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.

Description:
FIELD OF INVENTION  
       [0001]     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  
       [0002]     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. 
 
         [0003]     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).  
         [0004]     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.  
         [0005]     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.  
         [0006]     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.  
         [0007]     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.  
         [0008]     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.  
         [0009]     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.  
         [0010]     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.  
         [0011]     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  
       [0012]     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].  
         [0013]     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.  
         [0014]     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.  
         [0015]     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.  
         [0016]     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  
       [0017]     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. 
     
    
     DETAILED DESCRIPTION OF THE INVENTION  
       [0018]     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.  
         [0019]     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)-a-cyano3-phenoxybenzylalcohol under PTC conditions.  
         [0020]     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.  
         [0021]     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.  
         [0022]     In yet another embodiment of the invention, the quaternary ammonium salt is tetrabutylammoniumbromide.  
         [0023]     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.  
         [0024]     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.  
         [0025]     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.  
         [0026]     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.  
         [0027]     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.  
         [0028]     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.  
         [0029]     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.  
         [0030]     In another embodiment of the invention, the solvent recovered from distillation of dilute diastereomer-A is recycled for further batches of diastereomer-A formation.  
         [0031]     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.  
         [0032]     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.  
         [0033]     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.  
         [0034]     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%.  
         [0035]     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.  
         [0036]     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.  
         [0037]     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.  
         [0038]     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.  
         [0039]     In another embodiment of the invention, the solvent is selected from alcohols consisting of methanol, ethanol, isopropanol and hydrocarbon solvents like Hexane, Toluene, Heptane.  
         [0040]     In another embodiment of the invention, the solvent is more preferably lower alkanol like methanol.  
         [0041]     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%.  
         [0042]     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.  
         [0043]     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.  
         [0044]     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.  
         [0045]     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.  
         [0046]     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.  
         [0047]     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.  
         [0048]     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).  
         [0049]     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 600-120° 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.  
         [0050]     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.  
                         
 
         [0051]     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. 
         
