Process for producing optically active cysteine derivatives

Abstract

A process for producing optically active cysteine derivatives with high optical purity and good quality which is economically advantageous and is high in productivity even on a commercial scale is provided. A process for producing an optically active cysteine derivative which comprises synthesizing a D-form or L-form optically active cysteine derivative of the general formula (2) shown below (R 1 represents an amino-protecting group of the urethane or acyl type, R 0 represents a hydrogen atom or, taken together with R 1 , an amino-protecting group, R 2 represents an alkyl, aryl or aralkyl group, R 3 represents a univalent organic group and * represents the position of an asymmetric carbon) by reacting the corresponding D-form or L-form optically active amino acid derivative of the general formula (1) shown below with an alcohol of the general formula (3) shown below and a strong acid and/or a thionyl halide and recovering the above cysteine derivative (2) from the reaction mixture, the procedural series from reaction to recovery being carried out under conditions such that the medium contacting the above optically active cysteine derivative (2) is within the range from acidic to weakly basic to thereby recover the above cysteine derivative (2) from the reaction mixture while suppressing the decomposition and racemization thereof.

1 . A process for producing an optically active cysteine derivative represented by the general formula (2):  
       
         
           
           
               
               
           
         
         wherein R 1  represents an amino-protecting group of the urethane or acyl type, R 0  represents a hydrogen atom or, taken together with the above R 1 , an amino-protecting group, R 2  represents a univalent organic group selected from the group consisting of a substituted or unsubstituted alkyl group containing 1 to 7 carbon atoms, a substituted or unsubstituted aryl group containing 6 to 10 carbon atoms and a substituted or unsubstituted aralkyl group containing 7 to 10 carbon atoms, R 3  represents a univalent organic group capable of functioning as an ester-type carboxyl-protecting group by its being included in the structure represented by —COOR 3  and * represents the position of an asymmetric carbon atom, 
 which comprises  
 reacting a d-form or l-form optically active amino acid derivative represented by the general formula (1):  
                     
  wherein R 0 , R 1 , R 2  and * are as defined above,  
 with an alcohol represented by the general formula (3): 
 R 3 OH  (3) 
  wherein R 3  is as defined above,  
 and a strong acid and/or a thionyl halide to synthesize a D-form or L-form optically active cysteine derivative represented by said general formula (2),  
 and recovering the above optically active cysteine derivative (2) from the reaction mixture,  
 the procedural series from said reaction to said recovery being carried out under a condition such that the medium contacting the above optically active cysteine derivative (2) is within the range from acidic to weakly basic to thereby recover the above optically active cysteine derivative (2) from the reaction mixture while suppressing the decomposition and racemization thereof.  
 
       
     
     
         2 . The process for producing an optically active cysteine derivative according to  claim 1 , 
 wherein the decrease in optical purity during the procedural series from reaction to recovery is not more than 2%.    
     
     
         3 . The process for producing an optically active cysteine derivative according to  claim 1  or  2 , 
 wherein the strong acid remaining in the reaction mixture and/or hydrogen halide and sulfur dioxide formed as a byproduct are/is eliminated by neutralization using a base.  
 
     
     
         4 . The process for producing an optically active cysteine derivative according to  claim 1 ,  2  or  3 , 
 wherein the recovery of the optically active cysteine derivative of the general formula (2) from the reaction mixture is effected by extracting, using an extraction solvent, said optically active cysteine derivative from the reaction mixture as such or from the reaction mixture after reduction of the reaction solvent content.  
 
     
     
         5 . The process for producing an optically active cysteine derivative according to  claim 4 , 
 wherein addition of an inorganic salt and/or warming treatment is applied to the mixture composed of an organic phase and an aqueous phase as resulting from extraction of the optically active cysteine derivative of the general formula (2) using an extraction solvent, to thereby cause separation of said organic phase and aqueous phase, and to recover said organic phase containing said optically active cysteine derivative.    
     
     
         6 . The process for producing an optically active cysteine derivative according to  claim 4  or  5 , 
 wherein at least one of aromatic hydrocarbons and acetate esters is used as the extraction solvent.  
 
     
     
         7 . The process for producing an optically active cysteine derivative according to  claim 4 ,  5  or  6 , 
 wherein, in concentrating the organic phase containing the optically active cysteine derivative of the general formula (2), the solvent in coexistence is distilled off at a temperature not lower than the melting temperature of said optically active cysteine derivative or at a temperature not lower than the melting temperature of the concentrate comprising said optically active cysteine derivative as the main component, to thereby recover said optically active cysteine derivative in the form of an oily substance.  
 
     
     
         8 . The process for producing an optically active cysteine derivative according to  claim 7 , 
 wherein a solvent is further added to the optically active cysteine derivative of the general formula (2) as obtainable in the form of an oily substance, to give a solution of said optically active cysteine derivative.    
     
     
         9 . The process for producing an optically active cysteine derivative according to  claim 4 ,  5 ,  6 ,  7  or  8 , 
 wherein, in causing the optically active cysteine derivative of the general formula (2) to precipitate from the organic phase containing said optically active cysteine derivative, adding an aliphatic hydrocarbon as a poor solvent to said organic phase or a concentrate of said organic phase, and recovering the optically active cysteine derivative.  
 
