Synthesis of alpha--amino-alpha, alpha'- dihaloketones and process for the preparation of beta--amino acid derivatives by the use of the same

Abstract

The present invention provides a commercially profitable process for producing a β-amino acid ester derivative which comprises reacting an α-amino acid ester derivative with a base and a dihalomethane, reacting the same with a lithium amide and an alkyllithium in succession, and treating the reaction product with an acid in an alcohol.

1 . A process for producing an α-amino-α′,α′-dihaloketone derivative of the following formula (3):  
       
         
           
           
               
               
           
         
       
       wherein R 1  represents a substituted or unsubstituted alkyl group containing 1 to 18 carbon atoms, an aralkyl group containing 7 to 18 carbon atoms or an aryl group containing 6 to 18 carbon atoms, P 1  and P 2  each independently represents a hydrogen atom or an amino-protecting group or P 1  and P 2  taken together represents a phthaloyl group, excluding the case in which both P 1  and P 2  are hydrogen atoms, and X 1  and X 2  each independently represents a halogen atom, 
 which comprises reacting an α-amino acid ester derivative of the following formula (1):  
                     
 wherein R 1 , P 1  and P 2  are as respectively defined above, R 2  represents an alkyl group containing 1 to 5 carbon atoms or an aralkyl group containing 7 to 12 carbon atoms  
 with a base and a dihalomethane of the following formula (2): 
 CH 2 X 1 X 2   (2) 
 wherein X 1  and X 2  are as respectively defined above.  
 
     
     
         2 . The process according to  claim 1   wherein X 1  and X 2  each independently represents a chlorine atom or a bromine atom.    
     
     
         3 . The process according to  claim 1  or  2  
 wherein the base is a halomagnesium dialkylamide.  
 
     
     
         4 . The process according to  claim 1   wherein the dihalomethane of the formula (2) is dibromomethane    and the base is chloromagnesium diisopropylamide.    
     
     
         5 . The process according to  claim 1 ,  2 ,  3  or  4  
 wherein R 1  represents benzyl or phenyl,  
 R 2  represents methyl or ethyl,  
 P 1  represents t-butyloxycarbonyl, benzyloxycarbonyl, methyloxycarbonyl or ethyloxycarbonyl,  
 and P 2  represents hydrogen.  
 
     
     
         6 . The process according to  claim 1 ,  2 ,  3 ,  4  or  5  
 wherein the α-amino acid ester derivative of the formula (1) is an optically active L-phenylalanine derivative or an optically active L-phenylglycine derivative.  
 
     
     
         7 . A process for producing a β-amino acid ester derivative of the following formula (4):  
       
         
           
           
               
               
           
         
       
       wherein R 1  represents a substituted or unsubstituted alkyl group containing 1 to 18 carbon atoms, an aralkyl group containing 7 to 18 carbon atoms or an aryl group containing 6 to 18 carbon atoms, R 3  represents an alkyl group containing 1 to 5 carbon atoms, and P 1  and P 2  each independently represents a hydrogen atom or an amino-protecting group or P 1  and P 2  taken together represents a phthaloyl group, excluding the case in which both P 1  and P 2  are hydrogen atoms, 
 which comprises reacting an α-amino acid ester derivative of the following formula (1):  
                     
 wherein R 1 , P 1  and P 2  are as respectively defined above,  
 with a base and a dihalomethane of the following formula (2): 
 CH 2 X 1 X 2   (2) 
 wherein X 1  and X 2  each independently represents a halogen atom, to synthesize an α-amino-α′,α′-dihaloketone derivative of the following formula (3):  
                     
 wherein R 1 , P 1 , P 2 , X 1  and X 2  are as respectively defined above,  
 reacting this derivative with a lithium amide and an alkyllithium in succession,  
 and treating the reaction product with an acid in an alcohol.  
 
     
     
         8 . The process-according to  claim 7   wherein X 1  and X 2  each independently represents a chlorine atom or a bromine atom.    
     