 
         [0052]     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.  
         [0053]     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.  
         [0054]     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.  
         [0055]     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.  
         [0056]     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.  
         [0057]     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).  
         [0058]     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):  
       [0059]     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.  
         [0060]     Wt. of ester=441.5  
         [0061]     Ratio of SS:SR=46:48  
         [0062]     This material is used for preferential crystallization of esfenvalerate.  
       Example-2  
       [0063]     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.  
         [0064]     Wt. of crude=10.0 gms  
         [0065]     % purity of SS isomer=46.1  
       Example-3  
       [0066]     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.  
         [0067]     Wt. of crystals=8.86  
         [0068]     % purity of SS-isomer=46.57  
         [0069]     Wt. of ML=16.31 gms  
       Example-3A  
       [0070]     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.  
         [0071]     Wt. of crystals=0.51 g  
         [0072]     % purity of SS-isomer=95  
       Example-4  
       [0073]     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.  
         [0074]     Wt. of crystals=20.0 g  
         [0075]     % purity of SS-isomer=42.89  
         [0076]     Wt. of ML=115.86 gms  
       Example-4A  
       [0077]     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.  
         [0078]     Wt. of crystals=0.9 g  
         [0079]     % purity of SS isomer=98  
       Example-5  
       [0080]     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.  
         [0081]     Wt. of crystals=9.2 2  g  
         [0082]     % purity of SS-isomer=45.2%  
         [0083]     Wt. of ML=87.20 gms  
       Example-5A  
       [0084]     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.  
         [0085]     Wt. of crystals=6.80 g  
         [0086]     % purity of SS-isomer=57.1  
       Example-6  
       [0087]     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.  
         [0088]     Wt. of crystals=7.40 g  
         [0089]     % purity of SS-isomer=97.45%  
         [0090]     Wt. of ML=155.88 g  
       Example-7  
       [0091]     The mother liquor obtained from above example-6 was subjected to preferential crystallization as described below:  
         [0092]     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.  
         [0093]     Wt. of crystals=2.95 g  
         [0094]     % purity of SS-isomer=98.4%  
       Example-8  
       [0095]     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.  
         [0096]     Wt. of crystals=8.86 g  
         [0097]     % purity of SS-isomer=43.2%  
         [0098]     Wt. of ML=116.4 gms  
       Example-9  
       [0099]     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.  
         [0100]     Wt. of crystals=0.81 g  
         [0101]     % purity of SS-isomer=96.38%  
       Example-10  
       [0102]     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.  
         [0103]     Wt. of crystals=1.28 g  
         [0104]     % purity of SS-isomer=92.9%  
       Example-11  
       [0105]     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.  
         [0106]     Wt. of crystals=1.16 g  
         [0107]     % purity of SS-isomer=97.6%  
       Example-12  
       [0108]     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.  
         [0109]     Wt. of crystals=1.43 g  
         [0110]     % purity of SS-isomer=69%  
         [0111]     Wt. of ML=21.09  
       Example-13  
       [0112]     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.  
         [0113]     Wt. of crystals=0.1 g  
         [0114]     % purity of SS-isomer=77.2%  
         [0115]     Wt. of ML=20.46  
         [0116]     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.  
         [0117]     Wt. of crystals=2.85 g  
         [0118]     % purity of SS-isomer=54.2%  
       Example-14  
       [0119]     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.  
         [0120]     Wt. of crystals=13.31 g  
         [0121]     % purity of SS-isomer=96.5  
       Example-15  
       [0122]     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.  
         [0123]     Wt. of solids=6.43 g  
         [0124]     % purity of SS-isomer=49.83  
       Example-16  
       [0125]     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.  
         [0126]     Wt. of crystals=7.84 g  
         [0127]     % purity of SS-isomer=44.5  
       Example-17  
       [0128]     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.  
         [0129]     Wt. of Solids=5.63 g  
         [0130]     % purity of SS-isomer=45.23  
       Example-18  
       [0131]     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.  
         [0132]     Wt. of crystals=0.63 g  
         [0133]     % purity of SS-isomer=43.62  
         [0134]     Wt. of ML=110.68  
       Example-19  
       [0135]     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.  
         [0136]     Wt. of crystals=2.13 g  
         [0137]     % purity of SS-isomer=94.7  
         [0138]     Wt. of ML=106.29  
       Example-20  
       [0139]     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.  
         [0140]     Wt. of crystals=2.13 g  
         [0141]     % purity of SS-isomer=94.7  
       Example-21  
       [0142]     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.  
         [0143]     Wt. of crystals=1.67 g  
         [0144]     % purity of SS-isomer=98.2  
       Example-22  
       [0145]     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.  
         [0146]     Wt. of crystals=0.95 g  
         [0147]     % purity of SS-isomer=42.0  
       Example-23  
       [0148]     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.  
         [0149]     Wt. of crystals=3.46 g  
         [0150]     % purity of SS-isomer=47.02  
       Example-24  
       [0151]     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.  
         [0152]     Wt. of solids=1.39 g  
         [0153]     % of SS-isomer=94.0  
         [0154]     Wt. of ML=704.68  
       Example-25  
       [0155]     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.  
         [0156]     Wt. of solid: 9.54  
         [0157]     % purity of SS isomer=97.5  
