH 
                 11 
                 17 to 2 
                 142 
                 24.48 
                 94.03 
                 ML of KR-300 equilibrated 
               
               
                 KR-304 
                 30.55 
                 15.18 
                 EtOH 
                 7 
                 22 to 2 
                 48 
                 10.8 
                 46.2 
                 Two layers. Lower layer gummy 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 old samples mixed equilibrated 
               
               
                 KR-305 
                 230.13 
                 29.70 
                 MeOH 
                 13 
                 16 to 0 
                 118 
                 64.3 
                 65.23 
                 ML of KR-301 
               
               
                 KR-306 
                 90.83 
                 21.36 
                 MeOH 
                 9 
                 12 to −2 
                 170 
                 10.81 
                 93.52 
                 ML of KR-303, III cycle 
               
               
                 KR-307 
                 214.4 
                 30.18 
                 MeOH 
                 14 
                 26 to 13 
                 138 
                 — 
                 — 
                 After 60 hrs full crystals fallen out. 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 Dissolved and kept again for 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 crystalisation. No crystals, conc. 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 wt. 195.14 
               
               
                 KR-308 
                 165.76 
                 30.17 
                 MeOH 
                 12 
                 23 to 3 
                 174 
                 14.03 
                 89.79 
                 ML of KR-305, III cycle 
               
               
                 KR-309 
                 80.02 
                 24.25 
                 MeOH 
                 12 
                 25 to 9 
                 167 
                 17.35 
                 60.6 
                 No crystals, gumy layer separated 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 ML of KR-306, IV cycle 
               
               
                 KR-310 
                 136.91 
                 30.36 
                 MeOH 
                 10 
                 15 to −10 
                 115 
                 10.02 
                 95.63 
                 ML of KR-308, IV cycle 
               
               
                 KR-311 
                 195.94 
                 30.10 
                 MeOH 
                 21 
                 22 to 9 
                 142 
                 192.2 
                 45.68 
                 ML of KR-307, after 20 hrs. Full 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 crystals dissolved. Kept again for 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 crystallization 
               
               
                 KR-312 
                 57.6 
                 25.12 
                 MeOH 
                 11 
                 12 to −8 
                 230 
                 2.22 
                 89.87 
                 ML of KR-309, V cycle 
               
               
                 KR-313 
                 993 
                 29.8 
                 MeOH 
                 18 
                 22 to 0 
                 120 
                 260.70 
                 66.67 
                 Equilibrated fresh material 
               
               
                   
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                 % Purity 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                 of 
               
               
                   
                 Wt. of 
                 % 
                   
                 Seeding 
                 Temp. 
                   
                   
                 crystals 
               
               
                   
                 dia-A 
                 solution 
                 Solvent 
                 Temp. 
                 Profile 
                   
                 Wt. of crystals 
                 (SS) 
               
               
                 Expt. No. 
                 (gms) 
                 (w/w) 
                 system 
                 (° C.) 
                 (° C.) 
                 Time (hrs) 
                 (SS) 
                 (gms) 
                 Remarks 
               
               
                   
               
               
                 KR-314 
                 733 
                 30.02 
                 MeOH 
                 14 
                 20 to 8 
                 167 
                 78.26 
                 45.23 
                 ML of KR-313 
               
               
                 KR-315 
                 16.4 
                 27.38 
                 MeOH 
                 15 
                 24 to 12 
                 23 
                 5.40 
                 94.34 
                 Crystals of KR-313 dissolved in 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 MeOH and kept for crystallization 
               
               
                 KR-316 
                 1456.23 
                 35.09 
                 MeOH 
                 15 
                 25 to 6 
                 156 
                 169.47 
                 92.21 
                 All old samples mixed and taken 
               
               
                   
                   
                   
                   
                   
                   
                   
                 18.53 
                 75.46 
                 for crystallization 
               
               
                 KR-317 
                 126.89 
                 29.13 
                 MeOH 
                 8 
                 20 to −10 
                 144 
                 3.94 
                 93.9 
                 ML of KR-310, equilibrated 
               
               
                 KR-318 
                 1259 
                 33 
                 MeOH 
                 11 
                 15 to 0 
                 145 
                 122.73 
                 93.09 
                 ML of KR-316, equilibrated 
               
