Oxopyrrolidine compounds, preparation of said compounds and their use in the manufacturing of levetiracetam and analogues

Abstract

The present invention relates to an improved process for the preparation of (S)-(-)-α-ethyl-2-oxo-1-pyrrolidine acetamide and analogues thereof. The invention also relates to compounds of the general formula (6) wherein R 1 is methyl or ethyl; and R 2 is C 2 -C 4 alkyl, C 2 -C 4 alkenyl or C 2 -C 4 alkynyl, optionally substituted by one or more halogen, and their preparation processes.

1 . A compound of formula (6)  
       
         
           
           
               
               
           
         
       
       wherein 
 R 1  is methyl or ethyl; and  
 R 2  is C 2 -C 4  alkyl, C 2 -C 4  alkenyl or C 2 -C 4  alkynyl, optionally substituted by one or more halogen;  
 as well as the stereoisomers and mixtures thereof.  
 
     
     
         2 . The compound according to  claim 1 , wherein the R 2  substituent is present at position 4 on the ring structure, according to the following general formula (7).  
       
         
           
           
               
               
           
         
       
     
     
         3 . The compound according to  claim 2 , wherein R 1  is methyl and R 2  is propyl or 2,2-difluorovinyl.  
     
     
         4 . The compound according to  claim 2 , wherein R 1  is ethyl and R 2  is propyl or 2,2-difluorovinyl.  
     
     
         5 . The compound according to  claim 2 , wherein R 1  is methyl and R 2  is a substituent selected from 2-fluoro-2-methylpropyl, 2,2-difluoropropyl, cyclopropylmethyl and 2,2,2-trifluoroethyl.  
     
     
         6 . The compound according to  claim 2 , wherein R 1  is ethyl and R 2  is a substituent selected from 2-fluoro-2-methylpropyl, 2,2-difluoropropyl, cyclopropylmethyl and 2,2,2-trifluoroethyl.  
     
     
         7 . The compound according to  claim 1 , which is an S isomer, according to the following formula (8)  
       
         
           
           
               
               
           
         
       
     
     
         8 . A process for the manufacture of a compound according to  claim 1 , said process comprising following steps: 
 (a) reaction of a compound of formula (9)                          with an alcohol of formula R 1 OH wherein R 1  is as noted in  claim 1 ,    (b) reaction of the corresponding compound of formula (10) thus obtained                          with a R 2 -substituted-ethyl-4-bromobutyrate wherein R 2  is as noted in  claim 1 ,    (c) cyclisation of the corresponding compound of formula (11) thus obtained                          with a catalyst,    (d) isolation of the resulting compound.    
     
     
         9 . The process according to  claim 8 , wherein step (a) is performed in the presence of thionyl chloride and an alcohol.  
     
     
         10 . The process according to  claim 8 , wherein step (b) is performed in the presence of a base and an alcohol.  
     
     
         11 . The process according to  claim 8 , wherein the catalyst used in step (c) is pyridinol.  
     
     
         12 . The process for the manufacture of a compound according to  claim 1 , said process comprising a step of cyclisation of the compound of the formula (11)  
       
         
           
           
               
               
           
         
       
       wherein R 1  and R 2  are as in  claim 1 .  
     
     
         13 . A process for the manufacture of a compound according to  claim 1 , said process comprising following steps: 
 (a) reaction of an α-ketocarboxylic acid derivative of formula (12)                          wherein R 1  is as noted in  claim 1 , with a pyrrolidinone of formula (13)                          wherein R 2  is as noted in  claim 1 ,    (b) reaction of the corresponding compound of formula (14) thus obtained                          with hydrogen in the presence of an asymmetric hydrogenation catalyst, and    (c ) isolation of the resulting compound.    
     
     
         14 . A process for the manufacture of a compound according to  claim 1 , said process comprising following steps: 
 (a) reaction of a compound of formula (15)                          wherein R 1′  is C 1 -C 6  alkyl and X is Cl, Br, I, alkylsulphonate or sulfate; with a pyrrolidone of formula (13)                          wherein R 2  is as in  claim 1;     (b) reaction of the corresponding compound of formula (16) thus obtained                          with ethyl-X, wherein X is Cl, Br, I, alkylsulphonate or sulfate in the presence of an asymmetric alkylation catalyst or additive;    (c) optionally, when R 1′  is different from R 1 , reaction of the compound obtained in step (b) with an alcohol of formula R 1  OH, and    (d) isolation of the resulting compound of formula (6).    
     
     
         15 . A process for the manufacture of a compound according to  claim 1 , said process comprising following steps: 
 (a) reaction of a compound of general formula (20)                          wherein R 1  is as defined in  claim 1 , with a pyrrolidone of general formula (13)                          wherein R 2  is defined as in  claim 1;     (b) separation of the corresponding compound of formula (21) thus obtained                          wherein R 1  and R 2  are defined as in  claim 1;     (c) isolation of the resulting compound of formula (6).    
     
