PATENT DOCUMENT

Abstract:
A versatile, eco-friendly, and efficient method for the convenient conversion of esters and ester-like compounds into amides, peptides, carbamates, ureas, oxamides, oxamates, hydrazides, oxazolidinones, pyrazolones, oxazolidinediones, barbituric acids, and other molecules containing one or more OCN moieties in the presence of a diol or polyol is disclosed.

Full Description:
CROSS-REFERENCE TO RELATED APPLICATION  
       [0001]     This application claims the benefit of U.S. Provisional Application Ser. No. 60/474,785 filed Jun. 2, 2003 under 35 USC 119(e). The entire disclosure of this provisional application is herein incorporated by reference. 
     
    
     BACKGROUND OF THE INVENTION  
       [0002]     1. Field of the Invention  
         [0003]     The present invention relates to the field of synthetic organic chemistry, and in particular to the synthesis of compounds whose molecules contain one or more OCN moieties such as amides, peptides, oxamates, oxamides, hydrazides, carbamates, ureas, oxazolidinones, pyrazolones and barbituric acids.  
         [0004]     2. Description of Related Art  
         [0005]     Carboxamides, peptides, carbamates, substituted ureas, hydrazides, barbituric acids, and other families of organic compounds whose molecules contain one or more OCN moieties comprise very many commercially important drugs, agrochemicals (insecticides, herbicides, etc.) and nutraceuticals.  
         [0006]     The ammonolysis/aminolysis of carboxylic acid chlorides and anhydrides is the most frequently used-and most generally applicable-method for the preparation of carboxamides, both in the laboratory and in industry.  
         [0007]     Ammonolysis of an acid chloride or anhydride yields unsubstituted amides (primary amides) R—CO—NH2. In a similar vein, aminolysis an acid chloride or anhydride using a primary amine gives N-substituted amides (secondary amides) R—CO—NHR′, and when a secondary amine is used the aminolysis yields N,N-disubstituted amides (tertiary amides), R—CO—NR′12  
         [0008]     However, most acid chlorides and anhydrides are toxic and/or corrosive; their synthesis usually involves the use of even more toxic/corrosive inorganic compounds (thionyl chloride, phosphorus chlorides) which in turn are derived from elemental chlorine. All of these compounds are dangerous and must be handled and stored with extreme care on account of their reactivity towards water and of the irritant/corrosive nature of their hydrolysis products.  
         [0009]     Furthermore, the reaction of acyl halides with ammonia or amine liberates hydrogen chloride, a highly corrosive and noxious chemical which is usually disposed of by neutralization with aqueous alkali thereby producing aqueous effluents whose treatment adds to process costs.  
         [0010]     If the widely used Schotten-Baumann procedure is applied, aqueous effluents containing elevated salt loadings are generated too.  
         [0011]     When acetyl chloride or acetic anhydride (the two most important acylating agents) are employed, the reaction is highly exothermic and must be carefully controlled, usually by cooling or dilution [Smith, M. B.; March, J. “March&#39;s Advanced Organic Chemistry”, fifth edition, Wiley-interscience, New York, 2001, p506]. The danger of a sudden temperature increase, especially when large scale reactions are run, must always be guarded against.  
         [0012]     Finally, by-product formation (imides, ketene dimers) can complicate separations and reduce yields when anhydrides are used to acylate ammonia or primary amines and whenever acyl halides are employed.  
         [0013]     On the other hand, acylations of ammonia or amines by carboxylic acid esters (i.e. ester ammonolysis or aminolysis) at atmospheric pressure is a method of amide synthesis of rather limited scope at the present time.  
         [0014]     Thus, “the aminolysis of inactivated esters is known to be a difficult reaction, though it potentially constitutes a useful synthetic method as shown by the number of ways devised to facilitate it; uncatalysed aminolysis by primary amines requires temperatures higher than 200° C., whereas the corresponding reaction with secondary amines has never been reported [Matsumoto, K. et al “Direct aminolysis of inactivated and thermally unstable esters at high pressure” Chem. Ber. 122, 1357-1363 (1989)], “ester aminolysis, in general, occurs under harsh conditions that require high temperatures and extended reaction periods” [Varma, R. S.; Naicker, K. P. “Solvent-free synthesis of amides from non-enolizable esters and amines using microwave irradiation” Tetrahedron Letters, 40, 6177-6180 (1999)], and “The aminolysis of esters is generally a sluggish reaction unless esters having good leaving groups are used” [Hoegberg, T. et al, “Cyanide as an efficient and mild catalyst in the aminolysis of esters” J. Org. Chem. 52, 2033-2036 (1987)].  
         [0015]     Accordingly, ester ammonolysis/aminolysis is very seldom used, especially in large-scale processes, although it has many advantages: 
        1) Most carboxylic acids can be easily converted into methyl or ethyl esters.     2) The reactions between an ester and ammonia or an amine are not highly exothermic; therefore, they are safer to run-especially in industry.     3) Esters are generally much less toxic and much safer to handle/store than acid halides and anhydrides     4) The acylation of ammonia or an amine by methyl or ethyl esters yields an amide and an alcohol as the only reaction products.     5) The by-product alcohol can be recycled (into ester), therefore the process is environmentally friendly     6) It is possible to ammonolyze/aminolyze enolyzable esters, hydroxyesters, and mercapto-substituted esters     7) Monoacylation of an aliphatic diamine can be carried out with higher selectivity when an ester is used as acylating agent     8) The ammonolysis/aminolysis of an ester is the first step in important reaction sequences that eventually lead to heterocycles such as oxazolinones, oxazolidinones, oxazolidinediones, benzisoxazoles, benzimidazoles, pyrazolones, pyrazolidindiones, dihydrooxazinediones, barbituric acids, thiobarbituric acids, benzoxazoles, benzothiazoles, quinolones, pyridazinones, pyridones, hydroxypyrimidines, dihydroxypyrimidines and thiazoles.        
 
         [0024]     It is therefore clear that if the scope of ester ammonolysis/aminolysis were expanded, many synthetic amide producers would stop using acyl halides or acid anhydrides as acylating agents and turn to esters instead. It is also clear that synthetic sequences devised for obtaining new amides would undoubtedly favor ester ammonolysis/aminolysis over other acylation methods on account of its superior convenience, efficiency, environmental friendliness, and safety.  
         [0025]     The present invention addresses this desideratum by providing an improved method for ester ammonolysis/aminolysis and related reactions that greatly expands their scope and usefulness.  
       OBJECTS OF THE INVENTION  
       [0026]     To provide an improved method applicable to the synthesis of amides through ammonolysis/aminolysis of esters, lactones, gem-diacyloxy derivatives, and other ester-like compounds.  
         [0027]     To provide an improved method applicable to the synthesis of heterocyclic compounds that contain the OCN moiety, such as lactams, oxazolidinones, pyrazolones, oxazolidinediones, and barbituric acids from esters or ester-like compounds through cyclocondensation reactions involving said esters/ester-like compounds, ammonia or amines and, optionally a co-catalyst such as an alkaline metal carbonate or alkoxide.  
         [0028]     To provide an improved method applicable to the synthesis of carbamates, ureas, oxamates, oxamides, and hydrazides from esters or ester-like compounds.  
         [0029]     To provide an improved method aimed at liberating alcohols from their esters through ammonolysis/aminolysis.  
         [0030]     To provide an improved method applicable to the synthesis of compounds containing one or more OCN moieties from esters/ester-like compounds and ammonia (or an ammonia precursor) or an amine/amine precursor or any amine like compound.  
         [0031]     To provide an improved transamidation method.  
         [0032]     To provide an improved method applicable to the synthesis of compounds whose molecule contain two or more OCN moieties by ammonolysis/aminolysis of esters derived from dicarboxylic or polycarboxylic acids.  
         [0033]     To provide an improved method applicable to the synthesis of compounds whose molecules contain two or more OCN moieties through reaction of esters or ester-like compounds with diamines or polyamines.  
       SUMMARY OF THE INVENTION  
       [0034]     This applicant has unexpectedly discovered that some diols (especially 1,2-diols) and polyols catalyze the ammonolysis, aminolysis, and hydrazinolysis of esters and ester-like compounds via a catalytic cycle involving a transesterification reaction between the ester (or ester-like compound) and the diol/polyol. This discovery significantly widens the scope and heightens the usefulness of amide synthesis via ester ammonolysis/aminolysis; it also enhances the usefulness of a number of methods in synthetic heterocyclic chemistry which aim at the construction of rings containing the OCN moiety through cyclocondensation reactions. Furthermore, it is shown that superior synthetic methods based on the use of diols/polyols as catalysts/cocatalysts and/or solvents are applicable not only to the preparation of amides but also of carbamates, ureas, oxamides, oxamates, hydrazides and other similar molecules. Finally, it has been established that the same diols/polyols that catalyze the above-mentioned reactions can be advantageously used to catalyze or co-catalyze related chemical transformations such as transamidations.  
         [heading-0035]     Definitions  
         [0036]     By “Ester-like compound” is meant any organic compound whose molecules contain one or more CO 2 C moieties such as lactones-, gem-diacyloxy derivatives, and acetonides derived from alpha-hydroxyacids; said molecules may optionally comprise other functional groups.  
         [0037]     By “Amine” is meant any substance whose molecules contain a CNH2 or CNHC moiety, regardless of the presence or absence of other functional groups.  
         [0038]     By “Ammonia precursor” is meant any substance capable of generating ammonia “in situ”, such as urea-, ammonium carbonate, ammonium carbamate, etc. upon heating.  
         [0039]     By “Amine precursor” is meant any substance capable of generating a primary or secondary amine “in situ”, such as “DIMCARB” (N,N-dimethylammonium N,N-dimethylcarbamate) when heated.  
         [0040]     By “Hydrazine precursor” is meant any substance capable of generating hydrazine “in situ”, such as hydrazine monohydrate.  
         [0041]     By “Substituted hydrazine” is meant any hydrazine derivative wherein 1, 2 or 3 hydrogen atoms of the hydrazine molecule have been replaced by alkyl radicals and/or aryl radicals and/or heteroaryl radicals, regardless of the presence or absence of functional groups on said radicals.  
         [0042]     By “Substituted hydrazine precursor” is meant any substance capable of generating a “substituted hydrazine” “in situ” 
         [0043]     By “Diol” is meant any substance whose molecules contain two alcoholic hydroxyl (OH) functional groups, regardless of the presence or absence of other functional groups.  
         [0044]     By “Polyol” is meant any substance whose molecules contain 3 or more alcoholic hydroxyl (OH) functional groups, regardless of the presence or absence of other functional groups.  
         [0045]     By “Diamine” is meant any substance whose molecules contain (attached to carbon atoms) two NH2 moieties or two NH moieties or one of each kind of moiety regardless of the presence or absence of other functional groups.  
         [0046]     By “Polyamine” is meant any substance whose molecules contain (attached to carbon atoms) 3 or more NH2 or NH moieties in any possible combination, regardless of the presence or absence of other functional groups.  
         [0047]     By “Amine-like compound” is meant any substance whose molecules contain an NH2 or NH moiety, which possesses chemical properties similar to those of a primary or secondary amine: hydrazine would be an example. 
     
