Process for preparing beta-keto nitriles and salts thereof

Abstract

A process for preparing β-keto nitrites or salts thereof is provided by reacting a nitrile with a carboxylic ester in the presence of an alkali metal alkoxide or alkaline earth metal alkoxide. Alcohol formed as a by-product is distilled off. The volume of alcohol distilled off is continually replaced by metering in an essentially equal volume of nitrile. The nitrile is provided in excess based on the carboxylic ester to be converted.

1 . In a process for preparing β-keto nitrites of the general formula (1a) or salts thereof of the general formula (1b)  
     
       
         
         
             
             
         
       
     
     by reacting a nitrile of the general formula (2)  
       R 2 —CH 2 —C≡N  (2)  
     with carboxylic esters of the general formula (3)  
     
       
         
         
             
             
         
       
     
     in the presence of an alkali metal alkoxide or alkaline earth metal alkoxide,  
     wherein: 
 R 1  is a linear or branched, saturated or unsaturated, nonaromatic, aromatic or heteroaromatic C 1 -C 30 -hydrocarbon radical which is cyclic or contains cyclic groups and is optionally substituted by Q;  
 R 2  is hydrogen or a linear or branched alkyl radical;  
 Q is selected from the group comprising halogen, amino, hydroxyl, cyano, nitro, alkoxy, aryloxy, alkylthio, acyl, silyl, silyloxy, aryl, heteroaryl; and  
 M is an alkali metal or alkaline earth metal ion,  
 R is a C 1 -C 10 -alkyl radical,  
 the improvement comprising: 
 a) distilling off the alcohol R—OH formed as a by-product, optionally in the form of an azeotrope;  
 b) continually replacing the volume distilled off with an essentially equal volume of additional nitrile by such that overall the nitrile is provided in excess based on the carboxylic ester to be converted.  
 
 
   
   
       2 . The process of  claim 1 , wherein the carboxylic ester, the nitrile and the alkali metal or alkaline earth metal alkoxide are initially charged into a reaction vessel in essentially equimolar amounts.  
   
   
       3 . The process of  claim 1 , wherein the ratio of total nitrile added to carboxylic ester is from 4 to 6:1.  
   
   
       4 . The process of  claim 1 , wherein the continual further metered addition of the nitrile is effected continuously or in portions.  
   
   
       5 . The process of  claim 1 , wherein the alkali metal alkoxide used is sodium methoxide or sodium ethoxide.  
   
   
       6 . The process of  claim 1 , wherein the nitrile is selected from the group comprising acetonitrile, propionitrile and butyronitrile.  
   
   
       7 . The process of  claim 1 , wherein the carboxylic esters are selected from the group comprising optionally Q-substituted and optionally enantiomerically enriched or enantiomerically pure alpha-, beta- or gamma-amino acid esters or alpha-, beta- or gamma-hydroxy acid esters.  
   
   
       8 . The process of  claim 1 , wherein the reaction is effected at a temperature from 70 to 120° C.  
   
   
       9 . The process of  claim 1 , wherein the reaction is performed in the presence of an inert solvent.  
   
   
       10 . The process of  claim 1 , wherein the reaction is performed without addition of additional inert solvents.  
   
   
       11 . The process of  claim 1 , wherein the ratio of total nitrile added to carboxylic ester is from 2 to 10:1.  
   
   
       12 . The process of  claim 1 , wherein the ratio of total nitrile added to carboxylic ester is from 3 to 7:1.  
   
   
       13 . In a process for preparing β-keto nitrites of the general formula (1a) or salts thereof of the general formula (1b)  
     
       
         
         
             
             
         
       
     
     by reacting a nitrile of the general formula (2)  
       R 2 —CH 2 —C≡N  (2)  
     with carboxylic esters of the general formula (3)  
     
       
         
         
             
             
         
       
     
     in the presence of an alkali metal alkoxide or alkaline earth metal alkoxide,  
     wherein: 
 R 1  is a linear or branched, saturated or unsaturated, nonaromatic, aromatic or heteroaromatic C 1 -C 30 -hydrocarbon radical which is cyclic or contains cyclic groups and is optionally substituted by Q;  
 R 2  is hydrogen or a linear or branched alkyl radical;  
 Q is selected from the group comprising halogen, amino, hydroxyl, cyano, nitro, alkoxy, aryloxy, alkylthio, acyl, silyl, silyloxy, aryl, heteroaryl; and  
 M is an alkali metal or alkaline earth metal ion,  
 R is a C 1 -C 10 -alkyl radical,  
 the improvement comprising: 
 a) distilling off the alcohol R—OH formed as a by-product, optionally in the form of an azeotrope;  
 b) continually replacing the volume distilled off with an essentially equal volume of additional nitrile by such that overall the nitrile is provided in excess based on the carboxylic ester to be converted, wherein the ratio of total nitrile added to carboxylic ester is from 4 to 6:1.  
 
 
   
   
       14 . The process of  claim 13 , wherein the continual further metered addition of the nitrile is effected continuously or in portions.  
   
   
       15 . The process of  claim 13 , wherein the alkali metal alkoxide used is sodium methoxide or sodium ethoxide.  
   
   
       16 . The process of  claim 13 , wherein the nitrile is selected from the group comprising acetonitrile, propionitrile and butyronitrile.  
   
   
       17 . The process of  claim 13 , wherein the carboxylic esters are selected from the group comprising optionally Q-substituted and optionally enantiomerically enriched or enantiomerically pure alpha-, beta- or gamma-amino acid esters or alpha-, beta- or gamma-hydroxy acid esters.  
   
   
       18 . The process of  claim 13 , wherein the reaction is performed in the presence of an inert solvent.  
   
   
       19 . In a process for preparing β-keto nitriles of the general formula (1a) or salts thereof of the general formula (1b)  
     
       
         
         
             
             
         
       
     
     by reacting a nitrile of the general formula (2)  
       R 2 —CH 2 —C≡N  (2)  
     with carboxylic esters of the general formula (3)  
     
       
         
         
             
             
         
       
     
     in the presence of an alkali metal alkoxide or alkaline earth metal alkoxide,  
     wherein: 
 R 1  is a linear or branched, saturated or unsaturated, nonaromatic, aromatic or heteroaromatic C 1 -C 30 -hydrocarbon radical which is cyclic or contains cyclic groups and is optionally substituted by Q;  
 R 2  is methyl;  
 Q is selected from the group comprising halogen, amino, hydroxyl, cyano, nitro, alkoxy, aryloxy, alkylthio, acyl, silyl, silyloxy, aryl, heteroaryl; and  
 M is an alkali metal or alkaline earth metal ion,  
 R is a C 1 -C 10 -alkyl radical,  
 the improvement comprising: 
 a) distilling off the alcohol R—OH formed as a by-product, optionally in the form of an azeotrope;  
 b) continually replacing the volume distilled off with an essentially equal volume of additional nitrile by such that overall the nitrile is provided in excess based on the carboxylic ester to be converted, wherein the ratio of total nitrile added to carboxylic ester is from 4 to 6:1.  
 
 
   
   
       20 . The process of  claim 13 , wherein the carboxylic esters are selected from the group comprising optionally Q-substituted and optionally enantiomerically enriched or enantiomerically pure alpha-, beta- or gamma-amino acid esters or alpha-, beta- or gamma-hydroxy acid esters.