               
                 KR-319 
                 1137 
                 32.19 
                 MeOH 
                 10 
                 15 to 4 
                 186 
                 115.93 
                 88.4 
                 ML of KR-318, III cycle 
               
               
                 KR-320 
                 1433 
                 37.39 
                 MeOH 
                 13 
                 23 to 2 
                 165 
                 197.82 
                 80.9 
                 ML of KR-319, IV cycle 
               
               
                 KR-321 
                 1235.18 
                 35.40 
                 MeOH 
                 12 
                 24 to 2 
                 236 
                 30.21 
                 87.26 
                 ML of KR-320, V cycle 
               
               
                 KR-322 
                 48.8 
                 25.30 
                 MeOH 
                 12 
                 20 to 10 
                 70 
                 25.7 
                 44.16 
               
               
                 KR-323 
                 48.8 
                 25.0 
                 MeOH 
                 18 
                 23 to 15 
                 90 
                 18.8 
                 47.2 
                 Crystals of KR 322 and ML mixed 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 and kept for crystallization. Slurry 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 seed added. 
               
               
                 KR-324 
                 41.2 
                 27.0 
                 MeOH 
                 14 
                 18 to 11 
                 192 
                 — 
                 — 
                 Solids dissolved at RT. Crystals 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 of KR-323 equilibrated at 110° C. 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 and used for reaction 
               
               
                 KR-325 
                 414 
                 35.0 
                 Hexane/ 
                 −8 
                 15 to −10 
                 144 
                 10.0 
                 44.26 
                 ML of KR-324 conc. and used 
               
               
                   
                   
                   
                 IPA 
               
               
                 KR-326 
                 22.88 
                 30.31 
                 MeOH 
                 13 
                 28 to 13 
                 115 
                 23.43 
                 46.5 
                 46.50 
               
               
                 KR-327 
                 10.70 
                 21.7 
                 MeOH 
                 18 
                 20 to 15 
                 60 
                 4.07 
                 46.69 
               
               
                   
               
             
          
           
               
                   
                   
                   
                   
                   
                   
                   
                   
                 % Purity 
                   
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                 of 
               
               
                   
                 Wt. of 
                 % 
                   
                 Seeding 
                 Temp. 
                   
                 Wt. of 
                 crystals 
               
               
                   
                 dia-A 
                 solution 
                 Solvent 
                 Temp. 
                 Profile 
                 Time 
                 crystals 
                 (SS) 
               
               
                 Expt. No. 
                 (gms) 
                 (w/w) 
                 system 
                 (° C.) 
                 (° C.) 
                 (hrs) 
                 (SS) 
                 (gms) 
                 Remarks 
               
               
                   
               
               
                 KR-328 
                 10.60 
                 19.06 
                 MeOH 
                 19 
                 27 to 18 
                 47 
                 3.70 
                 46.90 
                 H 3 BO 3 : 0.56 gr dissolved after heating and 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 filtered 
               
               
                 KR-329 
                 11.43 
                 20.4 
                 MeOH 
                 18 
                 21 to 
                 67 
                 5.20 
                 46.70 
                 NaHSO 3 : 0.91 g dissolved after heating 
               
               
                 KR-330 
                 6.9 
                 25.17 
                 MeOH 
                 19 
                 22 to 19 
                 22 
                 2.07 
                 46.05 
               
               
                 KR-331 
                 29.39 
                 23.59 
                 MeOH 
                 23 
                 25 to 20 
                 90 
                 19.63 
                 45.72 
                 dia A-crystals from KR-326 to 330 expts) heated 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 dissolved, filtration 
               
               
                 KR- 
                 10.04 
                 25 
                 MeOH 
                 19 
                 25 to 19 
                 48 
                 4.4 
                 46.88 
                 Acid: 0.52 gm 
               
               
                 0332-I 
                   
                   
                   
                   
                   
                   
                   
                   
                 PTC: 0.018 gm 
               
               
                 KR- 
                 10.03 
                 24.46 
                 MeOH 
                 19 
                 25 to 19 
                 48 
                 4.69 
                 46.81 
                 ACOH: 1.0 ml 
               
