Processes for producing B-halogeno-a-amino-carboxylic acids and phenylcysteine derivatives and intermediates thereof

Abstract

An industrially advantageous method of producing β-halogeno-α-aminocarboxylic acids is provided. Methods are also provided of producing optically active N-protected-S-phenylcysteines having high optical purity and of intermediates thereof, respectively, in which the above production method is utilized. A method of producing β-halogeno-α-aminocarboxylic acids or salts thereof is disclosed which comprises halogenating the hydroxyl group of a β-hydroxy-α-aminocarboxylic acid (in which the basicity of the amino group in α-position is not masked by the presence of a substituent on said amino group) or a salt thereof with an acid with a halogenating agent. A method of producing optically active N-protected-S-phenylcysteines represented by the general formula (3) or salts thereof is further disclosed which comprises applying the above production method to optically active serine or a salt thereof and then carrying out treatment with an amino-protecting agent and reaction with thiophenol under a basic condition.

1 . A method of producing a β-halogeno-α-aminocarboxylic acid or a salt thereof which comprises halogenating the hydroxyl group of a β-hydroxy-α-aminocarboxylic acid, in which the basicity of the amino group in α-position is not masked by the presence of a substituent on said amino group, or a salt thereof with an acid by treating the same with a halogenating agent.  
     
     
         2 . The method of producing according to  claim 1 , 
 wherein the halogenating agent is a thionyl halide.    
     
     
         3 . The method of producing according to  claim 2 , 
 wherein the thionyl halide is thionyl chloride.    
     
     
         4 . The method of producing according to  claim 1 ,  2  or  3 , 
 wherein the halogenating agent is used in an amount of 1 to 10 moles per mole of the β-hydroxy-α-aminocarboxylic acid  
 
     
     
         5 . The method of producing according to any of claims  1  to 4, 
 wherein the treatment with the halogenating agent is carried out using a solvent containing an ether type solvent.  
 
     
     
         6 . The method of producing according to  claim 5 , wherein the ether type solvent is miscible with water.  
     
     
         7 . The method of producing according to  claim 6 , wherein the water-miscible ether type solvent comprises at least one species from the group consisting of 1,2-dimethoxyethane, 1,4-dioxane, tetrahydrofuran, diethylene glycol dimethyl ether, triethylene glycol dimethyl ether, tetraethylene glycol dimethyl ether and polyethylene glycol dimethyl ether.  
     
     
         8 . The method of producing according to any of  claims 1  to  7 , 
 wherein the treatment with the halogenating agent is carried out in the presence of a hydrogen halide.  
 
     
     
         9 . The method of producing according to  claim 8 , 
 wherein the hydrogen halide is used in an amount exceeding 2.0 molar equivalents relative to the β-hydroxy-α-aminocarboxylic acid.    
     
     
         10 . The method of producing according to  claim 8  or  9 , wherein the treatment with the halogenating agent is carried out in a state completely saturated or almost saturated with the hydrogen halide gas.  
     
     
         11 . The method of producing according to  claim 8 ,  9  or  10 , 
 wherein the hydrogen halide is hydrogen chloride.  
 
     
     
         12 . The method of producing according to any of  claims 1  to  11 , 
 wherein the treatment-with the chlorinating agent is carried out in the presence of an amine or a salt thereof.  
 
     
     
         13 . The method of producing according to  claim 12 , wherein the amine is a tertiary amine.  
     
     
         14 . The method of producing according to any of  claims 1  to  13 , 
 wherein the coexisting acid after treatment with the halogenating agent is converted to a salt form by means of a basic lithium compound, and dissolved in a medium composed of a water-miscible organic solvent and water while the β-halogeno-α-aminocarboxylic acid is caused to precipitate out in its free form.  
 
     
     
         15 . The method of producing according to  claim 14 , 
 wherein the water-miscible ether type solvent comprises at least one species selected from the group consisting of 1,2-dimethoxyethane, 1,4-dioxane, tetrahydrofuran, diethylene glycol dimethyl ether, triethylene glycol dimethyl ether, tetraethylene glycol dimethyl ether, polyethylene glycol dimethyl ether, acetonitrile, methanol, ethanol, n-propanol, isopropanol, tert-butanol and acetone.    
     