     
     
         10 . The process for producing an optically active cysteine derivative according to  claim 9 , 
 wherein the aliphatic hydrocarbon is hexane.    
     
     
         11 . The process for producing an optically active cysteine derivative according to  claim 1 ,  2  or  3 , 
 wherein the optically active cysteine derivative of the general formula (2) is recovered from an alcohol, water, or a mixed solvent composed thereof, without performing any extraction procedure.  
 
     
     
         12 . The process for producing an optically active cysteine derivative according to  claim 11 , 
 wherein the optically active cysteine derivative of the general formula (2) is recovered from the reaction mixture containing the alcohol of the general formula (3), water, or a mixed solvent composed thereof, either as such or distilled off said alcohol and/or supplemented with water so that the content of water in said reaction mixture may become not lower than 10% by weight relative to the total amount of said alcohol and water.    
     
     
         13 . The process for producing an optically active cysteine derivative according to  claim 1 ,  2  or  3 , 
 wherein, when a compound represented by the general formula (4):  
                     
  wherein R 2  and * are as defined above,  
 coexists, as a contaminant, in the optically active amino acid derivative of the general formula (1), R 1  being benzyloxycarbonyl, said compound of the general formula (4) is caused to remain substantially unreacted in the reaction step.  
 
     
     
         14 . The process for producing an optically active cysteine derivative according to  claim 13 , 
 wherein the compound of the general formula (4), which remains unreacted, is removed from the reaction mixture.    
     
     
         15 . The process for producing an optically active cysteine derivative according to  claim 14 , 
 wherein the compound of the general formula (4) is removed by filtration and/or a phase separation procedure comprising extraction and washing.    
     
     
         16 . The process for producing an optically active cysteine derivative according to  claim 15 , 
 wherein the phase separation procedure comprising extraction and washing is carried out under an acidic condition with addition of an inorganic salt and/or warming treatment, to thereby causing the compound of the general formula (4) to transfer to the aqueous phase.    
     
     
         17 . The process for producing an optically active cysteine derivative according to any of  claims 1  to  12 , 
 wherein, in general formula (1), R 2  is a phenyl group.  
 
     
     
         18 . The process for producing an optically active cysteine derivative according to  claim 17 , 
 wherein, in general formula (1), R 1  is a urethane-type protecting group.    
     
     
         19 . The process for producing an optically active cysteine derivative according to  claim 18 , 
 wherein the urethane-type protecting group is an aralkyloxycarbonyl group or a lower alkoxycarbonyl group.    
     
     
         20 . The process for producing an optically active cysteine derivative according to  claim 19 , 
 wherein said urethane-type protecting group is benzyloxycarbonyl, tert-butoxycarbonyl, methoxycarbonyl or ethoxycarbonyl.    
     
     
         21 . The process for producing an optically active cysteine derivative according to  claim 20 , 
 wherein the urethane-type protecting group is benzyloxycarbonyl.    
     
     
         22 . The process for producing an optically active cysteine derivative according to any of  claims 13  to  16 , 
 wherein, in general formula (1), R 2  is a phenyl group.  
 
     
     
         23 . The process for producing an optically active cysteine derivative according to  claim 17 ,  18 ,  19 ,  20 ,  21  or  22 , 
 wherein, in general formula (2), R 3  is a lower alkyl group containing 1 to 4 carbon atoms.  
 
     
     
         24 . The process for producing an optically active cysteine derivative according to  claim 23 , 
 wherein the lower alkyl group containing 1 to 4 carbon atoms is methyl.    
     
     
         25 . A method of crystallization of an optically active cysteine derivative represented by the general formula (2):  
       
         
           
           
               
               
           
         
         wherein R 0  represents a hydrogen atom, R 1  represents a urethane-type amino-protecting group, R 2  represents a phenyl group, R 3  represents a lower alkyl group containing 1 to 4 carbon atoms and * represents the position of an asymmetric carbon atom, 
 wherein the cysteine derivative of the general formula (2) is caused to precipitate as a crystal from a solution containing the cysteine derivative of the general formula (2) in an organic solvent miscible with an aliphatic hydrocarbon under acidic to weakly basic conditions by using an aliphatic hydrocarbon as a poor solvent, if necessary with cooling and/or concentration, while thereby effecting removal, from the cysteine derivative of the general formula (2), of a contaminant impurity existing therein.  
 
       
     
     
         26 . The method of crystallization according to  claim 25 , 
 wherein at least one of aromatic hydrocarbons, acetate esters and ethers is used as the aliphatic hydrocarbon-miscible organic solvent.    
     
     
         27 . The method of crystallization according to  claim 26 , 
 wherein toluene is used as the aromatic hydrocarbon, ethyl acetate as the acetate ester, or methyl tert-butyl ether as the ether.    
     
     
         28 . The method of crystallization according to  claim 25 ,  26  or 27, 
 wherein the poor solvent aliphatic hydrocarbon is hexane.  
 