    
     DETAILED DESCRIPTION OF THE INVENTION  
       [0048]     The instant method usually involves reacting one or more esters or ester-like compounds with one ore more amines or amine-like compounds in the presence of one or more diols/polyols, optionally in the presence of a co-catalyst (a metal, metal alkoxide, metal carbonate, metal cyanide, enzyme, tertiary amine, or any transesterification catalyst).  
         [0049]     Many variations on this basic process are possible and are, of course, within the scope of the present invention. For instance:  
         [0050]     1) Two stages might be employed: an initial transesterification step involving only the ester or ester-like compound, the diol/polyol and (optionally) a transesterification catalyst, with or without separation of by-product alcohol, and a final step wherein the initially obtained hydroxyester reacts with the amine or amine-like compound.  
         [0051]     2) The process might involve recycling of the mother liquor obtained after separating the amide.  
         [0052]     3) The process might involve superatmospheric or sub atmospheric pressures, high or low temperatures, use of inert solvents, inert atmospheres, etc.  
         [0053]     4) Instead of using an ester and an amine, an aminoester might be used as starting material.  
         [0054]     The effectiveness of a series of diols/polyols as nucleophilic catalysts in the acylation of monoethanolamine by ethyl acetate (using standardized conditions) was found to be:  
         [0055]     Ethylene glycol&gt;2,2-dimethyl-1,3-propanediol&gt;glycerol&gt;propylene glycol&gt;D-sorbitol&gt;blank (no catalyst present)˜diethylene glycol&gt;1,3-propanediol˜1,4-butanediol.  
         [0056]     Therefore, ethyleneglycol is the preferred catalyst/solvent, but the use of 2,2-dimethyl-1,3-propanediol, glycerol, or propylene glycol might be advantageous in specific instances.  
       DESCRIPTION OF PREFERRED EMBODIMENT  
       [0057]     Since amine nucleophilicity/steric accessibility and ester electrophilicity/steric accessibility vary widely, it is not possible to recommend a particular set of reaction conditions that will be applicable to all conceivable ester-amine combinations. Instead it was found convenient to categorize esters as possessing high, medium, or low “electrophilicity-steric accessibility” (i.e. intrinsic reactivity toward an “average amine”), and to categorize amines as having high, medium or low “nucleophilicity-steric accessibility” (i.e. intrinsic reactivity toward an “average ester”), thereby obtaining a 3×3 “intrinsic reactivity matrix”.  
         [0058]     On the basis of this matrix and of our experimental results, we have ranked the reactivity of different ester-amine pairs as follows.  
                                               INTRINSIC   INTRINSIC   INTRINSIC       REACTIVITY   ESTER   AMINE   COMPARATIVE       GROUP   REACTIVITY   REACTIVITY   REACTIVITY                   I   HIGH   HIGH   +++++       II   HIGH   MEDIUM   ++++           MEDIUM   HIGH       III   HIGH   LOW           MEDIUM   MEDIUM   +++           LOW   HIGH       IV   MEDIUM   LOW   ++           LOW   MEDIUM       V   LOW   LOW   +                 SYMBOLOGY:            +++++ VERY HIGH COMPARATIVE REACTIVITY            ++++ HIGH COMPARATIVE REACTIVITY            +++ MODERATE COMPARATIVE REACTIVITY            ++ LOW COMPARATIVE REACTIVITY            + VERY LOW COMPARATIVE REACTIVITY             
 
         [0059]     Therefore, five “reactivity groups” emerged, and it was possible to establish the preferred embodiment for each group.  
         [0060]     Before describing these 5 sets of conditions, it is important to identify the specific types of esters and amines that belong in each “intrinsic reactivity” category. High-reactivity esters.: formates, oxalates, carbonates, fumarates, aromatic esters (benzoates, naphthoates, etc.) bearing electron-withdrawing groups, heteroaromatic esters (furoates, pyridinecarboxylates, etc.)  
         [0061]     Medium-reactivity esters: sterically unhindered esters derived from saturated aliphatic carboxylic acids, benzoates, naphthoates, oxamates, crotonates, and cinnamates.  
         [0062]     Low-reactivity esters: sterically hindered esters derived from saturated, unsaturated or aromatic carboxylic acids, aromatic esters (benzoates, naphthoates, etc.) bearing electron-releasing substituents, heteroaromatic esters bearing electron-releasing groups, carbamates.  
         [0063]     High-reactivity amines: primary aliphatic amines devoid of steric hindrance, dimethylamine, monoethanolamine, morpholine, pyrrolidine, piperidine, primary aromatic amines bearing strongly electron-releasing groups, hydrazine.  
         [0064]     Medium-reactivity amines: secondary aliphatic amines (excepting dimethylamine), aniline, alpha-naphthylamine, beta-naphthylamine, primary aromatic amines bearing moderately electron-releasing substituents, ammonia, aminoacids salts.  
         [0065]     Low-reactivity amines: highly hindered primary aliphatic, secondary aliphatic and primary aromatic amines, secondary aliphatic-aromatic amines, secondary aromatic amines, heteroacyclic amines, primary aromatic amines bearing electron-withdrawing substituents.  
         [0066]     Preferred embodiments for the synthesis of amides belonging to each of the five “reactivity groups” are as follows.  
         [heading-0067]     Group I Amides  
         [0068]     Equimolar amounts of dry ethyl or (most preferably) methyl ester, dry amine and &gt;99% pure or (most preferably) anhydrous ethylene glycol are admixed, the reaction mixture is heated at reflux temperature until the reaction is complete as evidenced by disappearance of the ester or amine (T.L.C) and the amide is separated by means that are contingent upon its physical properties.  
         [0069]     NOTE: If a diester is used, 2 moles of amine per mol of ester should be employed. If the diamine is used, 2 moles of ester per mole of amine should be employed.  
         [heading-0070]     Group II Amides  
         [0071]     The procedure is similar to the one outlined for group I amides, except for the use of a molar ratio Glycol:ester:amine=4-10:1:1 and (most preferably) the addition of a catalytic amount of sodium methoxide  
         [heading-0072]     Group III Amides  
         [0073]     In general, the procedure is similar to the one outlined for “group II amides”, except for the use of a stoichiometric amount of sodium methoxide  
         [heading-0074]     Group IV Amides  
         [0075]     The procedure is similar to the one just given for synthesizing “group III amides”, but either superatmospheric pressures should be applied or the alcohol should be removed from the reaction medium as it is formed (Dean-Stark trap)  
         [heading-0076]     Group V Amides  
         [0077]     The general synthetic protocol is similar to that given above for “group IV amides” but higher pressures and/or temperatures must be applied.  
       EXAMPLES  
       [0078]     The following non-limiting examples are intended to promote a further understanding of the present invention.  
       Utility Example 1 
       [0079]    
       
         
               
             
               
             
               
               
               
             
               
               
             
               
               
               
             
               
             
               
               
             
               
               
               
             
               
             
               
               
               
             
           
               
                   
               
               
                   
               
               
                 Nicotinamide 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                 Starting Materials 
               
             
          
           
               
                 Ethyl Nicotinate 
                 0.5 
                 mol 
               
             
          
           
               
                 Ammonia (gas) 
                 excess, bubbled through system 
               
             
          
           
               
                 Ethylenglycol 
                 120 
                 ml 
               
             
          
           
               
                 Operating Conditions 
               
             
          
           
               
                 Pressure 
                 Atmospheric 
               
             
          
           
               
                 Temperature/time regime 
                 40-50° 
                 C./6 h. 
               
               
                 Reaction Progress 
               
               
                 Monitored by TLC 
               
               
                 Work-up 
               
             
          
           
               
                 1 liter of water added, the solution extracted with chloroform (5 × 
               
               
                 100 mL); the organic phase separated, chloroform eliminated by 
               
               
                 distillation at atmospheric pressure and the solid residue recrystallized 
               
               
                 from benzene. 5 g. of crystals were obtained, m.p. 128.5-129.5° C. 
               
               
                 (Literature 130° C.) 
               
             
          
           
               
                 Yield 
                 8% 
               
               
                   
               
             
          
         
       
     
       Comparative Example 1 
       [0080]    
       
         
               
             
               
               
             
               
               
               
               
             
               
               
               
             
               
               
               
               
             
               
               
             
               
               
               
             
               
               
               
               
             
           
               
                   
               
               
                   
               
               
                 Nicotinamide 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                   
                 Starting Materials 
               
             
          
           
               
                   
                 Ethyl Nicotinate 
                 0.5 
                 mol 
               
             
          
           
               
                   
                 Ammonia (gas) 
                 Excess, bubbled through system 
               
             
          
           
               
                   
                 Ethanol 
                 100 
                 mL 
               
               
                   
                 Sodium methoxide (catalyst) 
                 3.0 
                 g. 
               
             
          
           
               
                   
                 Operating Conditions 
               
             
          
           
               
                   
                 Pressure 
                 Atmospheric 
               
             
          
           
               
                   
                 Temperature/time regime 
                 55° 
                 C./26 h. 
               
               
                   
                 Reaction Progress 
               
               
                   
                 Monitored by TLC 
               
               
                   
                 Yield 
                 0% 
               
               
                   
                   
               
             
          
         
       
     
       Utility Example 2 
       [0081]    
       
         
               
             
               
             
               
               
               
             
               
               
             
               
               
               
             
               
             
               
               
             
               
               
               
             
               
               
             
               
               
               
             
               
             
               
               
               
             
           
               
                   
               
               
                   
               
               
                 3-Nitrobenzamide 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                 Starting Materials 
               
             
          
           
               
                 Methyl 3-Nitrobenzoate 
                 0.15 
                 mol 
               
             
          
           
               
                 Ammonia (gas) 
                 Excess, bubbled through system 
               
             
          
           
               
                 Ethylenglycol 
                 125 
                 mL 
               
               
                 Sodium methoxide (catalyst) 
                 0.09 
                 mol 
               
             
          
           
               
                 Operating Conditions 
               
             
          
           
               
                 Pressure 
                 Atmospheric 
               
             
          
           
               
                 Temperature/time regime 
                 40-45° 
                 C./20 h.; 
               
               
                   
                 then 40-45° 
                 C./{circumflex over ( )}5 h. 
               
             
          
           
               
                   
                 (after adding the catalyst) 
               
             
          
           
               
                 Reaction Progress 
                   
                   
               
               
                 Monitored by TLC 
               
               
                 Work-up 
               
             
          
           
               
                 The reaction mixture was heated to 100° C., mixed with 500 mL 
               
               
                 water, heated to 80° C., filtered while hot (to remove insoluble matter), 
               
               
                 cooled to 10° C., filtered to separate the precipitate, the crystals washed 
               
               
                 with cold water (100 mL) and dried at 70-80° C./12 h. 20 g. of yellowish 
               
               
                 crystals were obtained m.p. 143.3-144.1° C. (literature m.p. 143° C.). A 
               
               
                 second crop (3 g.) of crystals was obtained from the cooled mother liquor. 
               