     
         16 . The method of producing according to  claim 15 , 
 wherein the water-miscible organic solvent is acetone.    
     
     
         17 . The method of producing according to  claim 14 ,  15  or  16 , 
 wherein the volume ratio of the water-miscible organic solvent to water is not less than 1.  
 
     
     
         18 . The method of producing according to any of  claims 14  to  17 , 
 wherein the final cooling temperature in the step of precipitation is not higher than 10° C.  
 
     
     
         19 . The method of producing according to any of  claims 14  to  18 , 
 wherein the low-boiling components occurring in the reaction mixture are reduced or removed beforehand after treatment with the halogenating agent but before precipitation of the desired product.  
 
     
     
         20 . The method of producing according to any of  claims 1  to  13 , 
 wherein, after treatment with the halogenating agent, the β-halogeno-α-aminocarboxylic acid in hydrohalogenic acid salt form that has precipitated from the reaction mixture as such or after concentration thereof is recovered.  
 
     
     
         21 . The method of producing according to any of  claims 1  to  13 , 
 wherein, after treatment with the halogenating agent, the reaction solvent is replaced with water to give an aqueous solution containing the β-halogeno-α-aminocarboxylic acid.  
 
     
     
         22 . The method of producing according to any of  claims 1  to  21 , 
 wherein the β-hydroxy-α-aminocarboxylic acid is serine, threonine, allothreonine or β-phenylserine.  
 
     
     
         23 . The method of producing according to  claim 22 , 
 wherein the β-hydroxy-α-aminocarboxylic acid is serine.    
     
     
         24 . The method of producing according to any of  claims 1  to  23 , 
 wherein the β-hydroxy-α-aminocarboxylic acid is optically active.  
 
     
     
         25 . The method of producing according to  claim 23  or  24 , wherein the β-hydroxy-α-aminocarboxylic acid is L-serine.  
     
     
         26 . A method of purifying and isolating a β-halogeno-α-aminocarboxylic acid 
 which comprises causing a β-halogeno-α-aminocarboxylic acid, in which the basicity of the amino group in α-position is not masked by the presence of a substituent on said amino group, to crystallize out using water as a good solvent and a water-miscible organic solvent as a poor solvent.  
 
     
     
         27 . The method of purifying and isolating a β-halogeno-α-aminocarboxylic acid according to  claim 26 , 
 wherein the water-miscible organic solvent is acetone.  
 
     
     
         28 . The method of purifying and isolating a β-halogeno-α-aminocarboxylic acid according to  claim 27 , 
 wherein acetone is used as a poor solvent for causing the β-halogeno-α-aminocarboxylic acid to crystallize and precipitate out in its free form from an aqueous solution resulting from treatment of an aqueous solution containing the β-halogeno-α-aminocarboxylic acid and hydrohalogenic acid with a basic lithium compound for converting said hydrohalogenic acid to the salt thereof.  
 
     
     
         29 . The method of purifying and isolating a β-halogeno-α-aminocarboxylic acid according to  claim 26 ,  27  or  28 , 
 wherein the volume ratio of the water-miscible organic solvent to water in the step of crystallization is not less than 1.  
 
     
     
         30 . The method of purifying and isolating a β-halogeno-α-aminocarboxylic acid according to any of  claims 26  to  29 , 
 wherein the final cooling temperature in the step of crystallization is not higher than 10° C.  
 
     
     
         31 . The method of purifying and isolating a β-halogeno-α-aminocarboxylic acid according to any of  claims 26  to  30 , 
 wherein the β-halogeno-α-aminocarboxylic acid is β-chloroalanine, β-chloro-α-aminobutyric acid or β-chloro-α-phenyl-α-aminopropionic acid.  
 
     
     
         32 . The method of purifying and isolating a β-halogeno-α-aminocarboxylic acid according to  claim 31 , 
 wherein the β-halogeno-α-aminocarboxylic acid is β-chloroalanine.  
 
