Process for the preparation of Zonisamide and the intermediates thereof

Abstract

The present invention provides a novel and improved process for the preparation of Zonisamide and the intermediates thereof. In one aspect of the present invention, the process provides for: the preparation and isolation of a novel crystalline form of anhydrous 1,2-benzisoxazole-3-methanesulfonic acid of formula 1; the direct chlorination of the acid of formula 1 into its acid chloride of formula 2; and the in situ conversion of the intermediate acid chloride of formula 2 into Zonisamide.

1 . A process for the preparation of zonisamide, said process comprising the steps of: 
 (a) preparing 1,2-benzisoxazole-3-methanesulfonyl chloride in a reaction mixture; and    (b) treating the 1,2-benzisoxazole-3-methanesulfonyl chloride obtained in step (a) with at least one amidating agent to form zonisamide in situ.    
   
   
       2 . The process according to  claim 1  wherein the at least one amidating agent in step (b) is ammonia gas.  
   
   
       3 . The process according to  claim 1  or  2  wherein the amidation reaction is carried out in the presence of at least one organic solvent.  
   
   
       4 . The process according to  claim 3  wherein the at least one organic solvent is selected from the group consisting of C 3 -C 6  ketones, C 2 -C 4  nitriles and C 2 -C 7  esters.  
   
   
       5 . The process according to  claim 4  wherein the C 3 -C 6  ketones are selected from the group consisting of methyl isobutyl ketone and methyl ethyl ketone.  
   
   
       6 . The process according to  claim 4  wherein the C 2 -C 4  nitriles are selected from the group consisting of propionitrile and acetonitrile.  
   
   
       7 . The process according to  claim 3  wherein the at least one organic solvent is acetonitrile.  
   
   
       8 . The process according to  claim 4  wherein the C 2 -C 7  esters are selected from the group consisting of ethyl acetate, ethyl propionate, and isopropyl acetate.  
   
   
       9 . The process according to  claim 3  wherein the at least one organic solvent is ethyl acetate.  
   
   
       10 . The process of  claim 1  wherein the 1,2-benzisoxazole-3-methanesulfonyl chloride is prepared by a process comprising the steps of: 
 (a) preparing and subsequently isolating a crystalline form of anhydrous 1,2-benzisoxazole-3-methanesulfonic acid and    (b) directly chlorinating the crystalline form of anhydrous 1,2-benzisoxazole-3-methanesulfonic acid obtained in step (a) with at least one chlorinating agent in the presence of at least one aprotic organic solvent to form 1,2-benzisoxazole-3-methanesulfonyl chloride.    
   
   
       11 . The process according to  claim 10  wherein the amount of the at least one chlorinating agent of step (b) is about 0.5 to about 5 mol equivalents relative to the crystalline form of anhydrous 1,2-benzisoxazole-3-methanesulfonic acid.  
   
   
       12 . The process according to  claim 10  or  11  wherein the at least one chlorinating agent of step (b) is selected from the group consisting of oxalyl chloride, phosphorus pentachloride, and phosphorus oxychloride.  
   
   
       13 . The process according to  claim 10  or  11  wherein the at least one chlorinating agent of step (b) is phosphorus oxychloride.  
   
   
       14 . The process according to  claim 10  or  11  wherein the at least one aprotic organic solvent is selected from the group consisting of C 2 -C 4  nitriles, C 6 -C 9  aromatic hydrocarbons, C 3 -C 10  acyclic or cyclic ethers, C 3 -C 6  ketones, C 2 -C 7  esters, C 5 -C 10  aliphatic hydrocarbons; C 1  to C 3  chlorinated solvents and combinations thereof.  
   
   
       15 . The process according to  claim 12  wherein the at least one aprotic organic solvent is selected from the group consisting of C 2 -C 4  nitriles, C 6 -C 9  aromatic hydrocarbons, C 3 -C 10  acyclic or cyclic ethers, C 3 -C 6  ketones, C 2 -C 7  esters, C 5 -C 10  aliphatic hydrocarbons; C 1  to C 3  chlorinated solvents and combinations thereof.  
   
   
       16 . The process according to  claim 13  wherein the at least one aprotic organic solvent is selected from the group consisting of C 2 -C 4  nitriles, C 6 -C 9  aromatic hydrocarbons, C 3 -C 10  acyclic or cyclic ethers, C 3 -C 6  ketones, C 2 -C 7  esters, C 5 -C 10  aliphatic hydrocarbons; C 1  to C 3  chlorinated solvents and combinations thereof.  
   