             
          
           
               
                 Yield 
                 92% 
               
               
                   
               
             
          
         
       
     
       Comparative Example 2 
       [0082]    
       
         
               
             
               
             
               
               
               
             
               
               
             
               
               
               
             
               
             
               
               
             
               
               
               
             
               
             
               
               
               
             
           
               
                   
               
               
                   
               
               
                 3-Nitrobenzamide 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                 Starting Materials 
               
             
          
           
               
                 Methyl 3-Nitrobenoate 
                 0.15 
                 mol 
               
             
          
           
               
                 Ammonia (gas) 
                 Excess, bubbled through system 
               
             
          
           
               
                 Methanol (anhydrous) 
                 100 
                 mL 
               
               
                 Sodium methoxide (catalyst) 
                 8 
                 g. 
               
             
          
           
               
                 Operating Conditions 
               
             
          
           
               
                 Pressure 
                 Atmospheric 
               
             
          
           
               
                 Temperature/time regime 
                 60-65° 
                 C./26 h. 
               
               
                 Reaction Progress 
               
               
                 Monitored by TLC 
               
               
                 Work-up 
               
             
          
           
               
                 Most of the methanol was eliminated by distillation at atmospheric 
               
               
                 pressure. 500 mL of water were added and the mixture was cooled to room 
               
               
                 temperature. The precipitate was separated by filtration under reduced 
               
               
                 pressure, washed with water and dried at 70-75° C. during 12 hours. 17 
               
               
                 g. of cream-colored crystals were obtained, m.p. 142.7-143.3° C. 
               
             
          
           
               
                 Yield 
                 68% 
               
               
                   
               
             
          
         
       
     
       Comparative Example 3 
       [0083]    
       
         
               
             
               
             
               
               
               
             
               
               
             
               
               
               
             
               
             
               
               
             
               
               
               
             
               
               
             
               
               
               
             
               
             
               
               
             
           
               
                   
               
               
                   
               
               
                 3-Nitrobenzamide 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                 Starting Materials 
               
             
          
           
               
                 Methyl 3-Nitrobenoate 
                 0.057 
                 mol 
               
             
          
           
               
                 Ammonia (gas) 
                 Excess, bubbled through system 
               
             
          
           
               
                 n-Butanol 
                 180 
                 mL 
               
               
                 Sodium methoxide (catalyst) 
                 3 
                 g. 
               
             
          
           
               
                 Operating Conditions 
               
             
          
           
               
                 Pressure 
                 Atmospheric 
               
             
          
           
               
                 Temperature/time regime 
                 40-45° 
                 C./20 h.; then 
               
               
                   
                 40-45° 
                 C./8 h. 
               
             
          
           
               
                   
                 (after adding the catalyst 
               
             
          
           
               
                 Reaction Progress 
                   
                   
               
               
                 Monitored by TLC 
               
               
                 Work-up 
               
             
          
           
               
                 The solvent was eliminated by adding water (50 mL) and distilling 
               
               
                 the azeotrope at atmospheric pressure with further addition of 
               
               
                 water so as to keep a constant volume. The product was extracted 
               
               
                 with chloroform and the extract subjected to distillation at 
               
               
                 atmospheric pressure in order to eliminate the chloroform. Only 6 
               
               
                 g. of solid residue were recovered, most of which was shown by 
               
               
                 TLC to be Methyl 3-Nitrobenzoate. 
               
             
          
           
               
                 Yield 
                 Nil. 
               
               
                   
               
             
          
         
       
     
       Utility Example 3 
       [0084]    
       
         
               
             
               
             
               
               
               
             
               
             
               
               
               
             
               
             
               
               
               
             
           
               
                   
               
               
                   
               
               
                 N,N,N′,N′-tetramethylterephthaldiamide (method 1) 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                 Starting Materials 
               
             
          
           
               
                 Dimethyl terephthalate 
                 0.5 
                 mol 
               
               
                 Anhydrous dimethylamine 
                 1.1 
                 mol 
               
               
                 Ethylene Glycol 
                 400 
                 g. 
               
             
          
           
               
                 Operating Conditions 
               
             
          
           
               
                 Pressure 
                 50 
                 psi 
               
               
                 Temperature/time regime 
                 90-100° 
                 C./8 h 
               
             
          
           
               
                 Reaction Progress 
               
               
                 Monitored by TLC: Kodak&#39;s silica gel plates with flourescent 
               
               
                 indicator; benzene-acetone-ethyl acetate (34.5:61.5:4). 
               
               
                 Work-up 
               
               
                 The reaction mass was allowed to cool, mixed with saturated 
               
               
                 aqueous sodium chloride solution and exhaustively extracted with 
               
               
                 chloroform. The solvent was evaporated from the combined extracts and 
               
               
                 the residue was recrystallized in benzene and dried overnight at 70-80° C. 
               
             
          
           
               
                 Yield 
                 45% 
               
               
                   
               
             
          
         
       
     
       Utility Example 4 
       [0085]    
       
         
               
             
               
             
               
               
               
             
               
             
               
               
               
             
               
             
               
               
               
             
           
               
                   
               
               
                   
               
               
                 N,N,N′,N′-tetramethylterephthaldiamide (method 2) 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                 Starting Materials 
               
             
          
           
               
                 Dimethyl terephthalate 
                 0.5 
                 mol 
               
               
                 Anhydrous dimethylamine 
                 3.0 
                 mol 
               
               
                 Ethylene Glycol 
                 400 
                 mL 
               
             
          
           
               
                 Operating Conditions 
               
             
          
           
               
                 Pressure 
                 70 
                 psi 
               
               
                 Temperature/time regime 
                 90-100° 
                 C./7 h 
               
               
                 Reaction Progress 
               
               
                 Not monitored. 
               
               
                 Work-up 
               
             
          
           
               
                 The reaction mass was allowed to cool, mixed with saturated 
               
               
                 aqueous sodium chloride solution and exhaustively extracted with 
               
               
                 chloroform. The pooled extracts were distilled to eliminate chloroform and 
               
               
                 the residue was dried overnight at 70-80° C. The dry product melted at 
               
               
                 183-190° C. (literature m.p. 200-201° C.). The crude product was light 
               
               
                 brown, after recrystallization from 96% ethanol, it melted at 200-201° C. 
               
               
                 (white crystals). This product was characterized by IR and by 
               
               
                 determination of nitrogen content (Kjeldahl). 
               
             
          
           
               
                 Yield 
                 89.5% 
                 (crude) 
               
               
                   
               
             
          
         
       
     
       Utility Example 5 
       [0086]    
       
         
               
             
               
               
               
             
               
             
               
               
               
             
               
             
               
               
               
             
           
               
                   
               
               
                   
               
               
                 N,N,N′,N′-tetramethylterephthaldiamide (method 3) 
               
               
                   
               
             
             
               
                 Starting Materials 
               
             
          
           
               
                 Dimethyl terephthalate 
                 1.0 
                 mol 
               
               
                 Anhydrous dimethylamine 
                 6.0 
                 mol 
               
               
                 Ethylene Glycol 
                 800 
                 mL 
               
             
          
           
               
                 Operating Conditions 
               
             
          
           
               
                 Pressure 
                 60 
                 psi 
               
               
                 Temperature/time regime 
                 92-108° 
                 C./6 h. 
               
               
                 Reaction Progress 
               
               
                 Not monitored. 
               
               
                 Work-up 
               
             
          
           
               
                 The reaction mass was allowed to cool, mixed with saturated 
               
               
                 aqueous sodium chloride solution and exhaustively extracted with 
               
               
                 chloroform. The pooled extracts were distilled to eliminate chloro- 
               
               
                 form and the residue was dried overnight at 70-80° C., melting at 
               
               
                 187-190° C. (literature m.p. 200-201° C.). Its purity was 98.3% 
               
               
                 (HPLC) and its identity was confirmed by IR and by determination of 
               
               
                 nitrogen content (Kjeldahl). 
               
             
          
           
               
                 Yield (Crude) 
                 91% 
                   
               
               
                 Yield (Recrystallized from 96% ethanol) 
                 68% 
               
               
                   
               
             
          
         
       
     
       Utility Example 6 
       [0087]    
       
         
               
             
               
             
               
               
               
             
               
             
               
               
               
             
               
             
               
               
               
             
           
               
                   
               
               
                   
               
               
                 N,N,N′,N′-tetramethylterephthaldiamide (method 4) 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                 Starting Materials 
               
             
          
           
               
                 Dimethyl terephthalate 
                 1.0 
                 mol 
               
               
                 Anhydrous dimethylamine 
                 6.0 
                 mol 
               
               
                 Ethylene Glycol 
                 800 
                 mL 
               
             
          
           
               
                 Operating Conditions 
               
             
          
           
               
                 Pressure 
                 5 
                 psi 
               
               
                 Temperature/time regime 
                 59-63° 
                 C./22.5 h 
               
               
                 Reaction Progress 
               
               
                 Monitored by HPLC 
               
               
                 Work-up 
               
             
          
           
               
                 Unreacted dimethylamine and by-product methanol were 
               
               
                 eliminated by distillation at atmospheric pressure. The residue was cooled 
               
               
                 at 0-5° C., and filtered, the filter cake washed with cold acetone, drained 
               
               
                 and dried overnight at 100° C. 138.5 g. of crystals were obtained, with a 
               
               
                 purity of 98.8% (HPLC). The filtrate (1063 g.) contained 4.2% (w/w) 
               
               
                 tetramethylterephthaldiamide (44.7 g.) 
               
             
          
           
               
                 Yield (Total) 
                 83% 
                   
               
               
                 Yield (Isolated) 
                 63% 
               
               
                   
               
             
          
         
       
     
       Utility Example 7 
       [0088]    
       
         
               
             
               
             
               
               
               
             
               
             
               
               
               
             
               
             
               
               
               
             
           
               
                   
               
               
                   
               
               
                 N,N,N′,N′-tetramethylterephthaldiamide (method 5) 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                 Starting Materials 
               
             
          
           
               
                 Dimethyl terephthalate 
                 1.726 
                 mol 
               
               
                 Anhydrous dimethylamine 
                 6 
                 mol 
               
               
                 Ethylene Glycol 
                 685 
                 mL 
               
             
          
           
               
                 Operating Conditions 
               
             
          
           
               
                 Pressure 
                 35 
                 psi 
               
               
                 Temperature/time regime 
                 58-62° 
                 C./13 h 
               
               
                 Reaction Progress 
               
               
                 Not monitored. 
               
