Process for producing optically active alpha-methylcysteine derivative

Abstract

The present invention provides a simple industrial process for producing an L- or D-optically active α-methylcysteine derivative or its salt, which is a useful pharmaceutical intermediate, from readily available, inexpensive raw materials. In a process for producing an L- or D-optically active α-methylcysteine derivative or its salt, a racemic N-carbamoyl-α-methylcysteine derivative or its salt is D-selectively cyclized with hydantoinase to produce a D-5-methyl-5-thiomethylhydantoin derivative or its salt and an N-carbamoyl-α-methyl-L-cysteine derivative or its salt, which are then subjected to deprotection of the amino group and the sulfur atom, and hydrolysis.

1 . A process for producing a D-5-methyl-5-thiomethylhydantoin derivative represented by formula (2) or its salt: 
     
       
         
         
             
             
         
       
       (wherein R 1  represents a substituted or unsubstituted alkyl group having 1 to 20 carbon atoms, a substituted or unsubstituted aralkyl group having 7 to 20 carbon atoms, or a substituted or unsubstituted aryl group having 6 to 20 carbon atoms); and an N-carbamoyl-α-methyl-L-cysteine derivative represented by formula (3) or its salt: 
     
     
       
         
         
             
             
         
       
       (wherein R 1  represents the same as the above), the process comprising treating a racemic N-carbamoyl-α-methylcysteine derivative represented by formula (1) or its salt: 
     
     
       
         
         
             
             
         
       
       (wherein R 1  represents the same as the above) with hydantoinase to selectively cyclize the D-isomer. 
     
   
   
       2 . The process according to  claim 1 , wherein the hydantoinase is derived from microorganisms of the genus  Agrobacterium, Bacillus , or  Pseudomonas.    
   
   
       3 . The process according to  claim 2 , wherein the hydantoinase is derived from  Agrobacterium  sp. KNK712 (FERM BP-1900),  Bacillus  sp. KNK245 (FERM BP-4863), or  Pseudomonas putida  IFO12996. 
   
   
       4 . The process according to  claim 1 , wherein the hydantoinase is used as an immobilized enzyme. 
   
   
       5 . The process according to  claim 1 , wherein R 1  is a substituted or unsubstituted tertiary alkyl group having 4 to 15 carbon atoms. 
   
   
       6 . The process according to  claim 5 , wherein the tertiary alkyl group is a tert-butyl group. 
   
   
       7 . A racemic N-carbamoyl-α-methylcysteine derivative represented by formula (1) or its salt: 
     
       
         
         
             
             
         
       
       (wherein R 1  represents a substituted or unsubstituted alkyl group having 1 to 20 carbon atoms, a substituted or unsubstituted aralkyl group having 7 to 20 carbon atoms, or a substituted or unsubstituted aryl group having 6 to 20 carbon atoms). 
     
   
   
       8 . The compound according to  claim 7 , wherein R 1  is a tertiary alkyl group having 4 to 15 carbon atoms. 
   
   
       9 . The compound according to  claim 8 , wherein the tertiary alkyl group is a tert-butyl group. 
   
   
       10 . An L- or D-optically active N-carbamoyl-α-methylcysteine derivative represented by formula (3): 
     
       
         
         
             
             
         
       
       (wherein R 1  represents a substituted or unsubstituted alkyl group having 1 to 20 carbon atoms, a substituted or unsubstituted aralkyl group having 7 to 20 carbon atoms, or a substituted or unsubstituted aryl group having 6 to 20 carbon atoms), or formula (10): 
     
     
       
         
         
             
             
         
       
       (wherein R 1  represent the same as the above), or its salt. 
     
   
   
       11 . The compound according to  claim 10 , wherein R 1  is a tertiary alkyl group having 4 to 15 carbon atoms. 
   
   
       12 . The compound according to  claim 11 , wherein the tertiary alkyl group is a tert-butyl group. 
   
   
       13 . A D- or L-optically active 5-methyl-5-thiomethylhydantoin derivative represented by formula (2): 
     
       
         
         
             
             
         
       
       or formula (7): 
     
     
       
         
         
             
             
         
       
       (wherein R 1  is a tertiary alkyl group having 4 to 15 carbon atoms), or its salt. 
     
   
   
       14 . The compound according to  claim 13 , wherein the tertiary alkyl group is a tert-butyl group.