Process for producing optically active carboxylic acid substituted in 2-position

Abstract

A nitrous acid salt is added at a temperature of 10 to 80° C. to an aqueous solution which contains an optically active 2-aminocarboxylic acid (4) and a protonic acid, the amount of the latter acid being 1 to 3 equivalents to the former, and which has a proton concentration of 0.5 to 2 mol/kg to conduct a reaction to thereby produce an optically active 2-hydroxycarboxylic acid (1). Thionyl chloride and a basic compound are caused to act on the compound (1) to chlorinate it and simultaneously invert the configuration in the 2-position. Thus, an optically active 2-chlorocarboxylic acid chloride (5) is induced. The compound (5) is hydrolyzed to induce an optically active 2-chlorocarboxylic acid (2). The compound (2) is reacted with a thioacetic acid salt to incorporate an acetylthio group thereinto and simultaneously invert the configuration in the 2-position to thereby produce an optically active 2-acetylthiocarboxylic acid (3).

1 . A method of producing an optically active 2-hydroxycarboxylic acid represented by the general formula (1):  
     
       
         
         
             
             
         
       
       wherein R 1  represents a substituted or unsubstituted alkyl group containing 1 to 12 carbon atoms, a substituted or unsubstituted aryl group containing 6 to 14 carbon atoms or a substituted or unsubstituted aralkyl group containing 7 to 15 carbon atoms,  
       by reacting an optically active 2-aminocarboxylic acid represented by the general formula (4):  
       
         
           
           
               
               
           
         
       
       wherein R 1  is as defined above,  
       with a nitrite salt and a protonic acid in aqueous solution,  
       wherein the reaction is carried out by adding the nitrite salt to an aqueous solution containing said optically active 2-aminocarboxylic acid and 1 to 3 equivalents, relative to the optically active 2-aminocarboxylic acid, of the protonic acid and having a proton concentration of 0.5 to 2 mol/kg at a temperature of 10 to 80° C.  
     
   
   
       2 . (canceled)  
   
   
       3 . The method of production according to  claim 1  or  2 , 
 wherein the proton concentration is 1 to 2 mol/kg.    
   
   
       4 . The production method according to any of  claims 1  to  3 , 
 wherein the aqueous solution contains 2 to 3 equivalents, relative to the optically active 2-aminocarboxylic acid (4), of a protonic acid.    
   
   
       5 . The method of production according to any of  claims 1  to  4 , 
 wherein the temperature during nitrite salt addition and during reaction is 15 to 60° C.    
   
   
       6 . The method of production according to any of  claims 1  to  5 , 
 wherein the protonic acid is an inorganic acid.    
   
   
       7 . The method of production according to  claim 6 , 
 wherein the inorganic acid is sulfuric acid.    
   
   
       8 . The method of production according to any of  claims 1  to  7 , 
 wherein the nitrite salt is used in an amount of not less than 2 moles per mole of the optically active 2-aminocarboxylic acid (4).    
   
   
       9 . The method of production according to any of  claims 1  to  8 , 
 wherein the addition rate of the nitrite salt per hour is 0.2 to 1.5 moles per mole of the optically active 2-aminocarboxylic acid (4).    
   
   
       10 . The method of production according to any of  claims 1  to  9 , 
 wherein the addition of the nitrite salt is effected by adding an aqueous solution containing the same.    
   
   
       11 . A method of crystallizing out an optically active 2-hydroxycarboxylic acid represented by the general formula (1):  
     
       
         
         
             
             
         
       
       in which R 1  represents a substituted or unsubstituted alkyl group containing 1 to 12 carbon atoms, a substituted or unsubstituted aryl group containing 6 to 14 carbon atoms or a substituted or unsubstituted aralkyl group containing 7 to 15 carbon atoms,  
       which comprises causing crystallization of the optically active 2-hydroxycarboxylic acid by using t-butyl methyl ether and a hydrocarbon solvent.  
     
   
   
       12 . The method of crystallization according to  claim 11 , 
 wherein at least one of an α,β-unsaturated carboxylic acid and an optical isomer each corresponding to the optically active 2-hydroxycarboxylic acid (1) is removed as an impurity.    
   
   
       13 . (canceled)  
   
   
       14 . The method of crystallization according to any of  claims 11  to  13 , 
 wherein the volume ratio of t-butyl methyl ether to the hydrocarbon solvent is 1/20 to 1.    
   
   
       15 . The method of crystallization according to any of  claims 11  to  14 , 
 wherein the crystallization is caused by adding a hydrocarbon solvent to t-butyl methyl ether solution containing the optically active 2-hydroxycarboxylic acid (1) or by adding t-butyl methyl ether solution containing the optically active 2-hydroxycarboxylic acid (1) to a hydrocarbon solvent.    
   
   
       16 . The method of crystallization according to  claim 11  to  15 , 
 wherein the hydrocarbon solvent is an aliphatic hydrocarbon.    
   
   
       17 . The method of crystallization according to  claim 16 , 
 wherein the aliphatic hydrocarbon is at least one species selected from the group consisting of hexane, heptane and methylcyclohexane.    
   
   
       18 . (canceled)  
   
   
       19 . The method of crystallization according to any of  claims 11  to  18 , 
 wherein an extract obtained, by using t-butyl methyl ether, from an aqueous solution containing the optically active 2-hydroxycarboxylic acid (1) produced by the method according to any of  claims 1  to  10 , or a concentrate of said extract is subjected to said method of crystallization.    
   
   
       20 .- 62 . (canceled)