               
                 Work-up 
               
             
          
           
               
                 The reaction mass was allowed to cool, kept for a couple of hours 
               
               
                 ay 0-5° C. and filtered. The filter cake was washed with cold acetone, 
               
               
                 drained and dried overnight at 70-80° C. 266.3 g. of cream-colored 
               
               
                 crystals were obtained. 
               
             
          
           
               
                 Yield 
                 70.1% 
                 (isolated) 
               
               
                   
               
             
          
         
       
     
       Utility Example 8 
       [0089]    
       
         
               
             
               
             
               
               
               
             
               
             
               
               
               
             
               
             
           
               
                   
               
               
                   
               
               
                 N,N,N′,N′-tetramethylterephthaldiamide (method 6) 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                 Starting Materials 
               
             
          
           
               
                 Dimethyl terephthalate 
                 3 × 1.185 
                 mol 
               
               
                 Anhydrous dimethylamine 
                 3 × 6 
                 mol 
               
               
                 Ethylene Glycol 
                 1 
                 mL 
               
             
          
           
               
                 Operating Conditions 
               
             
          
           
               
                 Pressure 
                 10-11 
                 psi (first cycle) 
               
               
                   
                 8-13 
                 psi (second cycle) 
               
               
                   
                 7-10 
                 psi (third cycle) 
               
               
                 Temperature/time regime 
                 58-63° 
                 C./12 h 10 min (first cycle) 
               
               
                   
                 59-68° 
                 C./11 h (second cycle) 
               
               
                   
                 60-62° 
                 C./18 h 15 min (third cycle) 
               
               
                 Reaction Progress 
               
               
                 Monitored by HPLC. 
               
               
                 Work-up 
               
             
          
           
               
                 At the end of each cycle the reaction mixture was distilled at 
               
               
                 atmospheric pressure in order to eliminate the excess dimethylamine and 
               
               
                 by-product methanol. The residue was subjected to “clarification” by 
               
               
                 treating it with activated charcoal and celite while hot and then fil- 
               
               
                 tering. The filtrate was cooled at 0-5° C. and stirred during several 
               
               
                 hours, the precipitate separated by filtration, washed with cold ace- 
               
               
                 tone or cold isopropyl alcohol, drained and the filter cake dried over- 
               
               
                 night at 80-100° C. 
               
               
                 Yield 
               
               
                 First cycle gave an isolated yield of 67.3% 
               
               
                 Second cycle gave an isolated yield of 67.5% 
               
               
                 Third cycle gave an isolated yield of 84.5% 
               
               
                 Global yield 81.3% 
               
               
                 This product was 99.6% pure by HPLC. 
               
               
                   
               
             
          
         
       
     
       Comparative Example 4 
       [0090]    
       
         
               
             
               
               
             
               
               
               
               
             
               
               
             
               
               
               
               
             
           
               
                   
               
               
                   
               
               
                 N,N,N′,N′-tetramethylterephthaldiamide 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                   
                 Starting Materials 
               
             
          
           
               
                   
                 Dimethyl terephthalate 
                 1.0 
                 mol 
               
               
                   
                 Anhydrous dimethylamine 
                 6.0 
                 mol 
               
               
                   
                 N,N-dimethylformamide 
                 800 
                 mL 
               
             
          
           
               
                   
                 Operating Conditions 
               
             
          
           
               
                   
                 Pressure 
                 120 
                 psi 
               
               
                   
                 Temperature/time regime 
                 93-101° 
                 C./5.3 h.; then 
               
               
                   
                   
                 98-102° 
                 C./8.4 h. 
               
               
                   
                 Reaction Progress 
               
               
                   
                 Not monitored 
               
               
                   
                 Yield 
                 Less than 5% 
               
               
                   
                   
               
             
          
         
       
     
       Comparative Example 5 
       [0091]    
       
         
               
             
               
             
               
               
               
             
               
             
               
               
               
             
               
             
               
               
               
             
           
               
                   
               
               
                   
               
               
                 N,N,N′,N′-tetramethylterephthaldiamide 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                 Starting Materials 
               
             
          
           
               
                 Dimethyl terephthalate 
                 1.0 
                 mol 
               
               
                 Anhydrous dimethylamine 
                 10.3 
                 mol 
               
               
                 Methanol 
                 300 
                 mL 
               
             
          
           
               
                 Operating Conditions 
               
             
          
           
               
                 Pressure 
                 140 
                 psi 
               
               
                 Temperature/time regime 
                 88-100° 
                 C./5.5 h 
               
               
                 Reaction Progress 
               
               
                 Not monitored 
               
               
                 Work-up 
               
             
          
           
               
                 The reactions mixture was allowed to cool, diluted with water, 
               
               
                 saturated with sodium chloride, heated at 70-80° C. over 30 minutes, 
               
               
                 cooled and exhaustively extracted with chloroform, the solvent evaporated 
               
               
                 form the combined extracts and the residue dried overnight at 70-80° C. 
               
             
          
           
               
                 Yield 
                 22% 
               
               
                   
               
             
          
         
       
     
       Comparative Example 6 
       [0092]    
       
         
               
             
               
             
               
               
               
             
               
             
               
               
             
               
               
               
             
               
             
               
               
               
             
           
               
                   
               
               
                   
               
               
                 N,N,N′,N′-tetramethylterephthaldiamide 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                 Starting Materials 
               
             
          
           
               
                 Dimethyl terephthalate 
                 0.5 
                 mol 
               
               
                 Anhydrous dimethylamine, 
                 60% 
                 w/w 5 mol 
               
             
          
           
               
                 Operating Conditions 
               
             
          
           
               
                 Pressure 
                 Atmosphere 
               
             
          
           
               
                 Temperature/time regime 
                 Reflux/18 
                 h. 
               
               
                 Reaction Progress 
               
             
          
           
               
                 Monitored by TLC: Kodak silica gel TLC plates with fluorescent 
               
               
                 indicator, benzene-acetone-ethylacetate (34.5:61.5:4.0) 
               
               
                 Work-up 
               
               
                 Most of the excess dimethylamine was removed by heating, 
               
               
                 sodium chloride was added until a saturated solution was obtained. 
               
               
                 The product was extracted exhaustively with chloroform, the 
               
               
                 chloroform eliminated from the extract by evaporation and the residue 
               
               
                 dried overnight at 70-80 An off-white solid were obtained (m.p. 197- 
               
               
                 198° C.) (literature m.p. 200-201° C.) 
               
             
          
           
               
                 Yield 
                 45.5% 
               
               
                   
               
             
          
         
       
     
       Comparative Example 7 
       [0093]    
       
         
               
             
               
             
               
               
               
             
               
             
               
               
               
             
               
             
               
               
               
             
           
               
                   
               
               
                   
               
               
                 N,N,N′,N′-tetramethylterephthaldiamide 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                 Starting Materials 
               
             
          
           
               
                 Dimethyl terephthalate 
                 0.5 
                 mol 
               
               
                 Anhydrous dimethylamine 
                 11.1 
                 mol 
               
             
          
           
               
                 Operating Conditions 
               
             
          
           
               
                 Pressure 
                 125 
                 psi 
               
               
                 Temperature/time regime 
                 64-70° 
                 C./9 h. 
               
               
                 Reaction Progress 
               
               
                 Not monitored 
               
               
                 Work-up 
               
             
          
           
               
                 The reaction mixture was quenched with water, excess 
               
               
                 dimethylamine evaporated by heating at 70-80° C. during 1 h, and 
               
               
                 the product separated by exhaustive chloroform extraction. The 
               
               
                 chloroform was eliminated by distillation from the extract and 
               
               
                 the residue was dried overnight at 70-75° C. 
               
               
                 Note: an insoluble solid by-product was separated form the 
               
               
                 reaction mixture. Its properties matched those of 4-carboxy-N,N- 
               
               
                 dimethylbenzamide 
               
             
          
           
               
                 Yield 
                 44.5% 
               
               
                   
               
             
          
         
       
     
       Utility Example 9 
       [0094]    
       
         
               
             
               
             
               
               
               
             
               
               
             
               
               
               
             
               
             
               
               
             
               
               
               
             
               
             
               
               
               
             
           
               
                   
               
               
                   
               
               
                 2-Furancarboxamide 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                 Starting Materials 
               
             
          
           
               
                 Ethyl-2-Furancarboxylate 
                 0.5 
                 mol 
               
             
          
           
               
                 Ammonia (gas) 
                 Excess, bubbled through system 
               
             
          
           
               
                 Ethylene glycol 
                 150 
                 g. 
               
             
          
           
               
                 Operating Conditions 
               
             
          
           
               
                 Pressure 
                 Atmospheric 
               
             
          
           
               
                 Temperature/time regime 
                 48-49° 
                 C./12 h. 
               
               
                 Work-up 
               
             
          
           
               
                 One liter of water was added, pH was adjusted to 6.5-7.0 with 10% 
               
               
                 aqueous HCl, the aqueous solution was extracted with chloroform (5 × 
               
               
                 100 mL), the organic phase was separated and the chloroform eliminated 
               
               
                 by distillation at atmospheric pressure leaving 15 g. of a cream-colored 
               
               
                 residue, m.p. 141.8-142.7° C. 
               
               
                 The aqueous mother liquor was concentrated to 600 mL by 
               
               
                 evaporation, saturated with sodium chloride, extracted with chloroform 
               
               
                 (5 × 100 mL) and the extract treated as above, yielding another crop 
               
               
                 of cream-colored crystals. (15 g, m.p. 141.7-142.8° C.) 
               
             
          
           
               
                 Yield 
                 51% 
               
               
                   
               
             
          
         
       
     
       Utility Example 10 
       [0095]    
       
         
               
             
               
             
               
               
               
             
               
               
             
               
               
               
             
               
             
               
               
             
               
               
               
             
               
             
               
               
               
             
           
               
                   
               
               
                   
               
               
                 1-Naphthalenecarboxamide 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                 Starting Materials 
               
             
          
           
               
                 Ethyl-1-Naphthalenecarboxylate 
                 0.1 
                 mol 
               
             
          
           
               
                 Ammonia (gas) 
                 Excess, bubbled through system 
               
             
          
           
               
                 Ethylene glycol 
                 100 
                 g. 
               
               
                 Sodium methoxide (catalyst) 
                 3.0 
                 g. 
               
             
          
           
               
                 Operating Conditions 
               
             
          
           
               
                 Pressure 
                 Atmospheric 
               
             
          
           
               
                 Temperature/time regime 
                 35° 
                 C./20 h.; then 
               
               
                   
                 70-75° 
                 C./8 h. 
               
               
                 Reaction Progress 
               
               
                 Monitored by TLC 
               
               
                 Work-up 
               
             
          
           
               
                 The reaction mixture was allowed to cool to room temperature, 
               
               
                 1200 mL of water added, the solution&#39;s pH adjusted to 6.5 using 10% 
               
               
                 aqueous HCl, and allowed to cool at room temperature. The solid that 
               
               
                 precipitated was separated by filtration under reduced pressure, washed 
               
               
                 with cold water, dispersed into 300 mL anhydrous ethanol, recovered by 
               
               
                 filtration under reduced pressure and dried. 6.0 g. of yellowish powdery 
               
               
                 crystals were obtained, m.p. 206-206.8° C. (literature 202° C.) 
               