     
     
         33 . The method of purifying and isolating β-halogeno-α-aminocarboxylic acid according to any of  claims 26  to  32 , 
 wherein the β-halogeno-α-aminocarboxylic acid is optically active.  
 
     
     
         34 . The method of purifying and isolating a β-halogeno-α-aminocarboxylic acid according to  claim 32  or  33 , 
 wherein the β-halogeno-α-aminocarboxylic acid is β-chloro-L-alanine.  
 
     
     
         35 . A method of producing an optically active N-protected-β-chloroalanine of the general formula (2) or a salt thereof:  
       
         
           
           
               
               
           
         
       
       wherein R 1  represents an amino-protecting group and R 0  represents a hydrogen atom or, taken together with R 1 , an amino-protecting group, 
 which comprises preparing an optically active β-chloroalanine of the following formula (1) or a salt thereof:  
                     
 from an optically active serine or a salt thereof with an acid by the method of producing according to  claim 1   
 and then treating the same with an amino-protecting agent.  
 
     
     
         36 . The method of producing according to  claim 35 , 
 wherein the optically active β-chloroalanine is obtainable by the method of producing according to any of  claims 2  to  25 .    
     
     
         37 . The method of producing according to  claim 35  or  36 , 
 wherein the amino-protecting agent is benzyl chloroformate  
 and the optically active N-protected-β-chloroalanine is represented by the general formula (2) in which R 0  is a hydrogen atom and R 1  is a carbobenzyloxy group.  
 
     
     
         38 . A method of producing an optically active N-protected-S-phenylcysteine of the general formula (3) or a salt thereof:  
       
         
           
           
               
               
           
         
       
       wherein R 1  represents an amino-protecting group and R 0  represents a hydrogen atom or, taken together with R 1 , an amino-protecting group, 
 which comprises preparing an optically active N-protected-β-chloroalanine or a salt thereof by the method of producing according to  claim 35 ,  
 and then reacting the same with thiophenol under a basic condition.  
 
     
     
         39 . The method of producing according to  claim 38 , 
 wherein the optically active N-protected-β-chloroalanine is obtainable by the method of producing according to  claim 36 .    
     
     
         40 . The method of producing according to  claim 38  or  39 , 
 wherein the amino-protecting agent is benzyl chloroformate  
 and the optically active N-protected-S-phenylcysteine is represented by the general formula (3) in which R 0  is a hydrogen atom and R 1  is a carbobenzyloxy group.  
 
     
     
         41 . The method of producing according to any of  claims 38  to  40 , 
 wherein the treatment of optically active serine or a salt of optically active serine with an acid with the chlorinating agent, the treatment with the amino-protecting agent and the thiophenylation are carried out without isolating the respective intermediates.  
 
     
     
         42 . A method of producing an optically active N-protected-S-phenylcysteine of the general formula (3) or a salt thereof,  
       
         
           
           
               
               
           
         
       
       wherein R 1  represents an amino-protecting group and R 0  represents a hydrogen atom or, taken together with R 1 , an amino-protecting group, 
 which comprises treating an optically active β-chloroalanine or a salt thereof with an amino-protecting agent  
 and then reacting the thus-prepared optically active N-protected-β-chloroalanine of the general formula (2) or a salt thereof with thiophenol under a basic condition,  
                     
 wherein R 1  represents an amino-protecting group and R 0  represents a hydrogen atom or, taken together with R 1 , an amino-protecting group.  
 
     
     
         43 . The method of producing according to  claim 42 , 
 wherein the amino-protecting agent is benzyl chloroformate    and the optically active N-protected-β-chloroalanine and optically active N-protected-S-phenylcysteine are represented by the general formula (2) and the general formula (3), respectively, in which R 0  is a hydrogen atom and R 1  is a carbobenzyloxy group.    
     
     
         44 . The method of producing according to  claim 42  or  43 , 
 wherein the treatment with amino-protecting agent and the thiophenylation are carried out without isolating the respective intermediates.