               
                 332-II 
                   
                   
                   
                   
                   
                   
                   
                   
                 PTC 0.021 gm 
               
               
                 KR-333 
                 10.26 
                 25.48 
                 MeOH 
                 21 
                 26 to 15 
                 94 
                 4.75 
                 47.02 
                 PTC: 0.03 g 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 ACOH: 4 ml 
               
               
                 KR-334 
                 10.439 
                 28.59 
                 MeOH 
                 21 
                 26 to 15 
                 94 
                 6.05 
                 46.40 
                 Old sample mixed equilibrated 
               
               
                 KR-335 
                 35.95 
                 21.76 
                 MeOH 
                 18 
                 27 to 13 
                 69 
                 4.15 
                 46.78 
                 Mixed samples ML 326, 330, 331, 332-I, II 
               
               
                 KR-336 
                 9.56 
                 22.16 
                 MeOH 
                 17 
                 20 to 14 
                 95 
                 7.16 
                 44.65 
               
               
                 KR-337 
                 9.81 
                 24.62 
                 MeOH 
                 15 
                 22 to 9 
                 47 
                 6.58 
                 44.59 
               
               
                 KR-338 
                 10.12 
                 18.12 
                 MeOH 
                 15 
                 22 to 9 
                 41 
                 4.86 
                 44.86 
               
               
                 KR-339 
                 7.00 
                 14.45 
                 MeOH 
                 17 
                 25 to 14 
                 60 
                 2.8 
                 44.7 
                 Mixed cryst. Of KR-331, 332, 333, 334 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 equilibrated IPA:MeOH (25:75) 
               
               
                 KR-340 
                 10.72 
                 23.69 
                 MeOH 
                 18 
                 28 to 15 
                 29 
                 2.71 
                 46.2 
                 Dia-A pilot plant batch 
               
               
                   
               
             
          
           
               
                   
                   
                   
                   
                   
                   
                   
                   
                 % Purity of 
                   
               
               
                   
                 Wt. of 
                 % 
                   
                 Seeding 
                 Temp. 
                   
                 Wt. of 
                 crystals 
               
               
                   
                 dia-A 
                 solution 
                 Solvent 
                 Temp. 
                 Profile 
                 Time 
                 crystals 
                 (SS) 
               
               
                 Expt. No. 
                 (gms) 
                 (w/w) 
                 system 
                 (° C.) 
                 (° C.) 
                 (hrs) 
                 (SS) 
                 (gms) 
                 Remarks 
               
               
                   
               
               
                 KR-341 
                 9.87 
                 25.32 
                 MeOH/ 
                 18 
                 28 to 15 
                 29 
                 — 
                 — 
                 1% acetone added, No crystals 
               
               
                   
                   
                   
                 Acetone 
               
               
                 KR-342 
                 37.65 
                 22.46 
                 MeOH 
                 18 
                 25 to 4 
                 93 
                 25.3 
                 45.24 
                 Dia-A treated with NaOH and extracted with 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 CH 2 Cl 2   
               
               
                 KR-343 
                 6.98 
                 20.42 
                 MeOH 
                 15 
                 25 to 5 
                 215 
                 0.5 
                 89.44 
                 Flask broken while filtering solids SAF-31 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 material without equilibration 
               
               
                 KR-344 
                 23.11 
                 25.4 
                 MeOH 
                 15 
                 20 to 0 
                 150 
                 — 
                 — 
                 SAF equilibrated material, no crystals SAF-31 
               
               
                 KR-345 
                 20.20 
                 25.63 
                 MeOH 
                 15 
                 20 to 7 
                 50 
                 2.58 
                 97.77 
                 SAF-34 material ACCl addn. no eq. 
               