             
          
           
               
                 Yield 
                 35% 
               
               
                   
               
             
          
         
       
     
       Utility Example 11 
       [0096]    
       
         
               
             
               
             
               
               
               
             
               
             
               
               
             
               
               
               
             
               
             
               
               
               
             
           
               
                   
               
               
                   
               
               
                 N,N-Dimethylbenzamide 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                 Starting Materials 
               
             
          
           
               
                 Methyl benzoate 
                 0.5 
                 mol 
               
               
                 DIM-CARB 
                 2.5 
                 mol 
               
               
                 (Dimethylammonium 
               
               
                 N,N-Dimethylcarbamate) 
               
               
                 Ethylene glycol 
                 200 
                 mL 
               
               
                 Tetra iso-propyl 
                 0.1 
                 mol 
               
               
                 titanate (catalyst) 
               
             
          
           
               
                 Operating Conditions 
               
             
          
           
               
                 Pressure 
                 Atmospheric 
               
             
          
           
               
                 Temperature/time regime 
                 60-65° 
                 C./6 h.; then 
               
               
                   
                 72-75° 
                 C./24 h. 
               
               
                 Reaction Progress 
               
               
                 Monitored by TLC 
               
               
                 Work-up 
               
             
          
           
               
                 The unreacted DIM-CARB was eliminated by distillation at 
               
               
                 atmospheric pressure, 1500 ml water added, pH adjusted to 6.5 with 10% 
               
               
                 aqueous HCl and the solution thoroughly extracted with chloroform. 
               
               
                 Chloroform was eliminated from extract by distillation at atmospheric 
               
               
                 pressure, and the residue distilled under reduced pressure yielding 29.5 
               
               
                 g. of pure product (only one spot by thin layer chromatography) 
               
             
          
           
               
                 Yield 
                 40% 
               
               
                   
               
             
          
         
       
     
       Utility Example 12 
       [0097]    
       
         
               
             
               
             
               
               
               
             
               
               
             
               
               
               
             
               
             
               
               
             
               
               
               
             
               
             
               
               
               
             
           
               
                   
               
               
                   
               
               
                 Terephthaldiamide (Method 1) 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                 Starting Materials 
               
             
          
           
               
                 Dimethyl Terephthalate 
                 0.1 
                 mol 
               
             
          
           
               
                 Ammonia (gas) 
                 Excess, bubbled through system 
               
             
          
           
               
                 Magnesium Methoxide (catalyst) 
                 0.027 
                 mol 
               
               
                 Ethylene Glycol 
                 300 
                 mL 
               
             
          
           
               
                 Operating Conditions 
               
             
          
           
               
                 Pressure 
                 Atmospheric 
               
             
          
           
               
                 Temperature/time regime 
                 Room temperature/1 
                 h.; 
               
               
                   
                 then 80° 
                 C./24 h. 
               
               
                 Reaction Progress 
               
               
                 Monitored by TLC 
               
               
                 Work-up 
               
             
          
           
               
                 The reaction mixture was cooled to room temperature, 1800 mL 
               
               
                 water added, pH adjusted to 3 with 50% aqueous sulfuric acid. The 
               
               
                 system was heated to 70-80° C. and maintained at that temperature during 
               
               
                 30 minutes, cooled to room temperature and filtered under reduced 
               
               
                 pressure. The filter cake was washed thoroughly with water, drained and 
               
               
                 dried at 70-75° C. overnight. 16.3 g. of white, powdery crystals were 
               
               
                 obtained, m.p. 322.3-323.8° C. (Literature 330° C.) 
               
             
          
           
               
                 Yield 
                 99% 
               
               
                   
               
             
          
         
       
     
       Utility Example 13 
       [0098]    
       
         
               
             
               
             
               
               
               
             
               
             
               
               
             
               
               
               
             
               
             
               
               
               
             
           
               
                   
               
               
                   
               
               
                 Terephthaldiamide (Method 2) 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                 Starting Materials 
               
             
          
           
               
                 Dimethyl Terephthalate 
                 0.1 
                 mol 
               
               
                 Ammonium Carbonate 
                 2.0 
                 mol 
               
               
                 Ethylene Glycol 
                 350 
                 mL 
               
             
          
           
               
                 Operating Conditions 
               
             
          
           
               
                 Pressure 
                 Atmospheric 
               
             
          
           
               
                 Temperature/time regime 
                 75-80° 
                 C./40 h. 
               
               
                 Reaction Progress 
               
               
                 Monitored by TLC 
               
               
                 Work-up 
               
             
          
           
               
                 The reaction mixture was cooled to 20° C., 1.5 L water added, pH 
               
               
                 adjusted to 6 with concentrated aqueous hydrochloric acid, cooled to 20° 
               
               
                 C. and filtered under reduced pressure. The filter cake was washed with 
               
               
                 200 mL water, dried at 70-80° C. overnight, dispersed in 1 L methanol 
               
               
                 (absolute) at 70-75° C. during 30 minutes, and filtered under reduced 
               
               
                 pressure. 5.8 g. of white crystals were obtained (only one spot was 
               
               
                 observed by TLC) 
               
             
          
           
               
                 Yield 
                 35% 
               
               
                   
               
             
          
         
       
     
       Utility Example 14 
       [0099]    
       
         
               
             
               
             
               
               
               
             
               
             
               
               
             
               
               
               
             
               
             
               
               
               
             
           
               
                   
               
               
                   
               
               
                 Terephthaldiamide (Method 3) 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                 Starting Materials 
               
             
          
           
               
                 Dimethyl terephthalate 
                 0.1 
                 mol 
               
               
                 Urea 
                 4.0 
                 mol 
               
               
                 Ethylene Glycol 
                 350 
                 mL 
               
             
          
           
               
                 Operating Conditions 
               
             
          
           
               
                 Pressure 
                 Atmospheric 
               
             
          
           
               
                 Temperature/time regime 
                 120-125° 
                 C./30 h. 
               
               
                 Reaction Progress 
               
               
                 Monitored by TLC 
               
               
                 Work-up 
               
             
          
           
               
                 The reaction mixture was cooled to room temperature, 1 L water 
               
               
                 added, the pH adjusted to 7 with concentrated aqueous hydrochloric acid, 
               
               
                 heated to 80-85° C. and maintained at this temperature during 30 minutes. 
               
               
                 Then it was slowly cooled to room temperature, filtered under reduced 
               
               
                 pressure; the filter cake was washed with 200 mL cold water, drained, and 
               
               
                 dried at 70-80° C. during 24 h. 12.0 g. of white powdery crystals were 
               
               
                 obtained, m.p. 329.3-330.8° C. (literature m.p. 330° C.) 
               
             
          
           
               
                 Yield 
                 73% 
               
               
                   
               
             
          
         
       
     
       Utility Example 15 
       [0100]    
       
         
               
             
               
             
               
               
               
             
               
             
               
               
             
               
               
               
             
               
             
               
               
               
             
               
             
               
               
               
             
           
               
                   
               
               
                   
               
               
                 Barbituric acid 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                 Starting Materials 
               
             
          
           
               
                 Diethyl malonate 
                 0.5 
                 mol 
               
               
                 Urea 
                 0.55 
                 mol 
               
               
                 Sodium methoxide (catalyst) 
                 0.5 
                 mol 
               
               
                 Ethylene Glycol 
                 223 
                 g. 
               
             
          
           
               
                 Operating Conditions 
               
             
          
           
               
                 Pressure 
                 Atmospheric 
               
             
          
           
               
                 Temperature/time regime 
                 110° 
                 C./6 h. 
               
               
                 Reaction Progress 
               
             
          
           
               
                 Monitored by TLC using Merck&#39;s silica gel plates, benzene- 
               
               
                 methanol (1:1) 
               
             
          
           
               
                 Work-up 
                   
                   
               
             
          
           
               
                 The reaction mixture was cooled to 60° C., diluted with 500 mL 
               
               
                 water at 50° C., made acidic (to a blue color with congo red indicator) 
               
               
                 by addition of 55.8 g. concentrated aqueous hydrochloric acid, refri- 
               
               
                 gerated overnight and filtered. The filter cake was washed with 50 mL 
               
               
                 cold (10° C.) water and dried at 90° C. during 4 h. 44.6 g, of white 
               
               
                 crystals, m.p. 245° C. (dec.) were obtained (literature 248° C. “with 
               
               
                 some decomposition”) 
               
             
          
           
               
                 Yield 
                 70% 
               
               
                   
               
             
          
         
       
     
       Utility Example 16 
       [0101]    
       
         
               
             
               
             
               
               
               
             
               
             
               
               
             
               
               
               
             
               
             
               
               
               
             
               
             
               
               
               
             
           
               
                   
               
               
                   
               
               
                 N,N′-bis(4-hydroxyphenyl) oxamide (Method 1) 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                 Starting Materials 
               
             
          
           
               
                 N-(4-hydroxyphenyl) oxamate 
                 0.25 
                 mol 
               
               
                 p-Aminophenol 
                 0.25 
                 mol 
               
               
                 Ethylene Glycol 
                 150 
                 g. 
               
             
          
           
               
                 Operating Conditions 
               
             
          
           
               
                 Pressure 
                 Atmospheric 
               
             
          
           
               
                 Temperature/time regime 
                 80° 
                 C./5 h.; then 
               
               
                   
                 100° 
                 C./1 h. 
               
               
                 Reaction Progress 
               
             
          
           
               
                 Monitored by TLC using Merck&#39;s silica gel plates, benzene-acetone 
               
               
                 (3:1). 
               
             
          
           
               
                 Work-up 
                   
                   
               
             
          
           
               
                 The reaction mixture was allowed to cool, quenched with 800 mL 
               
               
                 water and filtered. The filter cake was washed with 200 mL water, then 
               
               
                 with 500 mL cold acetone, drained and dried overnight at 80° C. 52.0 g. 
               
               
                 of product were obtained, m.p. 350° C. (dec) 
               
             
          
           
               
                 Yield 
                 76% 
               
               
                   
               
             
          
         
       
     
       Utility Example 17 
       [0102]    
       
         
               
             
               
             
               
               
               
             
               
             
               
               
             
               
               
               
             
               
             
               
               
               
             
               
             
               
               
               
             
           
               
                   
               
               
                   
               
               
                 N,N′-bis(4-hydroxyphenyl) oxamide (Method 2) 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                 Starting Materials 
               
             
          
           
               
                 Diethyl oxalate 
                 0.15 
                 mol 
               
               
                 p-Aminophenol 
                 0.30 
                 mol 
               
               
                 Ethylene Glycol 
                 111 
                 g. 
               