     
     
         29 . The method of crystallization according to  claim 25 ,  26 ,  27  or  28 , 
 wherein the poor solvent aliphatic hydrocarbon is used in an amount of not less than 10% by weight relative to the total weight of the crystallization mixture.  
 
     
     
         30 . The method of crystallization according to  claim 25 ,  26 ,  27 ,  28  or  29 , 
 wherein the lower alkyl group containing 1 to 4 carbon atoms is methyl.  
 
     
     
         31 . The method of crystallization according to  claim 25 ,  26 ,  27 ,  28 ,  29  or  30 , 
 wherein the urethane-type protective group is an aralkyloxycarbonyl group or a lower alkoxycarbonyl group.  
 
     
     
         32 . The method of crystallization according to  claim 31 , 
 wherein the urethane-type protective group is benzyloxycarbonyl, tert-butoxycarbonyl, methoxycarbonyl or ethoxycarbonyl.    
     
     
         33 . The method of crystallization according to  claim 32 , 
 wherein the urethane-type protective group is benzyloxycarbonyl.    
     
     
         34 . The method of-crystallization according to  claim 25 ,  26 ,  27 ,  28 ,  29 ,  30 ,  31 ,  32  or  33 , 
 wherein at least one of the optical isomer of the cysteine derivative (2) and a dehydroalanine derivative represented by the general formula (5):  
                     
  wherein R 0 , R 1  and R 3  are the same as the definition of the general formula (2),  
 is the impurity existing in said cysteine derivative (2).  
 
     
     
         35 . The method of crystallization according to  claim 34 , 
 wherein the desired optically active cysteine derivative (2), which exists in excess, is caused to preferentially precipitate out by adjusting a crystallization condition so that the relative equilibrium solubility (ratio between amounts dissolved at equilibrium) in the impurity optical isomer-containing crystallization mixture between the desired optically active cysteine derivative (2) and the optical isomer thereof may be lower than the optical purity of the cysteine derivative prior to crystallization.    
     
     
         36 . The method of crystallization according to  claim 35 , 
 wherein the existence percentage of the desired optical isomer in the crystals as obtainable is not less than 98%.    
     
     
         37 . A method of crystallization of an optically active cysteine derivative represented by the general formula (2):  
       
         
           
           
               
               
           
         
         wherein R 0  represents a hydrogen atom, R 1  represents a urethane-type amino-protecting group, R 2  represents a phenyl group, R 3  represents a lower alkyl group containing 1 to 4 carbon atoms and * represents the position of an asymmetric carbon atom, 
 wherein the optically active cysteine derivative of the general formula (2) is caused to precipitate as a crystal from a solution containing the optically active cysteine derivative of the general formula (2) in a monohydric alcohol containing 1 to 4 carbon atoms under acidic to weakly basic conditions, if necessary with cooling and/or concentration, while thereby effecting removal, from the optical active cysteine derivative of the general formula (2), of a contaminant impurity existing therein.  
 
       
     
     
         38 . The method of crystallization according to  claim 37 , 
 wherein the lower alkyl group containing 1 to 4 carbon atoms is methyl and the monohydric alcohol containing 1 to 4 carbon atoms is methanol.    
     
     
         39 . The method of crystallization according to  claim 38 , 
 wherein the content of water in the methanol solution containing the optically active cysteine derivative of the general formula (2) is less than 10% by weight relative to the total amount of methanol and water.    
     
     
         40 . The method of crystallization according to  claim 37 ,  38  or  39 , 
 wherein the urethane-type protective group is an aralkyloxycarbonyl group or a lower alkoxycarbonyl group.  
 
     
     
         41 . The method of crystallization according to  claim 40 , 
 wherein the urethane-type protective group is benzyloxycarbonyl, tert-butoxycarbonyl, methoxycarbonyl or ethoxycarbonyl.    
     
     
         42 . The method of crystallization according to  claim 41 , 
 wherein the urethane-type protective group is benzyloxycarbonyl.    
     
     
         43 . The method of crystallization according to  claim 37 ,  38 ,  39 ,  40 ,  41  or  42 , 
 wherein at least one of the optical isomer of the optical active cysteine derivative of the general formula (2) and a dehydroalanine derivative represented by the general formula (5):  
                     
  wherein R 0 , R 1  and R 3 are the same as the definition of the general formula (2),  
 is the impurity existing in said optical active cysteine derivative (2).  
 
     
     
         44 . The method of crystallization according to  claim 43 , 
 wherein the desired optically active cysteine derivative (2), which exists in excess, is caused to preferentially precipitate out by adjusting a crystallization condition so that the relative equilibrium solubility (ratio between amounts dissolved at equilibrium) in the impurity optical isomer-containing crystallization mixture between the desired optically active cysteine derivative (2) and the optical isomer thereof may be lower than the optical purity of said cysteine derivative prior to crystallization.    
     
     
         45 . The method of crystallization according to  claim 44 , wherein the existence percentage of the desired optical isomer in the crystals as obtainable is not less than 98%.