               
                 KR-346 
                 20.10 
                 25.76 
                 MeOH 
                 15 
                 20 to 6 
                 72 
                 6.13 
                 48.76 
                 SAF-35 material in toluene normal addn. no 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 preferential 
               
               
                 KR-347 
                 38.42 
                 33.45 
                 MeOH 
                 15 
                 20 to 5 
                 140 
                 3.7 
                 96.41 
                 ML of KR-345 + SAF-34 
               
               
                 KR-348 
                 41.07 
                 33.6 
                 MeOH 
                 15 
                 20 to 8 
                 100 
                 5.79 
                 94 
                 SAF-38 material 
               
               
                 KR-349 
                 45.43 
                 32.96 
                 MeOH 
                 15 
                 20 to 7 
                 120 
                 7.43 
                 95 
                 SAF-39 material 
               
               
                 KR-350 
                 34.72 
                 32.16 
                 MeOH 
                 15 
                 20 to 2 
                 135 
                 3.90 
                 96.56 
                 ML of KR-347 
               
               
                 KR-351 
                 89.39 
                 33.86 
                 MeOH 
                 15 
                 20 to 10 
                 100 
                 20.45 
                 48.22 
                 SAF 36 + 37 material (Toluene expts.) 
               
               
                 KR-352 
                 48.18 
                 33.14 
                 MeOH 
                 15 
                 18 to 4 
                 126 
                 7.16 
                 96.80 
                 SAF-33 material 
               
               
                 KR-353 
                 38 
                 31.57 
                 MeOH 
                 10 
                 10 to 1 
                 118 
                 9.8 
                 71.96 
                 Crystals are gummy material two layers in 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 solution ML of KR-349 
               
               
                   
               
             
          
           
               
                   
                 Wt. of 
                   
                   
                 Seeding 
                 Temp. 
                   
                 Wt. of 
                 % Purity of crystals 
                   
               
               
                   
                 dia-A 
                 % solution 
                 Solvent 
                 Temp. 
                 Profile 
                 Time 
                 crystals 
                 (SS) 
               
               
                 Expt. No. 
                 (gms) 
                 (w/w) 
                 system 
                 (° C.) 
                 (° C.) 
                 (hrs) 
                 (SS) 
                 (gms) 
                 Remarks 
               
               
                   
               
               
                 KR-354 
                 99.99 
                 33.02 
                 MeOH 
                 12 
                 20 to 10 
                 94 
                 13.62 
                 96.27 
                 SAF-41 material, ACCl addition 
               
               
                 KR-355 
                 100 
                 32.98 
                 MeOH 
                 15 
                 20 to 4 
                 96 
                 21.89 
                 80.40 
                 KR-354 ML 
               
               
                 KR-356 
                 106.79 
                 32.35 
                 MeOH 
                 15 
                 20 to −7 
                 48 
                 — 
                 — 
                 KR-348, 350, 352 ML mixed. Two 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 layers found at 70° C. dil. to 20% 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 used for 356A expt. 
               
               
                 KR- 
                 106.79 
                 19.8 
                 MeOH 
                 7 
                 20 to −7 
                 100 
                 16.58 
                 95.45 
                 KR-356 solution diluted ot 20% 
               
               
                 356-A 
               
               
                 KR-357 
                 99.82 
                 25 
                 MeOH 
                 6 
                 20 to −2 
                 98 
                 15.79 
                 95.44 
                 KR-355 ML, II cycle 
               
               
                 KR-358 
                 106.21 
                 19.7 
                 MeOH 
                 6 
                 20 to −6 
                 95 
                 12.16 
                 96.70 
                 KR-356 ML I recycle; after addn. 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 0.37 g KF 
               
               
                 KR-359 
                 100.08 
                 24.93 
                 MeOH 
                 3 
                 26 to −2 
                 118 
                 14.15 
                 97.15 
                 ML of KR-357, 3 rd  cycle 
               
               
                 KR-360 
                 110 
                 19.9 
                 MeOH 
                 5 
                 18 to −8 
                 71 
                 11.00 
                 97.58 
                 ML of KR-358, II recycle 
               
               
                 KR-361 
                 100.33 
                 25.006 
                 MeOH 
                 6 
                 22 to −7 
                 168 
                 13.27 
                 91.33 
                 ML of KR-359, 4 th  cycle 
               
               
                 KR-362 
                 113.82 
                 19.99 
                 MeOH 
                 3 
                 16 to −8 
                 90 
                 11.33 
                 98.55 
                 ML of KR-360, III cycle 
               
               
                 KR-363 
                 116.53 
                 20.078 
                 MeOH 
                 6 
                 16 to −11 
                 125 
                  6.91 
                 95.96 
                 ML of KR-362, IV cycle 
               