             
          
           
               
                 Operating Conditions 
               
             
          
           
               
                 Pressure 
                 Atmospheric 
               
             
          
           
               
                 Temperature/time regime 
                 90° 
                 C./4 h. 
               
               
                 Reaction Progress 
               
             
          
           
               
                 Monitored by TLC using Merck&#39;s silica gel plates, benzene-acetone 
               
               
                 (3:1). 
               
             
          
           
               
                 Work-up 
                   
                   
               
             
          
           
               
                 The reaction mixture was allowed to cool, quenched with 400 mL 
               
               
                 water and filtered. The filter cake was washed with water, then with 
               
               
                 300 mL cold acetone, drained and dried overnight at 80° C. 25.8 g. 
               
               
                 of off-white crystals were obtained, m.p. 350° C. (dec) 
               
             
          
           
               
                 Yield 
                 96% 
               
               
                   
               
             
          
         
       
     
       Utility Example 18 
       [0103]    
       
         
               
             
               
             
               
               
               
             
               
             
               
               
             
               
               
               
             
               
             
               
               
               
             
               
             
               
               
               
             
           
               
                   
               
               
                   
               
               
                 N-(4-hydroxyphenyl) oxamic acid, 2-hydroxyethyl ester 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                 Starting Materials 
               
             
          
           
               
                 Diethyl oxalate 
                 0.9 
                 mol 
               
               
                 p-Aminophenol 
                 0.3 
                 mol 
               
               
                 Ethylene Glycol 
                 446 
                 g. 
               
             
          
           
               
                 Operating Conditions 
               
             
          
           
               
                 Pressure 
                 Atmospheric 
               
             
          
           
               
                 Temperature/time regime 
                 80-85° 
                 C./4 h. 
               
               
                 Reaction Progress 
               
             
          
           
               
                 Monitored by TLC using Merck&#39;s silica gel plates, benzene-acetone 
               
               
                 (3:1). 
               
             
          
           
               
                 Work-up 
                   
                   
               
             
          
           
               
                 The reaction mixture was allowed to cool, extracted with 2 × 200 
               
               
                 mL diethyl ether, diluted to a total volume of 3 L with water and stored 
               
               
                 at room temperarute for 2 h. Later it was filtered, the filter cake 
               
               
                 drained and dried at 80° C. overnight. 26.3 g. of purple crystals (m.p. 
               
               
                 160-162° C.) were obtained 
               
             
          
           
               
                 Yield 
                 39% 
               
               
                   
               
             
          
         
       
     
       Utility Example 19 
       [0104]    
       
         
               
             
               
             
               
               
               
             
               
             
               
               
             
               
               
               
             
               
             
               
               
               
             
               
             
               
               
               
             
           
               
                   
               
               
                   
               
               
                 N, N′-Diphenyloxamide 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                 Starting Materials 
               
             
          
           
               
                 Diethyl oxalate 
                 0.11 
                 mol 
               
               
                 Aniline 
                 0.88 
                 mol 
               
               
                 Ethylene Glycol 
                 150 
                 g. 
               
             
          
           
               
                 Operating Conditions 
               
             
          
           
               
                 Pressure 
                 Atmospheric 
               
             
          
           
               
                 Temperature/time regime 
                 120-125° 
                 C./6 h. 
               
               
                 Reaction Progress 
               
             
          
           
               
                 Monitored by observing changes in reaction mass. 
               
             
          
           
               
                 Work-up 
                   
                   
               
             
          
           
               
                 The reaction mixture was cooled to 5-10° C., and filtered. Later the 
               
               
                 filter cake was drained, dispersed in 100 mL cold ethanol, filtered, 
               
               
                 the filter cacke washed with 100 mL cold ethanol, drained, and dried 
               
               
                 at 70-80° C. overnight. 25.4 g. of yellowish crystals, m.p. 252-253° C. 
               
               
                 were obtained (lit m.p. 252-254° C.) 
               
             
          
           
               
                 Yield 
                 96% 
               
               
                   
               
             
          
         
       
     
       Utility Example 20 
       [0105]    
       
         
               
             
               
             
               
               
               
             
               
             
               
               
             
               
               
               
             
               
             
               
               
               
             
               
             
               
               
               
             
           
               
                   
               
               
                   
               
               
                 N-(2-hydroxyethyl)-N′-(4-hydroxyphenyl) oxamide 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                 Starting Materials 
               
             
          
           
               
                 Ethyl N-(4-hydroxyphenyl) oxamate 
                 0.25 
                 mol 
               
               
                 Monoethanolamine 
                 0.25 
                 mol 
               
               
                 Ethylene Glycol 
                 150 
                 g. 
               
             
          
           
               
                 Operating Conditions 
               
             
          
           
               
                 Pressure 
                 Atmospheric 
               
             
          
           
               
                 Temperature/time regime 
                 80-85° 
                 C./1 h. 
               
               
                 Reaction Progress 
               
             
          
           
               
                 Monitored by TLC using Merck&#39;s silica gel plates, benzene- 
               
               
                 dimethylformamide (25:4). 
               
             
          
           
               
                 Work-up 
                   
                   
               
             
          
           
               
                 The reaction mass was allowed to cool to room temperature (20 
               
               
                 ° C.) Later it was filtered, the filter cake drained, washed with cold water, 
               
               
                 drained again and dried at 80° C. overnight. 51.8 g. of off-white crystals 
               
               
                 (m.p. 234-235° C.) were obtained 
               
             
          
           
               
                 Yield 
                 93% 
               
               
                   
               
             
          
         
       
     
       Utility Example 21 
       [0106]    
       
         
               
             
               
             
               
               
               
             
               
             
               
               
             
               
               
               
             
               
             
               
               
               
             
               
             
               
               
               
             
           
               
                   
               
               
                   
               
               
                 N,N′-bis (2-hydroxyethyl) oxamide 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                 Starting Materials 
               
             
          
           
               
                 Diethyl oxalate 
                 0.25 
                 mol 
               
               
                 Monoethanolamine 
                 0.5 
                 mol 
               
               
                 Ethylene Glycol 
                 250 
                 g. 
               
             
          
           
               
                 Operating Conditions 
               
             
          
           
               
                 Pressure 
                 Atmospheric 
               
             
          
           
               
                 Temperature/time regime 
                 79-80° 
                 C./3 h. 
               
               
                 Reaction Progress 
               
             
          
           
               
                 Monitored by TLC using Merck&#39;s silica gel plates and benzene- 
               
               
                 dimethylformamide (25:4). 
               
             
          
           
               
                 Work-up 
                   
                   
               
             
          
           
               
                 The reaction mass was allowed to cool to room temperature, 
               
               
                 refrigerated (0° C.) and stirred for five minutes before filtration. The filter 
               
               
                 cake was drained, dried at 70-80° C. overnight, dispersed in ethanol (3 
               
               
                 parts ethanol to 1 part solid), the dispersion heated to boiling, cooled and 
               
               
                 filtered. The filter cake was washed with cold ethanol, drained and dried 
               
               
                 overnight at 60-80° C. 38.2 g. of white crystals (m.p. 169.9-170.3° C.) 
               
               
                 were obtained (literature m.p. 166-169° C.) 
               
             
          
           
               
                 Yield 
                 87% 
               
               
                   
               
             
          
         
       
     
       Utility Example 22 
       [0107]    
       
         
               
             
               
             
               
               
               
             
               
             
               
               
             
               
               
               
             
               
             
               
               
               
             
           
               
                   
               
               
                   
               
               
                 p-acetamidobenzoic acid 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                 Starting Materials 
               
             
          
           
               
                 Ethyl Acetate 
                 0.75 
                 mol 
               
               
                 Sodium p-aminobenzoate 
                 0.25 
                 mol 
               
               
                 Sodium methoxide (catalyst) 
                 0.25 
                 mol 
               
               
                 Ethylene Glycol 
                 150 
                 g. 
               
             
          
           
               
                 Operating Conditions 
               
             
          
           
               
                 Pressure 
                 Atmospheric 
               
               
                 Temperature/time regime 
                 75° C./8 h.; then 90° C./2 h.; 
               
               
                   
                 then 110° C./9 h.; then 120-125° 
               
               
                   
                 C./2.5 h.; then 135° C./4.5 h. 
               
             
          
           
               
                 Reaction Progress 
                   
                   
               
               
                 Monitored by TLC 
               
               
                 Work-up 
               
             
          
           
               
                 The reaction mass was allowed to cool to 40° C., transferred to a 
               
               
                 beaker, diluted with water to a total volume of 500 mL, pH adjusted to 
               
               
                 2-3 by addition of 51.3 g. concentrated hydrochloric acid, cooled to 
               
               
                 10° C., stirred during 30 min at that temperature and filtered. The 
               
               
                 filter cake was later drained, washed with 100 mL cold water, drained 
               
               
                 thoroughly and dried at 60-68° C. to constant weight. 21.5 g. of crys- 
               
               
                 tals (m.p. 258-259° C. (dec.))were obtained (literature 252° C.) 
               
             
          
           
               
                 Yield 
                 48% 
               
               
                   
               
             
          
         
       
     
       Utility Example 23 
       [0108]    
       
         
               
             
               
             
               
               
               
             
               
             
               
               
             
               
               
               
             
               
             
               
               
               
             
           
               
                   
               
               
                   
               
               
                 Phenacetin (method 1) 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                 Starting Materials 
               
             
          
           
               
                 Ethyl Acetate 
                 0.44 
                 mol 
               
               
                 p-phenetidine 
                 0.3 
                 mol 
               
               
                 Sodium methoxide (catalyst) 
                 0.1 
                 mol 
               
               
                 Ethylene Glycol 
                 150 
                 g. 
               
             
          
           
               
                 Operating Conditions 
               
             
          
           
               
                 Pressure 
                 Atmospheric 
               
             
          
           
               
                 Temperature/time regime 
                 106-110° 
                 C./3 h; 
               
               
                   
                 then 130° 
                 C./7 h. 
               
               
                 Reaction Progress 
               
               
                 Monitored by TLC 
               
               
                 Work-up 
               
             
          
           
               
                 The reaction mass was allowed to cool to room temperature, 
               
               
                 diluted with 250 mL water, stirred to control crystal size and filtered. 
               
               
                 The filter cake was then washed with 50 mL water, drained and dried to 
               
               
                 constant weight at 70-80° C. 31.6 g. of dark brown crystals were 
               
               
                 obtained, melting at 133.9-135.1° C. (literature 134-135° C.). 
               
             
          
           
               
                 Yield 
                 59% 
               
               
                   
               
             
          
         
       
     
       Utility Example 24 
       [0109]    
       
         
               
             
               
             
               
               
               
             
               
             
               
               
             
               
               
               
             
               
             
               
               
               
             
           
               
                   
               
               
                   
               
               
                 Phenacetin (method 2) 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                 Starting Materials 
               
             
          
           
               
                 Ethylene glycol diacetate 
                 0.25 
                 mol 
               
               
                 p-phenetidine 
                 0.25 
                 mol 
               
               
                 Sodium methoxide (catalyst) 
                 0.1 
                 mol 
               
               
                 Ethylene Glycol 
                 150 
                 g. 
               