     
         9 . The process according to  claim 7  or  8  
 wherein the base is a halomagnesium dialkylamide.  
 
     
     
         10 . The process according to  claim 7   wherein the dihalomethane of the formula (2) is dibromomethane and    the base is chloromagnesium diisopropylamide.    
     
     
         11 . The process according to  claim 7 ,  8 ,  9  or  10  
 wherein the lithium amide is lithium hexamethyldisilazide or lithium diisopropylamide,  
 the alkyllithium is n-butyllithium, and  
 the alcohol is methanol or ethanol.  
 
     
     
         12 . The process according to  claim 7 ,  8 ,  9 ,  10  or  11  
 wherein R 1  represents benzyl or phenyl,  
 R 2  represents methyl or ethyl,  
 P 1  represents t-butyloxycarbonyl, benzyloxycarbonyl, methyloxycarbonyl or ethyloxycarbonyl, and  
 P 2  represents hydrogen.  
 
     
     
         13 . The process according to  claim 7 ,  8 ,  9 ,  10 ,  11  or  12  
 wherein the α-amino acid ester derivative of the formula (1) is an optically active L-phenylalanine derivative or an optically active L-phenylglycine derivative.  
 
     
     
         14 . A process for producing a β-amino acid ester derivative of the following formula (4):  
       
         
           
           
               
               
           
         
       
       wherein R 1  represents a substituted or unsubstituted alkyl group containing 1 to 18 carbon atoms, an aralkyl group containing 7 to 18 carbon atoms or an aryl group containing 6 to 18 carbon atoms, R 3  represents an alkyl group containing 1 to 5 carbon atoms, and P 1  and P 2  each independently represents a hydrogen atom or an amino-protecting group or P 1  and P 2  taken together represents a phthaloyl group, excluding the case in which both P 1  and P 2  are hydrogen atoms, 
 which comprises reacting an α-amino-α′,α′-dihaloketone derivative of the following formula (3):  
                     
 wherein R 1 , P 1  and P 2  are as respectively defined above, and X 1  and X 2  each independently represents a halogen atom, with a lithium amide and an alkyllithium in succession,  
 and treating the reaction product with an acid in an alcohol.  
 
     
     
         15 . The process according to  claim 14   wherein X 1  and X 2  each independently represents a chlorine atom or a bromine atom.    
     
     
         16 . The process according to  claim 14  or  15  
 wherein the lithium amide is lithium hexamethyldisilazide or lithium diisopropylamide,  
 the alkyllithium is n-butyllithium,  
 and the alcohol is methanol or ethanol.  
 
     
     
         17 . The process according to  claim 14 ,  15  or  16  
 wherein R 1  represents benzyl or phenyl,  
 P 1  represents t-butyloxycarbonyl, benzyloxycarbonyl, methyloxycarbonyl or ethyloxycarbonyl,  
 and P 2  represents hydrogen.  
 
     
     
         18 . The process according to  claim 14 ,  15 ,  16  or  17  
 wherein the α-amino-α′,α′-dihaloketone derivative of the formula (3) is an optically active compound.  
 
     
     
         19 . An α-amino-α′,α′-dihaloketone derivative of the following general formula (3):  
       
         
           
           
               
               
           
         
         wherein P 1  and P 2  each independently represents a hydrogen atom or an amino-protecting group or P 1  and P 2  taken together represents a phthaloyl group, exclusive of the case in which both P 1  and P 2  are hydrogen atoms,  
         R 1  represents a benzyl group,  
         X 1  represents a bromine atom, and  
         X 2  represents a chlorine atom or a bromine atom.  
       
     
     
         20 . The α-amino-α′,α′-dihaloketone derivative according to  claim 19  
 wherein P 1  represents a t-butyloxycarbonyl, benzyloxycarbonyl, methyloxycarbonyl or ethyloxycarbonyl group, and  
 P 2  represents a hydrogen atom.