               
                 KR-364 
                 102 
                 20.03 
                 MeOH 
                 6 
                 16 to −8 
                 100 
                 10.34 
                 — 
                 ML of KR-361, V cycle 
               
               
                 KR-365 
                 106.62 
                 20.16 
                 MeOH 
                 5 
                 15 to −9 
                 116 
                 11.22 
                 95.54 
                 ML of KR-364, VI cycle 
               
               
                 KR-366 
                 129.32 
                 21.30 
                 MeOH 
                 4 
                 20 to −11 
                 168 
                  7.12 
                 95.3  
                 -ML of KR-363 
               
               
                 KR-367 
                 51.43 
                 33.00 
                 MeOH 
                 15 
                 20 to 8 
                 50 
                 11.24 
                 95.3  
                 SAF-42 material, New catalyst 
               
               
                   
               
             
          
           
               
                   
                 Wt. of 
                 % 
                   
                 Seeding 
                 Temp. 
                   
                 Wt. of 
                 % Purity of crystals 
                   
               
               
                   
                 dia-A 
                 solution 
                 Solvent 
                 Temp. 
                 Profile 
                   
                 crystals 
                 (SS) 
               
               
                 Expt. No. 
                 (gms) 
                 (w/w) 
                 system 
                 (° C.) 
                 (° C.) 
                 Time (hrs) 
                 (SS) 
                 (gms) 
                 Remarks 
               
               
                   
               
               
                 KR- 
                  51.45 
                 32.68 
                 MeOH 
                 14 
                 20-9 
                  72 
                 9.65 
                 90.8 
                 ML of KR-367 
               
               
                 367A 
               
               
                 KR-368 
                 107.21 
                 20.60 
                 MeOH 
                  6 
                 150 to −5 
                 170 
                 7.0  
                 93.4 
                 KR-365 ML + SAF 43 (11.0 g) 
               
               
                   
               
             
          
         
       
     
     
       
         
               
             
               
               
               
               
               
               
               
               
             
           
               
                 TABLE 2 
               
             
             
               
                   
               
               
                 ESTERS 
               
             
          
           
               
                   
                   
                   
                   
                   
                 Wt. of 
                 Ratio of 
                   
               
               
                   
                 Reaction 
                   
                   
                   
                 dia-A 
                 isomers 
               
               
                 Expt. No. 
                 conditions 
                 Solvent 
                 Catalyst 
                 Mode of addition 
                 (gms) 
                 (SR:SS) 
                 Remarks 
               
               
                   
               
               
                 SAF-32 
                 Addn. at −5° C. for 
                 DCE 
                 TBAB 
                 Normal addition 
                  43.01 g 
                 46.7:42.7 
                 *Normal addition 
               
               
                   
                 90 min. and 
                   
                   
                   
                   
                   
                 is MPBA + ACCl to 
               
               
                   
                 maintained RM @ 
                   
                   
                   
                   
                   
                 NaCN and PTC solution. 
               
               
                   
                 −3 to +2 for 90 min. 
                   
                   
                   
                   
                   
                 This material is used 
               
               
                   
                 and +2 to +3 for 120 min. 
                   
                   
                   
                   
                   
                 for KR-352. 
               
               
                   
                   
                   
                   
                   
                   
                   
                 ACCl = Acid chloride 
               
               
                 SAF-33 
                 ACCl addition at −4° C. 
                 DCE 
                 TBAB 
                 ACCl addition dropwise to 
                 48.182 g 
                 45.78:48.3  
                 — 
               
               
                   
                 for 75 min. and 
                   
                   
                 MPBAcyanohydrin 
               
               
                   
                 maintained RM @ 
               
               
                   
                 −1 to −4 for 150 min. 
               
               
                 SAF-34 
                 Addition of ACCl 
                 DCE 
                 TBAB 
                 ACCl addition dropwise to 
                  41.27 g 
                  45.5:45.22 
                 This material is used 
               
               
                   
                 at −10° C. 
                   