             
          
           
               
                 Operating Conditions 
               
             
          
           
               
                 Pressure 
                 Atmospheric 
               
             
          
           
               
                 Temperature/time regime 
                 120-125° 
                 C./3 h 
               
               
                 Reaction Progress 
               
               
                 Monitored by TLC 
               
               
                 Work-up 
               
             
          
           
               
                 The reaction mass was allowed to cool to room temperature, 
               
               
                 diluted with 200 mL water, stirred to control crystal size and filtered. 
               
               
                 The filter cake was then washed with 50 mL water, drained and dried to 
               
               
                 constant weight at 70-80° C. 33.4 g. of dark brown crystals were 
               
               
                 obtained, melting at 134-135.2° C. 
               
             
          
           
               
                 Yield 
                 75% 
               
               
                   
               
             
          
         
       
     
       Utility Example 25 
       [0110]    
       
         
               
             
               
             
               
               
               
             
               
             
               
               
             
               
               
               
             
               
             
               
               
               
             
           
               
                   
               
               
                   
               
               
                 Phenacetin (method 3) 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                 Starting Materials 
               
             
          
           
               
                 Triacetin 
                 0.2 
                 mol 
               
               
                 p-phenetidine 
                 0.2 
                 mol 
               
               
                 Sodium methoxide (catalyst) 
                 0.1 
                 mol 
               
               
                 Ethylene Glycol 
                 150 
                 g. 
               
             
          
           
               
                 Operating Conditions 
               
             
          
           
               
                 Pressure 
                 Atmospheric 
               
             
          
           
               
                 Temperature/time regime 
                 120-125° 
                 C./3 h 
               
               
                 Reaction Progress 
               
               
                 Monitored by TLC 
               
               
                 Work-up 
               
             
          
           
               
                 The reaction mass was allowed to cool to room temperature, 
               
               
                 diluted with 200 mL water, stirred for 30 minutes to control crystal 
               
               
                 size and filtered. The filter cake was then washed with 200 mL water, 
               
               
                 drained thoroughly and dried to constant weight at 70-80° C. 28.3 g. 
               
               
                 of dark brown crystals were obtained, melting at 134-135.5° C. 
               
             
          
           
               
                 Yield 
                 79% 
               
               
                   
               
             
          
         
       
     
       Utility Example 26 
       [0111]    
       
         
               
             
               
             
               
               
               
             
               
             
               
               
             
               
               
               
             
               
             
               
               
               
             
           
               
                   
               
               
                   
               
               
                 N-cyclohexylbenzamide 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                 Starting Materials 
               
             
          
           
               
                 Ethyl benzoate 
                 0.5 
                 mol (75 g) 
               
               
                 Cyclohexyylamine 
                 0.6 
                 mol (59.5 g) 
               
               
                 Sodium methoxide (catalyst) 
                 10 
                 g. 
               
               
                 Ethylene Glycol 
                 50 
                 g. 
               
             
          
           
               
                 Operating Conditions 
               
             
          
           
               
                 Pressure 
                 Atmospheric 
               
             
          
           
               
                 Temperature/time regime 
                 120° 
                 C./7 h; then 
               
               
                   
                 125° 
                 C./6 h. 
               
               
                 Reaction Progress 
               
               
                 Monitored by TLC 
               
               
                 Work-up 
               
             
          
           
               
                 The reaction mass was allowed to cool to room temperature, 
               
               
                 transferred to a beaker, diluted with 700 mL methanol and 300 mL water, 
               
               
                 its pH adjusted to 7 using a few milliliters of concentrated aqueous 
               
               
                 hydrochloric acid, stirred for one hour and filtered. The filter cake was 
               
               
                 then washed with water, drained and dried at 70-80° C. overnight. 32.5 g. 
               
               
                 of white crystals (m.p. 149.3-150.7° C.) were obtained (lit m.p. 148-149 
               
               
                 ° C.) 
               
             
          
           
               
                 Yield 
                 32% 
               
               
                   
               
             
          
         
       
     
       Utility Example 27 
       [0112]    
       
         
               
             
               
             
               
               
               
             
               
               
             
               
               
               
             
               
             
               
               
             
               
               
               
             
               
             
               
               
               
             
           
               
                   
               
               
                   
               
               
                 Palmitamide 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                 Starting Materials 
               
             
          
           
               
                 Methyl palmitate 
                 0.5 
                 mol (135 g) 
               
             
          
           
               
                 Ammonia 
                 Excess, bubbled through the 
               
               
                   
                 system. 
               
             
          
           
               
                 Sodium methoxide (catalyst) 
                 5 
                 g. 
               
               
                 Ethylene Glycol 
                 50 
                 g. 
               
             
          
           
               
                 Operating Conditions 
               
             
          
           
               
                 Pressure 
                 Atmospheric 
               
             
          
           
               
                 Temperature/time regime 
                 65° 
                 C./8 h. 
               
             
          
           
               
                 Reaction Progress 
               
               
                 Monitored by means of the qualitative ferric hydroxamate test for 
               
               
                 esters. 
               
               
                 Work-up 
               
               
                 The reaction mass was cooled, transfered to a beaker, diluted with 
               
               
                 500 mL methanol and 200 mL water, stirred for 30 minutes and 
               
               
                 filtered. The filter cake was then washed with water, drained and 
               
               
                 dried at 70-80° C. overnight. 116 g. of white powdery crystals 
               
               
                 (m.p. 102-103° C.) were obtained (literature m.p. 106-107° C.); 
               
               
                 the IR spectrum (KBr pellet) shows the “amide I Band” at 1647.42 
               
               
                 CM −1  and the “C—N Stretch” at 1421.72 CM −1 . 
               
             
          
           
               
                 Yield 
                 91% 
               
               
                   
               
             
          
         
       
     
       Utility Example 28 
       [0113]    
       
         
               
             
               
             
               
               
               
             
               
             
               
               
             
               
               
               
             
               
             
               
               
               
             
           
               
                   
               
               
                   
               
               
                 N,N-Diethylnicotinamide (Nikethamide) 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                 Starting Materials 
               
             
          
           
               
                 Ethyl nicotinate 
                 0.5 
                 mol 
               
               
                 Diethylamine 
                 1.5 
                 mol 
               
               
                 Sodium methoxide (catalyst) 
                 4.9 
                 g. 
               
               
                 Ethylene Glycol 
                 150 
                 g. 
               
             
          
           
               
                 Operating Conditions 
               
             
          
           
               
                 Pressure 
                 Atmospheric 
               
             
          
           
               
                 Temperature/time regime 
                 85° 
                 C./25 h. 
               
               
                 Reaction Progress 
               
               
                 Monitored by TLC 
               
               
                 Work-up 
               
             
          
           
               
                 The unreacted diethylamine was separated by distillation of the 
               
               
                 reaction mass at atmospheric pressure (70 mL of liquid were collected), 
               
               
                 the residue was transferred to a beaker, diluted with water to a total 
               
               
                 volume of 1200 mL, extracted with 5 × 100 mL chloroform and the 
               
               
                 combined organic phases distilled at atmospheric pressure to eliminate 
               
               
                 the solvent. The residue weighed 33.3 g.; its purity was found to be 98% 
               
               
                 by perchloric acid titration in glacial acetic acid. 
               
             
          
           
               
                 Yield 
                 37% 
               
               
                   
               
             
          
         
       
     
       Utility Example 29 
       [0114]    
       
         
               
             
               
             
               
               
               
             
               
             
               
               
             
               
               
               
             
               
             
               
               
               
             
           
               
                   
               
               
                   
               
               
                 m-chloroformanilide 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                 Starting Materials 
               
             
          
           
               
                 Ethyl formate 
                 1.5 
                 mol (111 g) 
               
               
                 m-chloraniline 
                 0.5 
                 mol (64 g) 
               
               
                 Sodium methoxide (catalyst) 
                 10 
                 g. 
               
               
                 Ethylene Glycol 
                 50 
                 g. 
               
             
          
           
               
                 Operating Conditions 
               
             
          
           
               
                 Pressure 
                 Atmospheric 
               
             
          
           
               
                 Temperature/time regime 
                 65-72° 
                 C./24 h. 
               
               
                 Reaction Progress 
               
             
          
           
               
                 Monitored by TLC: Merck&#39;s silica gel plates; benzene-methanol 
               
               
                 (20:3) 
               
               
                 Work-up 
               
               
                 The unreacted ester and the by-product ethanol (60 mL) were 
               
               
                 removed from the reaction mass by distillation at atmospheric pressure. 
               
               
                 The residue was allowed to cool, quenched with 200 mL water, its pH 
               
               
                 adjusted to 6 by adding concentrated aqueous hydrochloric acid (2-3 mL) 
               
               
                 and the mixture heated during 30 minutes. A biphasic system was 
               
               
                 obtained, the phases separated in a funnel and the organic (lower) phase 
               
               
                 was washed with 300 mL water and then cooled, yielding crystals that 
               
               
                 weighed 61.5 g and melted at 57-58.5° C. (literature 57-58° C.). 
               
             
          
           
               
                 Yield 
                 79% 
               
               
                   
               
             
          
         
       
     
       Utility Example 30 
       [0115]    
       
         
               
             
               
             
               
               
               
             
               
             
               
               
             
               
               
               
             
               
             
               
               
               
             
           
               
                   
               
               
                   
               
               
                 Ethyleneurea 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                 Starting Materials 
               
             
          
           
               
                 Urea 
                 0.25 
                 mol (15 g) 
               
               
                 Ethylenediamine 
                 0.25 
                 mol (15 g) 
               
               
                 Ethylene Glycol 
                 1.45 
                 mol (90 g) 
               
             
          
           
               
                 Operating Conditions 
               
             
          
           
               
                 Pressure 
                 Atmospheric 
               
             
          
           
               
                 Temperature/time regime 
                 115-117° 
                 C./4.5 h; then 
               
               
                   
                 140-145° 
                 C./4.5 h 
               
               
                 Reaction Progress 
               
             
          
           
               
                 Monitored by detection of evolved ammonia. 
               
               
                 Work-up 
               
               
                 Ethylene glycol was removed from the reaction mixture by 
               
               
                 distillation at about 18 mm Hg (pot Temperature 115-160° C.; vapor 
               
               
                 temperature 94-98° C.). The distillation residue, which solidified upon 
               
               
                 cooling to room temperature, was dispersed in 100 mL hot n-butanol, 
               
               
                 cooled and filtered. The filter cake was then drained and dried to constant 
               
               
                 weight. A second crop of crystals was harvested from the mother liquor 
               
               
                 the following day. Altogether, 10.7 g. were obtained, melting at 133° C. 
               