       Example-26  
       [0158]     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.  
         [0159]     Wt. of solids−7.05 g  
         [0160]     % of SS-isomer=43.3 g  
       Example-27  
       [0161]     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.  
         [0162]     Wt. of solids=6.7 g  
         [0163]     % of SS-Isomer=42.27  
       Example-28  
       [0164]     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.  
         [0165]     Wt. of solids−2.54 g  
         [0166]     % of SS-isomer=81.35  
       Example-29  
       [0167]     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.  
         [0168]     Wt. of solids−4.75 g  
         [0169]     % of SS-Isomer=47.02  
       Example-30  
       [0170]     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.  
         [0171]     Wt. of solids=4.4 g  
         [0172]     % of SS-Isomer=46.88  
       Example-31  
       [0173]     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.  
         [0174]     Wt. of solids=2.8 g  
         [0175]     % of SS-isomer=44.7  
       Example-32  
       [0176]     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.  
         [0177]     Wt. of crystals=49.44 g  
         [0178]     % purity of SS-isomer=95.67  
         [0179]     Wt. of ML=857.10 g  
       Example-33  
       [0180]     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.  
         [0181]     Wt. of crystals=64.3 g  
         [0182]     % purity of SS-isomer=65.23  
         [0183]     Wt. of ML=670.84 g  
       Example-34  
       [0184]     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.  
         [0185]     Wt. of crystals=14.03 g  
         [0186]     % purity of SS-isomer=89.79  
         [0187]     Wt. of ML=518.2 g  
       Example-35  
       [0188]     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.  
         [0189]     Wt. of solids=10.22 g  
         [0190]     % purity of SS-isomer=95.63  
         [0191]     Wt. of ML=857.10 g  
       Example-36  
       [0192]     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.  
         [0193]     Wt. of crystals=3.94 g  
         [0194]     % purity of SS-isomer=93.9  
         [0195]     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  
       [0196]     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  
       [0197]     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.  
         [0198]     Wt. of crystals=2.58  
         [0199]     90% purity of SS-isomer=96.4  
       Example-39  
       [0200]     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.  
         [0201]     Wt. of crystals=16.5 g  
         [0202]     % purity of SS-isomer=95.2%  
         [0203]     Wt. of ML=506.0 gms  
       Example-40  
       [0204]     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.  
         [0205]     Wt. of crystals=12.16  
         [0206]     % purity=96.7%  
         [0207]     Wt. of ML=515.84 g  
       Example-41  
       [0208]     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.  
         [0209]     Wt. of crystals=11.0 g  
         [0210]     % purity of SS-isomer=97.5  
         [0211]     Wt. of ML=530.06 g.  
       Example-42  
       [0212]     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.  
         [0213]     Wt. of crystals=11.33 g  
         [0214]     % purity of SS=98.55  
         [0215]     Wt. of ML=552.29 g  
       Example-43  
       [0216]     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.  
         [0217]     Wt. of crystals=6.91  
         [0218]     % purity=95.9  
         [0219]     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  
       [0220]     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.  
         [0221]     Wt. of crystals=11.2 g  
         [0222]     % purity of SS-isomer=95.3  
         [0223]     wt. of ML=140.45 g  
       Example-45  
       [0224]     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.  
         [0225]     Wt. of solid=9.65 g  
         [0226]     % Purity of crystals=96.5  
         [0227]     Wt. of ML=144.04 gms  
       Example-46  
     Preparation of Diastereomer-A  
       [0228]     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.  
         [0229]     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.  
         [0230]     Wt. of diastereomer-A=3.89 kg  
         [0231]     Ratio of SR:SS=45.2:43.5  
       Example-47  
       [0232]     The material obtained from example 46 is used for preferential crystallization of esfenvalarate in an iterative manner as described below:  
         [0233]     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).  
         [0234]     Wt. of crystals=0.516 kg  
         [0235]     % Purity of crystals=96.5  
         [0236]     Wt. of ML=10.67 kg  
       Example-47A  
       [0237]     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  
         [0238]     Wt. of crystals=0.432 kg  
         [0239]     % Purity of crystals =97.2  
         [0240]     Wt. of ML=10.887 kgs  
       Example-47B  
       [0241]     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.  
         [0242]     Wt. of crystals=0.408 kg  
         [0243]     % Purity of crystals=97.5  
         [0244]     Wt. of ML=11.122 kgs  
       Example-47C  
       [0245]     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.  
         [0246]     Wt. of crystals=0.384 kg  
         [0247]     % Purity of crystals=96.8  
         [0248]     Wt. of ML=10.89 kgs  
       Example-47D  
       [0249]     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.  
         [0250]     Wt. of crystals=0.184 kg  
         [0251]     % Purity of crystals=92.4  
         [0252]     Wt. of ML=10.826 kgs  
       Example-47E  
       [0253]     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.  
         [0254]     Wt. of crystals=0.256 kg  
         [0255]     % Purity of crystals=94.5  
         [0256]     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.        
 
         [0261]     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   25to10   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, res to red 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)                  
 
         [0262]    
       
         
               
             
               
               
               
               
               
               
               
               
             
           
               
                 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