Processes for preparing zonisamide intermediates and novel crystalline forms of zonisamide intermediates

Abstract

The present invention relates to a novel sulfonation of an intermediate of zonisamide. The sulfonation processes using chlorosulfonic acid as well as acetic anhydride and sulfuric acid in an organic solvent are disclosed. Crystalline forms of benzisoxazole methane sulfonic acid (BOS-H) and its salts (BOS-Na, BOS-Ca, and BOS-Ba) and their novel preparation processes are disclosed.

1 - 7 . (Canceled)  
     
     
         8 . A process for preparing an intermediate of zonisamide comprising the steps of: 
 a) preparing an acyl sulfate in a solution;    b) adding benzisoxazole acetic acid to the solution to obtain a mixture wherein the benzisoxazole acetic acid is sulfonated by the acyl sulfate to form the intermediate of zonisamide;    c) heating the mixture; and    d) isolating the intermediate of zonisamide.    
     
     
         9 . The process according to  claim 8 , wherein the intermediate of zonisamide is benzisoxazole methane sulfonic acid.  
     
     
         10 . The process according to  claim 8 , wherein the acyl sulfate is formed by preparing a mixture in a solvent, wherein the mixture is selected from the group consisting of (i) an anhydride and sulfuric acid, and (ii) an acyl halide and sulfuric acid.  
     
     
         11 . The process according to  claim 10 , wherein the acyl sulfate is formed in situ.  
     
     
         12 . The process according to  claim 10 , wherein the anhydride is selected from the group consisting of acetic anhydride, propionic anhydride and butyric anhydride.  
     
     
         13 . The process according to  claim 10 , wherein the anhydride is acetic anhydride.  
     
     
         14 . The process according to  claim 10 , wherein the acyl sulfate is selected from the group consisting of acetyl sulfate, propionyl sulfate and butyryl sulfate.  
     
     
         15 . The process according to  claim 10 , wherein the solvent is selected from the group consisting of a polar solvent and a non-polar solvent.  
     
     
         16 . The process according to  claim 15 , wherein the polar solvent is selected from the group consisting of ethyl acetate, ethylcellosolve, methylcellosolve, dichloroethane, dichloromethane, chloroform or mixture thereof.  
     
     
         17 . The process according to  claim 15 , wherein the non-polar solvent is selected from the group consisting of toluene, heptane, hexane, alkane or mixture thereof.  
     
     
         18 . The process according to  claim 15 , wherein the solvent is ethyl acetate.  
     
     
         19 . The process according to  claim 8 , wherein the benzisoxazole acetic acid is added to the solution in a molar ratio of benzisoxazole acetic acid: acyl sulfate of about 1:1 to about 1:1.3.  
     
     
         20 . The process according to  claim 8 , wherein the mixture is heated at a temperature between about 5° C. to about 150° C.  
     
     
         21 . The process according to  claim 8 , wherein the mixture is heated at a temperature between about 5° C. to about 120° C.  
     
     
         22 . The process according to  claim 8 , wherein the mixture is heated at a temperature between about 20° C. to about 80° C.  
     
     
         23 . A process for preparing an intermediate of zonisamide comprising the steps of: 
 a) preparing a mixture of benzisoxazole acetic acid and an anhydride in a solvent to form a mixture;    b) preparing an acyl sulfate in the mixture wherein the benzisoxazole acetic acid is sulfonated by the acyl sulfate to form the intermediate of zonisamide;    c) heating the mixture; and    d) isolating the intermediate of zonisamide.    
     
     
         24 . The process according to  claim 23 , wherein the acyl sulfate is formed by adding sulfuric acid drop-wise to the mixture containing benzisoxazole acetic acid and the anhydride.  
     
     
         25 . Benisoxazole methane sulfonic acid as prepared according to claim  1 , wherein the benzisoxazole methane sulfonic acid is substantially free of disulfonated benzisoxazole derivatives.  
     
     
         26 . Benisoxazole methane sulfonic acid as prepared according to  claim 8 , wherein the benzisoxazole methane sulfonic acid is substantially free of disulfonated benzisoxazole derivatives.  
     
     
         27 . Benisoxazole methane sulfonic acid as prepared according to  claim 23 , wherein the benzisoxazole methane sulfonic acid is substantially free of disulfonated benzisoxazole derivatives.  
     
     
         28 - 31 . (Canceled)  
     
     
         32 . A crystalline BOS-Na Form I.  
     
     
         33 . A crystalline BOS-Na Form I, characterized by an X-Ray powder diffraction pattern (XRD) having main peaks at about 5.0, 17.3, 18.0, 18.6 and 19.7±0.2 degrees two theta.  
     
     
         34 . A crystalline BOS-Na Form I, characterized by an X-Ray powder diffraction pattern (XRD) having main peaks at about 5.0, 15.7, 16.5, 17.3, 18.6, 19.1, 19.7, 21.5, 22.8, 23.2, 23.5 and 24.3±0.2 degrees two theta.  
     
