Process for making risperidone and intermediates therefor

Abstract

The formation of risperidone is enhanced by the use of enriched Z-isomer oxime intermediate(s) of formula (3) or (7). The oxime(s) can be isomerically enriched by a variety of techniques including the use of the novel acetic acid salt thereof, which affords, inter alia, resolution of the isomers and/or by heat conversion.

1 - 15 . (canceled) 
     
     
         16 . A process, which comprises:
 providing an enriched Z-isomer oxime of formula (3) or (7):   
       
         
           
           
               
               
           
         
         as an acetic acid salt thereof, wherein said enriched Z-isomer oxime contains at least 80% of said Z-isomer; and 
         converting said enriched Z-isomer oxime into risperidone. 
       
     
     
         17 . The process according to  claim 16 , wherein said enriched Z-isomer oxime contains at least 90% of said Z-isomer. 
     
     
         18 . The process according to  claim 17 , wherein said enriched Z-isomer oxime contains at least 98% of said Z-isomer. 
     
     
         19 . The process according to  claim 16 , wherein said providing step comprises preferentially precipitating said enriched Z-isomer oxime as an acetic acid salt thereof from a solution containing said oxime of formula (3) or (7) in Z- and E-isomer forms and isolating said precipitated enriched Z-isomer oxime salt from said solution. 
     
     
         20 . The process according to  claim 19 , wherein said providing step comprises forming said oxime of formula (3) or (7) as a mixture of Z- and E-isomers in the presence of acetic acid and wherein said preferential precipitation occurs substantially spontaneously upon formation of said oxime isomers. 
     
     
         21 . The process according to  claim 16 , wherein said providing step comprises heating an oxime of formula (3) or (7) that contains an E-isomer thereof in a solvent to convert a sufficient amount of said E-isomer into Z-isomer to obtain said enriched Z-isomer oxime. 
     
     
         22 . The process according to  claim 21 , wherein said heating is carried out in the presence of an acid catalyst. 
     
     
         23 . The process according to  claim 22 , wherein said acid catalyst is selected from the group consisting of acetic acid, ammonium acetate, and piperidine acetate. 
     
     
         24 . The process according to  claim 23 , which further comprises cooling said enriched Z-isomer and precipitating said enriched Z-isomer from said solvent as said enriched Z-isomer oxime salt. 
     
     
         25 - 30 . (canceled) 
     
     
         31 . The process according to  claim 16 , wherein said enriched Z-isomer is the Z-isomer of an oxime of formula (7). 
     
     
         32 . The process according to  claim 31 , wherein said converting step comprises cyclizing said oxime of formula (7) to form risperidone. 
     
     
         33 - 39 . (canceled) 
     
     
         40 . The process according to  claim 32 , wherein said converting step further comprises liberating the enriched Z-isomer oxime of formula (7) from said enriched Z-isomer oxime salt prior to said cyclizing. 
     
     
         41 . The process according to  claim 16 , wherein said enriched Z-isomer is the Z-isomer of the oxime of formula (3). 
     
     
         42 . The process according to  claim 41 , wherein said converting step comprises alkylating and cyclizing. 
     
     
         43 . The process according to  claim 42 , wherein said converting step further comprises liberating the enriched Z-isomer oxime of formula (3) from said enriched Z-isomer oxime salt before said alkylating and cyclizing steps. 
     
     
         44 . The process according to  claim 43 , wherein said alkylating comprises reacting said enriched Z-isomer oxime of formula (3) with a compound of formula (5) 
       
         
           
           
               
               
           
         
       
       to form a compound of formula (7) 
       
         
           
           
               
               
           
         
       
     
     
         45 . The process according to  claim 44 , wherein said cyclizing comprises treating said compound of formula (7) with base to form risperidone. 
     
     
         46 . The process according to  claim 43 , wherein said cyclizing comprises treating said enriched Z-isomer oxime of formula (3) with base to form a compound of formula (4) 
       
         
           
           
               
               
           
         
       
     
     
         47 . The process according to  claim 46 , wherein said alkylating comprises reacting said compound of formula (4) with a compound of formula (5) 
       
         
           
           
               
               
           
         
       
       to form risperidone.