                   
                 MPBAcyanohydrin 
                   
                   
                 for KR-345 
               
               
                 SAF-35 
                 Addition of ACCl 
                 Toluene 
                 TEBA 
                 *Normal addition 
                  44.05 
                 41.942.82 
                 This material is used 
               
               
                   
                 at 27° C. 60 minutes 
                   
                   
                   
                   
                   
                 for KR-346 
               
               
                   
                 and maintained @ 
               
               
                   
                 27° C. for 300 min. 
               
               
                 SAF-36 
                 Addition of ACCl at −5° C. 
                 Toluene 
                 TEBA 
                 ACCl addition 
                  45.0 
                  44.5:44.97 
                 — 
               
               
                   
                 for 80 minutes and 
                   
                   
                 dropwise to 
               
               
                   
                 maintained the reaction 
                   
                   
                 MPBAcyanohydrin 
               
               
                   
                 mixture at −3 to −5 for 2 hrs 
               
               
                   
                 and left overnight 
               
               
                 SAF-37 
                 Addition of ACCl at 
                 Toluene 
                 TEBA 
                 ACCl addition 
                  45.0 
                  41.5:42.72 
               
               
                   
                 25° C. in 45 min. and 
                   
                   
                 dropwise to 
               
               
                   
                 maintained the RM @ 
                   
                   
                 MPBAcyanohydrin 
               
               
                   
                 26° C.; for 300 minutes 
               
               
                 SAF-38 
                 Addition of ACCl at 
                 DCE 
                 N,N- 
                 ACCl addition 
                  41.07 
                 44.52:43.5  
                 This material is 
               
               
                   
                 0° C. to +4 for 85 min. 
                   
                 dimethyl, 
                 dropwise to 
                   
                   
                 used for KR-348 
               
               
                   
                 maintained the RM at 0 
                   
                 N-butyl-α- 
                 MPBAcyanohydrin 
               
               
                   
                 to −1 for 300 min. 
                   
                 phenyl- 
               
               
                   
                   
                   
                 ethyl- 
               
               
                   
                   
                   
                 ammonium- 
               
               
                   
                   
                   
                 bromide 
               
               
                 SAF-39 
                 Addition of ACCl at 0 to −1° C. 
                 DCM 
                 TBAB 
                 ACCl addition 
                  45.43 
                 43.94:41.14 
                 This material is 
               
               
                   
                 for 60 min and RM 
                   
                   
                 dropwise to 
                   
                   
                 used for KR-349 
               
               
                   
                 maintained at 0 to −2 for 
                   
                   
                 MPBAcyanohydrin 
               
               
                   
                 180 min 
               
               
                 SAF-40 
                 Addition of ACCl at 25° C. 
                 DCE 
                 TBAB 
                 ACCl addition 
                  6.82 
                 42.5:41.5 
                 Material lost 
               
               
                   
                 for 105 min and maintained 
                   
                   
                 dropwise to 
                   
                   
                 while conc. 
               
               
                   
                 RM at 25° C for 200 hrs 
                   
                   
                 MPBAcyanohydrin 
               
               
                 SAF-41 
                 Addition of ACCl at −5 to 
                 DCE 
                 TBAB 
                 ACCl addition 
                  20.09 
                 43:44 
                 This material is 
               
               
                   
                 −7° C. for 60 min. and 
                   
                   
                 dropwise to 
                   
                   
                 used for KR-354 
               
               
                   
                 maintained RM at −3 to −0° C. 
                   
                   
                 MPBAcyanohydrin 
               
               
                   
                 for 150 min. 
               
               
                 SAF-42 
                 Addition of ACCl at −3 to 
                 DCE 
                 N,N- 
                 ACCl addition 
                  37.00 g 
                 43.2:41.8 
                 This material is 
               
               
                   
                 −2° C. for 85 min. and 
                   
                 dimethyl, 
                 dropwise to 
                   
                   
                 used for KR-367 
               
               
                   
                 maintained RM at −3 to −1° C. 
                   
                 N-butyl- 
                 MPBAcyanohydrin 
               
               
                   
                 for 135 min. 
                   
                 α-phenyl- 
               
               
                   
                   
                   
                 ethyl- 
               
               
                   
                   
                   
                 ammonium- 
               
               
                   
                   
                   
                 bromide