     
         35 . A crystalline BOS-Na Form I, characterized by a Fourier Transform Infra Red Spectroscopy (FTIR) spectrum having peaks at about 3546, 3485, 3440, 1641, 669 and 593 cm −1 .  
     
     
         36 . A crystalline BOS-Na Form I, characterized by a Fourier Transform Infra Red Spectroscopy (FTIR) spectrum having peaks at about 3546, 3485, 3440, 1612, 1513, 1439, 1410, 1382, 1234, 1199, 1048, 918, 855, 760, 669 and 593 cm −1 .  
     
     
         37 . A crystalline BOS-Na Form I of  claim 32 , wherein the BOS-Na Form I has a water content of about 7%.  
     
     
         38 - 43 . (Canceled).  
     
     
         44 . A crystalline BOS-Na Form III.  
     
     
         45 . A crystalline BOS-Na Form III, characterized by an X-Ray Powder Diffraction pattern (XRD) having main peaks at about 5.0, 5.3, and 17.8±0.2 degrees two theta.  
     
     
         46 . A crystalline BOS-Na Form III, characterized by an X-Ray Powder Diffraction pattern (XRD) having main peaks at about 5.0, 5.3, 15.7, 17.8 and 21.4±0.2 degrees two theta.  
     
     
         47 . A crystalline BOS-Na Form III, characterized by a Fourier Transform Infra Red Spectroscopy (FTIR) spectrum having peaks at about 3604, 1065, 812 and 696 cm −1.    
     
     
         48 . A crystalline BOS-Na Form III, characterized by a Fourier Transform Infra Red Spectroscopy (FTIR) spectrum having peaks at about 3604, 3495, 3067, 2998, 2951, 1605, 1516, 1438, 1382, 1215, 1136, 1065, 1052, 777, 747, 696, 588 and 521 cm −1 .  
     
     
         49 . A crystalline BOS-Na Form V.  
     
     
         50 . A crystalline BOS-Na Form V, characterized by an X-Ray Powder Diffraction pattern (XRD) having main peaks at about 6.7, 10.9, 16.1, 21.0, 21.2 and 22.2±0.2 degrees two theta.  
     
     
         51 . A crystalline BOS-Na Form V, characterized by a Fourier Transform Infra Red Spectroscopy (FTIR) spectrum having peaks at 3601, 3520, 1587, 1055, 793 and 753 cm −1 .  
     
     
         52 . The crystalline BOS-Na Form V as in  claim 49 , wherein the BOS-Na Form V has a water content of less than about 1.5%.  
     
     
         53 . A crystalline BOS-Ba Form I.  
     
     
         54 . A crystalline BOS-Ba Form I, characterized by an X-Ray Diffraction pattern having main peaks at about 5.2, 10.4, 12.0, 13.8, 15.6, 17.0, 23.9 and 25.4±0.2 degrees two theta.  
     
     
         55 . A crystalline BOS-Na Form I, characterized by a Fourier Transform Infra Red Spectroscopy (FTIR) spectrum having peaks at about 3544, 3491, 2985, 2943, 1626, 1610, 1509, 1437, 1383, 1369, 1223, 1209, 1175, 1153, 1055, 1043, 911, 869, 752, 651, 603, 543 and 511 cm −1 .  
     
     
         56 . The crystalline BOS-Ba Form I of  claim 53 , wherein the BOS-Ba Form I has a water content about 3.5%.  
     
     
         57 . A crystalline BOS-Ca Form I.  
     
     
         58 . A crystalline BOS-Ca Form I, characterized by an X-Ray Diffraction pattern having main peaks at about 5.4, 11.7, 16.0, 16.7, 17.7, 18.1, 19.1, 20.8, 24.5, 24.9 and 29.2±0.2 degrees two theta.  
     
     
         59 . A crystalline BOS-H monohydrate Form I.  
     
     
         60 . A crystalline BOS-H monohydrate Form I, characterized by an X-Ray Diffraction pattern having main peaks at about 13.8, 14.4, 17.4, 17.8, 21.8, 22.2, 25.8, 27.8±0.2 degrees two theta.  
     
     
         61 . The crystalline BOS-H monohydrate Form I of  claim 59 , wherein the BOS-H monohydrate Form I has a water content about 7.6%.  
     
     
         62 . A process of preparing a BOS-Na Form I, comprising the steps of: 
 1) preparing a mixture of chlorosulfonic acid in an organic solvent;    2) adding benzisoxazole acetic acid (BOA) BOA to the mixture;    3) treating the mixture from step 2) with NaOH to raise the pH; and    4) isolating the BOS-Na Form I.    
     
     
         63 . The process according to  claim 62 , wherein the pH is raised to about 10.  
     
     
         64 . The process according to  claim 62 , wherein the organic solvent is ethyl acetate.  
     