   
       17 . The process according to  claim 14  wherein the C 2 -C 4  nitriles are selected from the group consisting of acetonitrile and propionitrile; the C 6 -C 9  aromatic hydrocarbons are selected from the group consisting of benzene, toluene, and xylenes; the C 3 -C 10  acyclic or cyclic ethers are selected from the group consisting of dimethoxyethane, diethyl ether, diisopropyl ether, and tetrahydrofuran; the C 3 -C 6  ketones are selected from the group consisting of methyl isobutyl ketone and methyl ethyl ketone; the C 2 -C 7  esters are selected from the group consisting of ethyl acetate, ethyl propionate, and isopropyl acetate; the C 5 -C 10  aliphatic hydrocarbons are selected from the group consisting of hexanes, heptanes, and octanes; and the C 1  to C 3  chlorinated solvents are selected from the group consisting of dichloromethane and chloroform.  
   
   
       18 . The process according to  claim 15  or  16  wherein the C 2 -C 4  nitriles are selected from the group consisting of acetonitrile and propionitrile; the C 6 -C 9  aromatic hydrocarbons are selected from the group consisting of benzene, toluene, and xylenes; the C 3 -C 10  acyclic or cyclic ethers are selected from the group consisting of dimethoxyethane, diethyl ether, diisopropyl ether, and tetrahydrofuran; the C 3 -C 6  ketones are selected from the group consisting of methyl isobutyl ketone and methyl ethyl ketone; the C 2 -C 7  esters are selected from the group consisting of ethyl acetate, ethyl propionate, and isopropyl acetate; the C 5 -C 10  aliphatic hydrocarbons are selected from the group consisting of hexanes, heptanes, and octanes; and the C 1  to C 3  chlorinated solvents are selected from the group consisting of dichloromethane and chloroform.  
   
   
       19 . The process according to  claim 10  or  11  wherein the at least one aprotic organic solvent of step (b) is acetonitrile.  
   
   
       20 . The process according to  claim 12  wherein the at least one aprotic organic solvent of step (b) is acetonitrile.  
   
   
       21 . The process according to  claim 13  wherein the at least one aprotic organic solvent of step (b) is acetonitrile.  
   
   
       22 . The process according to  claim 10  or  11  wherein the at least one aprotic organic solvent of step (b) is xylenes.  
   
   
       23 . The process according to  claim 12  wherein the at least one aprotic organic solvent of step (b) is xylenes.  
   
   
       24 . The process according to  claim 13  wherein the at least one aprotic organic solvent of step (b) is xylenes.  
   
   
       25 . The process of  claim 10  wherein the crystalline form of anhydrous 1,2-benzisoxazole-3-methanesulfonic acid is prepared by a process comprising the steps of: 
 (a) preparing 1,2-benzisoxazole-3-methanesulfonic acid in a reaction mixture;    (b) adding at least one anti-solvent to the mixture from step (a) to precipitate the crystalline form of anhydrous 1,2-benzisoxazole-3-methanesulfonic acid; and    (c) isolating the crystalline form of anhydrous 1,2-benzisoxazole-3-methanesulfonic acid.    
   
   
       26 . The process according to  claim 25  wherein the at least one anti-solvent is selected from the group consisting of C 6 -C 9  aromatic hydrocarbons and C 5 -C 10  aliphatic hydrocarbons.  
   
   
       27 . The process according to  claim 26  wherein the C 6 -C 9  aromatic hydrocarbons are selected from the group consisting of benzene, toluene, and xylenes; and the C 5 -C 10  aliphatic hydrocarbons are selected from the group consisting of hexanes, heptanes, and octanes.  
   
   
       28 . The process according to  claim 25  wherein the at least one anti-solvent is xylenes.  
   
   
       29 . A crystalline form of anhydrous 1,2-benzisoxazole-3-methanesulfonic acid when prepared by the process according to any one of  claims 25  to  28 .  
   
   
       30 . The crystalline form of anhydrous 1,2-benzisoxazole-3-methanesulfonic acid of  claim 29  characterized by an X-Ray powder diffraction (XRPD) pattern having characteristic peaks at about 9.32±0.2, 13.59±0.2, 13.78±0.2, 18.64±0.2, 22.03±0.2, 22.27±0.2, 25.31±0.2 and 25.56±0.2 degrees two theta.  
   
   
       31 . The crystalline form of anhydrous 1,2-benzisoxazole-3-methanesulfonic acid of  claim 29  characterized by an XRPD pattern having peaks at about 9.32±0.2, 13.59±0.2, 13.78±0.2, 17.31±0.2, 18.64±0.2, 19.20±0.2, 20.07±0.2, 20.11±0.2, 22.03±0.2, 22.27±0.2, 24.02±0.2, 24.19±0.2, 24.37±0.2, 24.69±0.2, 25.31±0.2, 25.56±0.2, 26.65±0.2, 28.09±0.2, 30.74±0.2, and 31.17±0.2 degrees two theta.  
   
   
       32 . The crystalline form of anhydrous 1,2-benzisoxazole-3-methanesulfonic acid according to any one of  claims 29  to  31  having a water content of less than about 2.0%.  
   
   
       33 . The crystalline form of anhydrous 1,2-benzisoxazole-3-methanesulfonic acid according to  claim 32  having a water content of about 0.8% to about 1.5%.