Method for preparing (1R,4S)-2-azabicyclo[2.2.1]hept-5-ene-3-one derivatives

Abstract

A biotechnological method is described for preparing compounds of the general formulas wherein R 1 is acyl or acyloxy and R 2 is a hydrogen atom or C 1-10 alkyl, comprising the conversion of a lactam of the general formula by means of a hydrolase in the presence of a nucleophile and in the presence of a base in a constant pH range. Also described is the subsequent conversion of the compound of general formula I into the optically active 1-amino-4-(hydroxymethyl)-2-cyclopentene of the formula

1 . Method for preparing optically active compounds of the general formulas  
       
         
           
           
               
               
           
         
       
       wherein R 1  is acyl or acyloxy and R 2  is a hydrogen atom or C 1-10  alkyl,  
       wherein a racemic lactam of the general formula  
       
         
           
           
               
               
           
         
       
       is converted by means of a hydrolase in the presence of a nucleophile and in the presence of a base in a constant pH range.  
     
     
         2 . Method according to  claim 1 , characterized in that a protease or lipase is used as the hydrolase.  
     
     
         3 . Method according to  claim 2 , characterized in that a serinprotease is used as the protease.  
     
     
         4 . Method according to  claim 3 , characterized in that a subtilisin is used as the serinprotease.  
     
     
         5 . Method according to at least one of  claims 1  to  4 , characterized in that 2-acetyl-2-azabicyclo[2.2.1]hept-5-ene-3-one or 2-ethoxycarbonyl-2-azabicyclo[2.2.1]hept-5-ene-3-one is used as the racemic lactam of general formula III.  
     
     
         6 . Method according to at least one of  claims 1  to  5 , characterized in that the conversion is conducted in water, a buffer solution, a C 1-10  alcohol or in a mixture of these with an aprotic organic solvent.  
     
     
         7 . Method according to at least one of  claims 1  to  6 , characterized in that the reaction is conducted at a temperature of 10 to 60° C.  
     
     
         8 . Method for the preparation of optically active 1-amino-4-(hydroxymethyl)-2-cyclopentene derivatives of the general formula  
       
         
           
           
               
               
           
         
       
       wherein R 1  is the same as in  claim 1 , characterized in that a lactam of the general formula  
       
         
           
           
               
               
           
         
       
       wherein R 1  is the same as in  claim 1 , is converted by means of a hydrolase in the presence of a nucleophile and in the presence of a base in a constant pH range into the compound of the general formula  
       
         
           
           
               
               
           
         
       
       and this is reduced to the compound of general formula IV.  
     
     
         9 . Method for the preparation of (1R,4S)-1-amino-4-(hydroxymethyl)-2-cyclopentene of the formula  
       
         
           
           
               
               
           
         
       
       or its salts, characterized in that a lactam of the general formula  
       
         
           
           
               
               
           
         
       
       wherein R 1  is the same as in  claim 1 , is converted by means of a hydrolase in the presence of a nucleophile and in the presence of a base in a constant pH range into the compound of the general formula  
       
         
           
           
               
               
           
         
       
       wherein R 1  is the same as in  claim 1 , this is then reduced to the compound of the general formula  
       
         
           
           
               
               
           
         
       
       wherein R 1  is the same, and this is then hydrolyzed to the compound of formula V.  
     
     
         10 . (1S,4R)-acetylamino-2-cyclopentene-1-carboxylic acid C 2-10  alkyl esters, excluding (1S,4R)-acetylamino-2-cyclopentene-1-carboxylic acid ethyl ester.  
     
     
         11 . (1S,4R)-acetylamino-2-cyclopentene-1-carboxylic acid ethyl ester or propyl ester.