     
         65 . A process of preparing a BOS-Na Form 1, comprising the steps of: 
 1) preparing a mixture of an anhydride and sulfuric acid to form an acyl sulfate in the presence of an organic solvent;    2) adding benzisoxazole acetic acid (BOA) to the mixture;    3) treating the mixture from step 2) with NaOH to raise the pH;    4) cooling the mixture from step 3) to form a precipitate;    5) drying the precipitate; and    6) keeping the dry precipitate at room temperature to obtain the BOS-Na Form I.    
     
     
         66 . The process according to  claim 65 , wherein the solvent is ethyl acetate.  
     
     
         67 . The process according to  claim 65 , wherein the step 6) is performed for about 5 months.  
     
     
         68 . A process of preparing a BOS-Na Form II, comprising the steps of: 
 1) preparing a mixture of an anhydride and sulfuric acid to form an acyl sulfate in the presence of ethyl acetate;    2) adding benzisoxazole acetic acid (BOA) to the mixture;    3) treating the mixture from step 2) with NaOH to raise the pH;    4) cooling the mixture to form a precipitate; and    5) drying the precipitate at 80° C. to obtain the BOS-Na Form II.    
     
     
         69 . A process of preparing a BOS-Na Form III, comprising the steps of: 
 1) preparing a mixture of an anhydride and sulfuric acid to form an acyl sulfate in the presence of toluene;    2) adding benzisoxazole acetic acid (BOA) to the mixture;    3) treating the mixture from step 2) with NaOH to raise the pH;    4) cooling the mixture from step 3) to form a precipitate; and    5) drying the precipitate at 80° C. to obtain the BOS-Na Form III.    
     
     
         70 . A process of preparing a BOS-Na Form V, comprising the steps of: 
 1) preparing a mixture of an anhydride and sulfuric acid to form an acyl sulfate;    2) adding benzisoxazole acetic acid (BOA) to the mixture;    3) treating the mixture from step 2) with NaOH to raise the pH;    4) cooling the mixture from step 3) to form a precipitate; and    5) drying the precipitate at about 85° C. to obtain the BOS-Na Form V.    
     
     
         71 . A process of preparing a BOS-Ba Form I, comprising the steps of: 
 1) preparing a mixture of chlorosulfonic acid and an organic solvent;    2) adding benzisoxazole acetic acid (BOA) to the mixture;    3) treating the mixture from step 2) with Ba(OH) 2 ; and    4) isolating the BOS-Ba Form I.    
     
     
         72 . The process according to  claim 71 , wherein the organic solvent is methylene chloride.  
     
     
         73 . A process of preparing a BOS-Ca Form 1, comprising the steps of. 
 1) preparing a mixture of chlorosulfonic acid and an organic solvent;    2) adding benzisoxazole acetic acid (BOA) to the mixture;    3) treating the mixture from step 2) with Ca(OH) 2 ; and    4) isolating the BOS-Ca Form I.    
     
     
         74 . The process according to  claim 73 , wherein the pH is raised to about 12.  
     
     
         75 . The process according to  claim 73 , wherein the organic solvent is methylene chloride.  
     
     
         76 . The process according to claim  1 , wherein the sodium salt of benzisoxazole methane sulfonic acid is thereafter converted to 1,2-benzisoxazole-3-methane sulfonamide.  
     
     
         77 . The process according to  claim 8 , wherein the sodium salt of benzisoxazole methane sulfonic acid is thereafter converted to 1,2-benzisoxazole-3-methane sulfonamide.  
     
     
         78 . The process according to  claim 23 , wherein the sodium salt of benzisoxazole methane sulfonic acid is thereafter converted to 1,2-benzisoxazole-3-methane sulfonamide.  
     
     
         79 . 1,2-benzisoxazole-3-methane sulfonamide prepared in accordance with the process of  claim 76 .  
     
     
         80 . 1,2-benzisoxazole-3-methane sulfonamide prepared in accordance with the process of  claim 77 .  
     
     
         81 . 1,2-benzisoxazole-3-methane sulfonamide prepared in accordance with the process of  claim 78 .  
     
     
         82 . The process according to  claim 62 , wherein the BOS-Na Form I is thereafter converted to 1,2-benzisoxazole-3-methane sulfonamide.  
     
     
         83 . The process according to  claim 65 , wherein the BOS-Na Form I is thereafter converted to 1,2-benzisoxazole-3-methane sulfonamide.  
     
     
         84 . The process according to  claim 68 , wherein the BOS-Na Form II is thereafter converted to 1,2-benzisoxazole-3-methane sulfonamide.  
     
     
         85 . The process according to  claim 69 , wherein the BOS-Na Form II is thereafter converted to 1,2-benzisoxazole-3-methane sulfonamide.  
     
     
         86 . The process according to  claim 70 , wherein the BOS-Na Form V is thereafter converted to 1,2-benzisoxazole-3-methane sulfonamide.  
     
     
         87 . The process according to  claim 71 , wherein the BOS-Ba Form I is thereafter converted to 1,2-benzisoxazole-3-methane sulfonamide.  
     
     
         88 . The process according to  claim 73 , wherein the BOS-Ca Form I is thereafter converted to 1,2-benzisoxazole-3-methane sulfonamide.