     
         16 . A process for the manufacture of a compound of formula (22′)  
       
         
           
           
               
               
           
         
       
       wherein R 2′  is hydrogen, C 1 -C 4  alkyl, C 2 -C 4  alkenyl or C 2 -C 4  alkynyl, optionally substituted by one or more halogen, said process comprising the ammonolysis of the corresponding compound of formula (6′)  
       
         
           
           
               
               
           
         
       
       wherein R 1′  is C 1 -C 6  alkyl and R 2′  is hydrogen, C 1 -C 4  alkyl, C 2 -C 4  alkenyl or C 2 -C 4  alkynyl, optionally substituted by one or more halogen, in the presence of water.  
     
     
         17 . The process according to  claim 16 , wherein said ammonolysis is performed in a mixture of water and an alcohol.  
     
     
         18 . The process according  claim 16 , wherein said ammonolysis is performed in a 30-80% (w/w) NH 3  solution in water.  
     
     
         19 . The process according to  claim 16 , wherein said ammonolysis is performed at 0 to 25° C.  
     
     
         20 . The process according to  claim 16 , wherein the molar ratio of NH 3  to the compound of formula (6′) is at least 4.  
     
     
         21 . The process according to  claim 16 , wherein a compound of formula (6′) is used wherein R 1′  is methyl and R 2′  is hydrogen.  
     
     
         22 . The process according to  claim 16 , wherein a compound of formula (6′) is used wherein R 1′  is ethyl and R 2′  is hydrogen.  
     
     
         23 . The process according to  claim 16 , wherein a compound of formula (6′) is used wherein the R 2′  substituent is present at position 4 on the ring structure, according to the following general formula (7′)  
       
         
           
           
               
               
           
         
       
     
     
         24 . The process according to  claim 16 , wherein a compound of formula (6′) or (7′) is used wherein R 2′  is selected from the group of propyl, 2,2-difluorovinyl, 2-fluoro-2-methylpropyl, 2,2-difluoropropyl, cyclopropylmethyl and 2,2,2-trifluoroethyl.  
     
     
         25 . The process according to  claim 16 , wherein compound (6′) is an S isomer according to the following formula (8′)  
       
         
           
           
               
               
           
         
       
     
     
         26 . The process according to  claim 16 , wherein compound (6′) is obtained by a process comprising following steps: 
 (a) reaction of a compound of formula (9)                          with an alcohol of formula R 1′ OH wherein R 1′  is as noted in  claim 16 ,    (b) reaction of the corresponding compound of formula (10′) thus obtained                          with a R 2′ -substituted-ethyl-4-bromobutyrate wherein R 2′  is as noted in  claim 16 ,    (c) cyclisation of the corresponding compound of formula (11′) thus obtained                          in the presence of a catalyst, and    (d) isolation of the resulting compound.    
     
     
         27 . The process according to  claim 16 , wherein compound (6′) is obtained by a process comprising a step of cyclisation of a compound of formula (11′)  
       
         
           
           
               
               
           
         
       
       wherein R 1′  and R 2′  are as noted in  claim 16 .  
     
     
         28 . The process according to  claim 16 , wherein compound (6′) is obtained by a process comprising following steps: 
 (a) reaction of an α-ketocarboxylic acid derivative of formula (12′)                          wherein R 1′  is as noted in  claim 16 , with a pyrrolidinone of formula (13′)                          wherein R 2′  is as noted in  claim 16 ,    (b) reaction of the corresponding compound of formula (14′) thus obtained                          with hydrogen in the presence of an asymmetric hydrogenation catalyst, and    (c) isolation of the resulting compound.    
     
     
         29 . The process according to  claim 16 , wherein compound (6′) is obtained by a process comprising following steps: 
 (a) reaction of a compound of formula (15′)                          wherein R 1′  is as noted in  claim 16  and X is Cl, Br, I, alkylsulphonate or sulfate; with a pyrrolidone of formula (13′)                          wherein R 2′  is as in  claim 16 ,    (b) reaction of the corresponding compound of formula (16′) thus obtained                          with ethyl-X, wherein X is Cl, Br, I, alkylsulphonate or sulfate in the presence of an asymmetric alkylation catalyst or additive,    (c) isolation of the resulting compound.    
     
     
         30 . The process according to  claim 16 , wherein compound (6′) is obtained by a process comprising following steps: 
 (a) reaction of a compound of general formula (20′)                          wherein R 1′  is as noted in  claim 16 , with a pyrrolidone of general formula (13′)                          wherein R 2′  is defined as in  claim 16 ,    (b) separation of the corresponding compound of formula (21′) thus obtained, and                          (c) isolation of the resulting compound of formula (6′).