               
                 (literature 133-135° C. 
               
             
          
           
               
                 Yield 
                 50% 
               
               
                   
               
             
          
         
       
     
       Utility Example 31 
       [0116]    
       
         
               
             
               
             
               
               
               
             
               
             
               
               
             
               
               
               
             
               
             
               
               
               
             
           
               
                   
               
               
                   
               
               
                 3-methyl-1-phenyl-5-pyrazolone 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                 Starting Materials 
               
             
          
           
               
                 Ethyl acetoacetate 
                 0.192 
                 mol (25 g) 
               
               
                 Phenylhydrazine 
                 0.186 
                 mol (21 g) 
               
               
                 Ethylene Glycol 
                 1.8 
                 mol (111 g) 
               
             
          
           
               
                 Operating Conditions 
               
             
          
           
               
                 Pressure 
                 Atmospheric 
               
             
          
           
               
                 Temperature/time regime 
                 120° 
                 C./2 h 
               
               
                 Reaction Progress 
               
               
                 Monitored by TLC 
               
               
                 Work-up 
               
             
          
           
               
                 The reaction mass was allowed to cool to 40-45° C., quenched with 
               
               
                 100 mL water, left undisturbed during 30 minutes, stirred for 3 hours and 
               
               
                 filtered. The filter cake was washed with water, drained thoroughly and 
               
               
                 dried at 70° C. to constant weight. 29.2 g. of ochre-colored crystals (m.p. 
               
               
                 124.5-126.0° C.) were obtained. (Literature 127° C.) 
               
             
          
           
               
                 Yield 
                 91% 
               
               
                   
               
             
          
         
       
     
       Utility Example 32 
       [0117]    
       
         
               
             
               
             
               
               
               
             
               
             
               
               
             
               
               
               
             
               
             
               
               
               
             
           
               
                   
               
               
                   
               
               
                 N-(2-hydroxyethyl)-2-oxazolidinone 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                 Starting Materials 
               
             
          
           
               
                 Diethly carbonate 
                 1.1 
                 mol (130 g) 
               
               
                 Diethanolamine 
                 0.955 
                 mol (100 g) 
               
               
                 Ethylene Glycol 
                 230 
                 g. 
               
             
          
           
               
                 Operating Conditions 
               
             
          
           
               
                 Pressure 
                 Atmospheric 
               
             
          
           
               
                 Temperature/time regime 
                 98-103° 
                 C./12.5 h 
               
               
                 Reaction Progress 
               
             
          
           
               
                 Monitored by TLC and using a spot test for diethanolamine 
               
               
                 (sodium nitroferricyanide/acetaldehyde/aqueous sodium carbonate) 
               
               
                 Work-up 
               
               
                 By-product ethanol, excess diethyl carbonate and ethylene glycol 
               
               
                 (291 mL) were separated from product by distilling at atmospheric 
               
               
                 pressure first and then at about 20 mm Hg at 25° C. The product fraction 
               
               
                 weighed 123.9 g, (refraction index 1.482) (literature 1.483) 
               
             
          
           
               
                 Yield 
                 99% 
               
               
                   
               
             
          
         
       
     
       Utility Example 33 
       [0118]    
       
         
               
             
               
             
               
               
               
             
               
             
               
               
             
               
               
               
             
               
             
               
               
               
             
           
               
                   
               
               
                   
               
               
                 N,N′-bis-[tris-(hydroxymethyl)methyl-] oxamide 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                 Starting Materials 
               
             
          
           
               
                 Diethly Oxalate 
                 0.125 
                 mol 
               
               
                 tris(hydroxymethyl)aminomethane 
                 0.25 
                 mol 
               
               
                 Ethylene Glycol 
                 100 
                 g. 
               
             
          
           
               
                 Operating Conditions 
               
             
          
           
               
                 Pressure 
                 Atmospheric 
               
             
          
           
               
                 Temperature/time regime 
                 100-105° 
                 C./6 h. 
               
               
                 Reaction Progress 
               
               
                 Monitored by TLC 
               
               
                 Work-up 
               
             
          
           
               
                 The reaction mixture was cooled to 20° C., filtered under reduced 
               
               
                 pressure, the filter cake washed with 50 mL absolute ethanol, drained well 
               
               
                 and dried at 70-80° C. overnight. 34.0 g. of white crystals were obtained 
               
               
                 with m.p. 216-217° C. (literature 216-218° C.) 
               
             
          
           
               
                 Yield 
                 92% 
               
               
                   
               
             
          
         
       
     
       Utility Example 34 
       [0119]    
       
         
               
             
               
             
               
               
               
             
               
             
               
               
             
               
               
               
             
               
             
               
               
               
             
           
               
                   
               
               
                   
               
               
                 N-acetylglycine 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                 Starting Materials 
               
             
          
           
               
                 Ethyl Acetate 
                 0.5 
                 mol 
               
               
                 Sodium glycinate 
                 0.5 
                 mol 
               
               
                 Sodium methoxide (catalyst) 
                 0.25 
                 mol 
               
               
                 Ethylene Glycol 
                 100 
                 g. 
               
             
          
           
               
                 Operating Conditions 
               
             
          
           
               
                 Pressure 
                 Atmospheric 
               
             
          
           
               
                 Temperature/time regime 
                 75° 
                 C./10 h. 
               
               
                 Reaction Progress 
               
               
                 Monitored by TLC 
               
               
                 Work-up 
               
             
          
           
               
                 The reaction mixture was allowed to cool to room temperature, 300 
               
               
                 mL water added, pH adjusted to 2-3 by adding 50.8 g. concentrated 
               
               
                 aqueous hydrochloric acid, cooled to 10-15° C. and maintained at this 
               
               
                 temperature during 1 h. Later it was filtered, the filter cake washed with 
               
               
                 100 mL cold water, drained and dried overnight at 70-80° C. 30.3 g. of 
               
               
                 yellowish white crystals were obtained with m.p. (dec.) 204-205° C. 
               
               
                 (literature 206-208° C.) 
               
             
          
           
               
                 Yield 
                 52% 
               
               
                   
               
             
          
         
       
     
       Utility Example 35 
       [0120]    
       
         
               
             
               
             
               
               
               
             
               
             
               
               
             
               
               
               
             
               
             
               
               
               
             
               
             
               
               
               
             
           
               
                   
               
               
                   
               
               
                 Hippuric acid 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                 Starting Materials 
               
             
          
           
               
                 Methyl benzoate 
                 0.5 
                 mol 
               
               
                 Sodium glycinate 
                 0.5 
                 mol 
               
               
                 Ethylene Glycol 
                 100 
                 g. 
               
             
          
           
               
                 Operating Conditions 
               
             
          
           
               
                 Pressure 
                 Atmospheric 
               
             
          
           
               
                 Temperature/time regime 
                 114-127° 
                 C./5 h. 
               
               
                 Reaction Progress 
               
             
          
           
               
                 Monitored by TLC using Merck&#39;s silica gel plates and n-butanol: 
               
               
                 ethanol:water at 2:2:1 
               
             
          
           
               
                 Work-up 
                   
                   
               
             
          
           
               
                 The reaction mixture was diluted with 450 mL water, extracted with 
               
               
                 3 × 100 mL light petroleum ether, pH adjusted to 3.0 by addition of 53.5 
               
               
                 g. concentrated aqueous hydrochloric acid, cooled to 10° C. Then it was 
               
               
                 filtered under reduced pressure, the filter cake washed with 600 mL cold 
               
               
                 water, drained and dried overnight at 70-80° C. 52.2 g. of white crystals 
               
               
                 were obtained, m.p. 186-187° C. (literature 187-190° C.) 
               
             
          
           
               
                 Yield 
                 58% 
               
               
                   
               
             
          
         
       
     
       Utility Example 36 
       [0121]    
       
         
               
             
               
             
               
               
               
             
               
               
             
               
               
               
             
               
             
               
               
             
               
               
               
             
               
             
               
               
               
             
           
               
                   
               
               
                   
               
               
                 N,N′-bis(4-methoxyphenyl) oxamide 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                 Starting Materials 
               
             
          
           
               
                 Diethyl oxalate 
                 0.075 
                 mol 
               
               
                 p-Anisidine 
                 0.151 
                 mol 
               
             
          
           
               
                 Nitrogen 
                 Only for system inertization 
               
             
          
           
               
                 Ethylene Glycol 
                 75 
                 g. 
               
             
          
           
               
                 Operating Conditions 
               
             
          
           
               
                 Pressure 
                 Atmospheric 
               
             
          
           
               
                 Temperature/time regime 
                 120-125° 
                 C./9 h. 
               
               
                 Reaction Progress 
               
             
          
           
               
                 Monitored by TLC using Merck&#39;s silica gel plates, benzene-acetone 
               
               
                 (3:1). 
               
               
                 Work-up 
               
               
                 The reaction mixture was cooled at 10° C. and filtered. The filter 
               
               
                 cake was washed with cold methanol (120 mL), drained and dried at 90- 
               
               
                 95° C. overnight. 16.9 g. of cream-colored crystals, m.p. 266-267° C. 
               
               
                 were obtained (literature 270-271° C.) 
               
             
          
           
               
                 Yield 
                 75% 
               
               
                   
               
             
          
         
       
     
       Utility Example 37 
       [0122]    
       
         
               
             
               
             
               
               
               
             
               
             
               
               
             
               
               
               
             
               
             
               
               
               
             
           
               
                   
               
               
                   
               
               
                 N-Benzylbenzamide 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                 Starting Materials 
               
             
          
           
               
                 Ethyl benzoate 
                 0.5 
                 mol (75 g) 
               
               
                 benzylamine 
                 0.6 
                 mol (64 g) 
               
               
                 Sodium methoxide (catalyst) 
                 15 
                 g. 
               
               
                 Ethylene Glycol 
                 50 
                 g. 
               
             
          
           
               
                 Operating Conditions 
               
             
          
           
               
                 Pressure 
                 Atmospheric 
               
             
          
           
               
                 Temperature/time regime 
                 110-120° 
                 C./18 h. 
               
               
                 Reaction Progress 
               
             
          
           
               
                 Monitored by TLC: Merck&#39;s silica gel plates; benzene-methanol 
               
               
                 (20:3) 
               
               
                 Work-up 
               
               
                 The reaction mass was allowed to cool to 50° C., transferred to a 
               
               
                 beaker, quenched with 400 mL. water and 150 mL methanol, stirred 
               
               
                 during 15 minutes, its pH adjusted to 3 by adding 20 mL of concentrated 
               
               
                 aqueous hydrochloric acid, cooled and filtered. The filter cake was then 
               
               
                 drained, washed with 400 mL water, drained again and dried overnight at 
               
               
                 70-75° C. 103 g. of white crystals (m.p. 102-103° C.) were obtained 
               
               
                 (literature m.p. 105° C.) 
               
             
          
           
               
                 Yield 
                 97.5%