Novel sulfonation method for zonisamide intermediate in zonisamide synthesis and their novel crystal forms
AssigneeTeva Pharmaceutical Industries Ltd.
InventorsTamar Nidam, Marioara Mendelovici, Eduard Schwartz, Shlomit Wizel
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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.
Claims88
A process for preparing an intermediate of zonisamide, comprising the steps of:
- a) preparing a mixture of chlorosulfonic acid and an organic solvent;
- b) adding benzisoxazole acetic acid to the mixture;
- c) heating the mixture;
- and
- d) isolating the intermediate of zonisamide.
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 wherein the benzisoxazole acid is sulfonated by the acyl sulfate to form the intermediate of zonisamide;
- c) heating the solution;
- and
- d) isolating the intermediate of zonisamide.
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 acid is sulfonated by the acyl sulfate to form the intermediate of zonisamide;
- c) heating the mixture;
- and
- d) isolating the intermediate of zonisamide.
A crystalline form of benzisoxazole methane sulfonic acid.
A crystalline BOS-Na Form I.
A crystalline BOS-Na Form I, characterized by an X-Ray powder diffraction (XRD) having the main peaks at about 5.0, 17.3, 18.0, 18.6, and 19.7±0.2 degrees two theta.
A crystalline BOS-Na Form I, characterized by an X-Ray powder diffraction (XRD) having the 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.
A crystalline BOS-Na Form I, characterized by a Furier Transform Infra Red Spectroscopy (FTIR) spectrum having the following peaks at about 3546, 3485, 3440, 1641, 669 and 593 cm−1.
A crystalline BOS-Na Form I, characterized by a Furier Transform Infra Red Spectroscopy (FTIR) spectrum having the following peaks at about 3546, 3485, 3440, 1612, 1513, 1439, 1410, 1382, 1234, 1199, 1048, 918, 855, 760, 669 and 593 cm−1.
A crystalline BOS-Na Form II.
A crystalline BOS-Na Form II, characterized by an X-Ray Powder Diffraction (XRD) having the main peaks at about 5.3, 16.6, 21.3 and 26.7±0.2 degrees two theta.
A crystalline BOS-Na Form II, characterized by an X-Ray Powder Diffraction (XRD) having the main peaks at about 5.3, 15.9, 16.6, 21.3 and 26.7±0.2 degrees two theta.
A crystalline BOS-Na Form II, characterized by a Furier Transform Infra Red Spectroscopy (FTIR) spectrum having the following peaks at about 3597 and 3591 cm−1.
A crystalline BOS-Na Form II, characterized by a Furier Transform Infra Red Spectroscopy (FTIR) spectrum having the following peaks at about 3597, 3535, 3496, 3067, 2998, 2951, 1606, 1516, 1438, 1382, 1213, 1064, 1055, 743, 663, 588, 541 and 522 cm−1.
A crystalline BOS-Na Form III.
A crystalline BOS-Na Form III, characterized by an X-Ray Powder Diffraction (XRD) having the main peaks at about 5.0, 5.3, and 17.8±0.2 degrees two theta.
A crystalline BOS-Na Form III, characterized by an X-Ray Powder Diffraction (XRD) having the main peaks at about 5.0, 5.3, 15.7, 17.8 and 21.4±0.2 degrees two theta.
A crystalline BOS-Na Form III, characterized by a Furier Transform Infra Red Spectroscopy (FTIR) spectrum having the following peaks at about 3604, 1065, 812 and 696 cm−1.
A crystalline BOS-Na Form III, characterized by a Furier Transform Infra Red Spectroscopy (FTIR) spectrum having the following peaks at about 3604, 3495, 3067, 2998, 2951, 1605, 1516, 1438, 1382, 1215, 1136, 1065, 1052, 777, 747, 696, 588 and 521 cm−1.
A crystalline BOS-Na Form V.
A crystalline BOS-Na Form V, characterized by X-Ray Powder Diffraction (XRD) having the main peaks at about 6.7, 10.9, 16.1, 21.0, 21.2 and 22.2±degrees two theta.
A crystalline BOS-Na Form V, characterized by a Furier Transform Infra Red Spectroscopy (FTIR) spectrum having the following peaks at 3601, 3520, 1587, 1055, 793 and 753 cm−1.
A crystalline BOS-Ba Form I.
A crystalline BOS-Ba Form I, characterized by the following X-Ray Diffraction 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.
A crysalline BOS-Na Form I, characterized by a Furier Transform Infra Red Spectroscopy (FTIR) spectrum having the following 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.
A crystalline BOS-Ca Form I.
A crystalline BOS-Ca Form I, characterized by having the following X-Ray Diffraction 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.
A crystalline BOS-H monohydrate Form I.
A crystalline BOS-H monohydrate Form I, characterized by having the following X-Ray Diffraction 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.
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 BOA to the mixture;
- 3) treating the mixture with NaOH to raise pH;
- and 4) isolating the BOS-Na Form I.
A process of preparing a BOS-Na Form I, comprising the steps of:
- 1) preparing a mixture of an anhydride and sulfuric acid to form acyl-sulfate in the presence of an organic solvent;
- 2) adding BOA to the mixture;
- 3) treating the mixture with NaOH to raise pH;
- 4) cooling the mixture to form a precipitate;
- 5) drying the precipitate;
- and 6) keeping the dry precipitate at room temperature to obtain the BOS-Na Form I.
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 acyl-sulfate in the presence of ethyl acetate;
- 2) adding BOA to the mixture;
- and 3) treating the mixture with NaOH to raise pH;
- 4) cooling the mixture to form a precipiate;
- and 5) drying the preciptate at 80° C. to obtain the BOS-Na Form II.
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 acyl-sulfate in the presence of toluene;
- 2) adding BOA to the mixture;
- 3) treating the mixture with NaOH to raise pH;
- 4) cooling the mixture to form a precipitate;
- and 5) drying the preciptate at 80° C. to obtain the BOS-Na Form III.
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 acyl-sulfate;
- 2) adding BOA to the mixture;
- 3) treating the mixture with NaOH to raise pH;
- 4) cooling the mixture to form a precipitate;
- and 5) drying the preciptate at about 85° C. to obtain the BOS-Na Form V.
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 BOA to the mixture;
- 3) treating the mixture with Ba(OH)2;
- and 4) isolating the BOS-Ba Form I.
A process of preparing a BOS-Ca Form I, comprising the steps of:
- 1) preparing a mixture of chlorosulfonic acid and an organic solvent;
- 2) adding BOA the mixture;
- 3) treating the mixture with Ca(OH)2;
- and 4) isolating the BOS-Ca Form I.
Dependencies are inferred from the claim text.