Process for the production of paroxetine

Abstract

The synthesis of paroxetine can be made more convenient by using a solvent system comprising an aliphatic alcohol and a hydrocarbon co-solvent. The solvent system is used particularly in the hydrolysis of paroxetine phenylcarbamate and preferably uses butanol and toluene as the system.

We claim:  
     
         1 . A process for the production of paroxetine, which comprises hydrolyzing a paroxetine phenylcarbamate of formula (3)  
       
         
           
           
               
               
           
         
       
       with a hydrolyzing agent in a solvent system comprising an aliphatic alcohol and a hydrocarbon co-solvent, to form a paroxetine compound of formula (1)  
       
         
           
           
               
               
           
         
       
     
     
         2 . The process according to  claim 1 , wherein said alcohol has a boiling point from about 70° C. to about 150° C.  
     
     
         3 . The process according to  claim 2 , wherein said alcohol is selected from the group consisting of ethanol, n-propanol, isopropanol, 1-butanol, 2-butanol and tertiary butanol.  
     
     
         4 . The process according to  claim 3 , wherein said alcohol is 1-butanol.  
     
     
         5 . The process according to  claim 1 , wherein said hydrocarbon co-solvent is selected from the group consisting of benzene, cyclohexane, xylene, toluene, and combination of two or more thereof.  
     
     
         6 . The process according to  claim 3 , wherein said hydrocarbon co-solvent is selected from the group consisting of benzene, cyclohexane, xylene, toluene, and combination of two or more thereof.  
     
     
         7 . The process according to  claim 4 , wherein said hydrocarbon co-solvent is selected from the group consisting of benzene, cyclohexane, xylene, toluene, and combination of two or more thereof.  
     
     
         8 . The process according to  claim 7 , wherein said co-solvent is toluene.  
     
     
         9 . The process according to  claim 1 , wherein the ratio of said alcohol solvent to said co-solvent is within the range of 100-1:1 based on volume.  
     
     
         10 . The process according to  claim 9 , wherein said solvent system comprises 1-butanol and toluene in a volume ratio of about 2.5:1.  
     
     
         11 . The process according to  claim 1 , wherein said hydrolyzing agent is an alkali metal-containing compound.  
     
     
         12  The process according to  claim 11 , wherein said hydrolyzing agent is selected from the group consisting of an alkali metal hydroxide, an alkali metal alkoxide, an alkali metal carbonate, and combinations of two or more thereof.  
     
     
         13 . The process according to  claim 12 , wherein said hydrolyzing agent is potassium hydroxide.  
     
     
         14 . The process according to  claim 1 , wherein said hydrolyzing proceeds essentially in solution.  
     
     
         15 . The process according to  claim 1 , which further comprises reacting N-methylparoxetine of formula (2)  
       
         
           
           
               
               
           
         
       
       with a phenyl haloformate to form said paroxetine phenylcarbamate of formula (3).  
     
     
         16 . The process according to  claim 15 , wherein said phenyl haloformate is phenyl chloroformate.  
     
     
         17 . The process according to  claim 16 , wherein said N-methylparoxetine is reacted with said phenyl haloformate in a hydrocarbon solvent.  
     
     
         18 . The process according to  claim 16 , wherein said hydrocarbon solvent is used in said solvent system as said co-solvent.  
     
     
         19 . The process according to  claim 18 , wherein the mixture of N-methyl paroxetine, phenyl haloformate, and hydrocarbon solvent is substantially not subjected to any processing steps.  
     
     
         20 . The process according to  claim 18 , wherein said paroxetine phenylcarbamate is not isolated before being subjected to said hydrolyzing reaction.  
     
     
         21 . The process according to  claim 1 , which further comprises converting said paroxetine into a pharmaceutically acceptable acid addition salt thereof.  
     
     
         22 . The process according to  claim 21 , wherein said pharmaceutically acceptable acid addition salt is paroxetine hydrochloride.  
     
     
         23 . The process according to  claim 21 , wherein said pharmaceutically acceptable acid addition salt is paroxetine mesylate.  
     
     
         24 . A process for the production of paroxetine and/or pharmaceutically acceptable acid addition salts thereof, which comprises contacting paroxetine phenylcarbamate of formula (3) with potassium hydroxide in a butanol and toluene solvent under reflux to form paroxetine; recovering said paroxetine; and optionally exposing the paroxetine to a suitable acid.  
     
     
         25 . The process according to  claim 24 , which further comprises contacting N-methylparoxetine with phenyl chloroformate in toluene under reflux conditions to form said paroxetine phenylcarbamate.