Method for Producing Alpha-substituted Cysteine or Salt Thereof or Synthetic Intermediate of Alpha-substituted Cysteine

Abstract

According to the present invention, it becomes possible to perform a process for converting into an α-substituted cysteine represented by general formula (1) or a salt thereof at low cost and on an industrial scale by employing a process that is routed through a compound represented by general formula (3) to a compound represented by general formula (6). Particularly, by employing a process that is routed through a compound represented by general formula (7-2), it becomes possible to detach a tert-butyl protection group in a simple manner and to produce the compound represented by general formula (1) with high purity. Furthermore, by employing a process that is routed through tert-butylthiomethanol or a process that is routed through a compound represented by general formula (9), it becomes possible to produce a compound represented by general formula (2) without generating bischloromethylether that is an oncogenic substance. In the production of an α-substituted-D-cysteine or a salt thereof, it becomes possible to perform a process for converting the compound represented by general formula (2) into a compound represented by general formula (3S) in one step by allowing an enzyme or the like to act on the compound represented by general formula (2).

1 . A method for producing an α-substituted cysteine represented by General Formula (1): 
       
         
           
           
               
               
           
         
         wherein R 2  represents a C 1 -C 4  alkyl group or a salt thereof, said method comprising the steps of: 
         (a) converting, by Curtius rearrangement reaction, a compound represented by General Formula (5): 
       
       
         
           
           
               
               
           
         
         wherein R 1  represents a C 1 -C 10  alkyl group which is optionally substituted, a C 7 -C 20  aralkyl group which is optionally substituted, or a C 6 -C 12  aryl group which is optionally substituted, and R 2  has the same meaning as R 2  in the General Formula (1), to obtain a compound represented by General Formula (6): 
       
       
         
           
           
               
               
           
         
         wherein R 1  and R 2  have the same meanings as R 1  and R 2  in the General Formula (5), and 
         (b) subjecting said compound represented by General Formula (6) to a process of converting the isocyanate group to an amino group, a process of hydrolyzing the ester group, and a process of removing the tert-butyl group by action of an acid. 
       
     
     
         2 . The method of  claim 1 , wherein said step (b) comprises the steps of:
 (b-1) allowing an acid to act on a compound represented by General Formula (6):   
       
         
           
           
               
               
           
         
         wherein R 1  represents a C 1 -C 10  alkyl group which is optionally substituted, a C 7 -C 20  aralkyl group which is optionally substituted, or a C 6 -C 12  aryl group which is optionally substituted, and R 2  has the same meaning as R 2  in the General Formula (1), 
         to construct a thiazolidinone ring, for conversion into a compound represented by General Formula (7-1): 
       
       
         
           
           
               
               
           
         
       
       wherein R 1  and R 2  have the same meanings as R 1  and R 2  in the General Formula (6);
 (b-2) allowing an acid or a base to act on said compound represented by the General Formula (7-1) to hydrolyze the ester group, to obtain a compound represented by General Formula (7-2): 
 
       
         
           
           
               
               
           
         
         wherein R 2  has the same meaning as R 2  in the General Formula (7-1); and 
         (c) allowing an acid or a base to act on said compound represented by the General Formula (7-2) to open the thiazolidinone ring, to produce said α-substituted cysteine represented by the General Formula (1) or salt thereof. 
       
     
     
         3 . A method for producing an α-substituted cysteine represented by General Formula (1): 
       
         
           
           
               
               
           
         
         wherein R 2  represents a C 1 -C 4  alkyl group or a salt thereof, said method comprising the steps of: 
         (a) allowing an acid or a base to act on a compound represented by General Formula (7-1): 
       
       
         
           
           
               
               
           
         
         wherein R 1  represents a C 1 -C 10  alkyl group which is optionally substituted, a C 7 -C 20  aralkyl group which is optionally substituted, or a C 6 -C 12  aryl group which is optionally substituted, and R 2  has the same meaning as R 2  in the General Formula (1) to hydrolyze the ester group, to obtain a compound represented by General Formula (7-2): 
       
       
         
           
           
               
               
           
         
         wherein R 2  has the same meaning as R 2  in the General Formula (7-1); and 
         (b) allowing an acid or a base to act on said compound represented by General Formula (7-2) to open the thiazolidinone ring. 
       
     
     
         4 . The method of  claim 3 , said method comprising the step of:
 (c) allowing an acid to act on a compound represented by General Formula (6):   
       
         
           
           
               
               
           
         
       
       wherein R 1  represents a C 1 -C 10  alkyl group which is optionally substituted, a C 7 -C 20  aralkyl group which is optionally substituted, or a C 6 -C 12  aryl group which is optionally substituted, and R 2  has the same meaning as R 2  in the General Formula (1) to construct a thiazolidinone ring, to obtain a compound represented by General Formula (7-1): 
       
         
           
           
               
               
           
         
       
       wherein R 1  and R 2  have the same meanings as R 1  and R 2  in the General Formula (6).