Claims
- 1. A process of preparing BOS-Cl, comprising the step of chlorinating at least one compound selected from the group consisting of BOS-H and salts and esters thereof, with SOCl2 in an organic solvent.
- 2. The process according to claim 1, wherein the compound is BOS-H.
- 3. The process according to claim 1, wherein the compound is BOS-Na.
- 4. The process according to one of claims 1-3, wherein the organic solvent is formamide.
- 5. The process according to claim 4, wherein the formamide is di-substituted formamide.
- 6. The process according to claim 5, wherein the di-substituted formamide comprises at least one C1-C6 alkyl substituent.
- 7. The process according to claim 6, wherein the di-substituted formamide is DMF.
- 8. The process according to claim 7, wherein the eq. ratio of SOCl2 and DMF is about 0.5:1.
- 9. The process according to claim 7, wherein the eq. ratio of SOCl2 and DMF is about 1:1.
- 10. The process according to claim 7, wherein the eq. ratio of SOCl2 and DMF is about 1.5:1.
- 11. The process according to claim 7, wherein the eq. ratio of SOCl2 and DMF is about 3:1.
- 12. A process of preparing BOS-Cl, comprising the step of chlorinating at least one compound selected from the group consisting of BOS-H and salts and esters thereof, with SOCl2 in an inert organic solvent and in the presence of a catalyst.
- 13. The process according to claim 12, wherein the compound is BOS-H.
- 14. The process according to claim 12, wherein the compound is BOS-Na.
- 15. The process according to one of claims 12-14, wherein the inert organic solvent is selected from the group consisting of ethyl acetate, chlorobenzene, ethers, THF, MTBE, chloroform, methylene chloride, dichloroethane, dichloromethane, toluene and mixtures thereof.
- 16. The process according to claim 15, wherein the inert organic solvent is toluene.
- 17. The process according to claim 12, wherein the catalyst is formamide.
- 18. The process according to claim 17, wherein the formamide is a lower alkyl substituted formamide, wherein the alkyl is C1-C6.
- 19. The process according to claim 18, wherein the lower alkyl substituted formamide is mono-substituted formamide.
- 20. The process according to claim 19, wherein the mono-substituted formamide is N-methyl formamide.
- 21. The process according to claim 18, wherein the lower alkyl substituted formamide is di-substituted formamide.
- 22. The process according to claim 21, wherein the di-substituted formamide comprises at least one C1-C6 alkyl substituent.
- 23. The process according to claim 21, wherein the di-substituted formamide is selected from the group consisting of DMF, N,N-dipropyl formamide, and N-methyl formanilide.
- 24. The process according to claim 23, wherein the di-substituted formamide is DMF.
- 25. The process according to claim 24, wherein the SOCl2 is about 2 to about 6 eq. relative to the BOS-Na.
- 26. The process according to claim 24, wherein the SOCl2 is about 3 to about 4 eq. relative to the BOS-Na.
- 27. The process according to claim 24, wherein the DMF is about 3 to about 50% mole relative to the BOS-Na.
- 28. The process according to claim 24, wherein the DMF is about 5 to about 30% mole relative to the BOS-Na.
- 29. The process according to claim 24, wherein the DMF is about 10% mole relative to the BOS-Na.
- 30. The process according to claim 24, wherein the chlorinating step is performed at a temperature between room temperature and the reflux temperature of toluene.
- 31. The process according to claim 24, wherein the chlorinating step is performed at about 50° to about 60° C.
- 32. The process according to claim 24, wherein the SOCl2 is added over about 2 to about 6 hours.
- 33. The process according to claim 24, wherein the SOCl2 is added over about 3 to about 4 hours.
- 34. A process of preparing zonisamide, comprising the step of amidating BOS-Cl in the presence of aqueous ammonia in a biphasic system, wherein the biphasic system contains a first aqueous solvent phase and a second water-immiscible solvent phase.
- 35. The process according to claim 34, wherein the first aqueous solvent phase is aqueous ammonia and the second water-immiscible solvent solvent phase is toluene.
- 36. The process according to claim 35, wherein the aqueous ammonia is about 20% wt.
- 37. The process according to claim 36, wherein the amidating step is performed at a temperature of about 20° C.
- 38. The process according to claim 36, wherein the amidating step is performed for about 20 hours.
- 39. A process of preparing zonisamide, comprising the step of amidating BOS-Cl in a solvent selected from the group consisting of acetone, MEK, MIBK, and ethylacetate and in the presence of masked ammonia.
- 40. The process according to claim 39, wherein the masked ammonia is ammonium salt selected from the group consisting of ammonium carbonate, ammonium acetate and ammonium formate.
- 41. The process according to claim 39, wherein the masked ammonia is ammonium carbonate.
- 42. The process according to claim 41, wherein the ammonium carbonate is about 3 to about 10 eq. relative to BOS-Cl.
- 43. The process according to claim 41, wherein the ammonium carbonate is in the amount of about 5 to about 6 eq. relative to BOS-Cl.
- 44. The process according to claim 41, wherein the amidating step is performed at a temperature of about −10 to about 100° C.
- 45. The process according to claim 41, wherein the amidating step is preformed at a temperature of about 50° C.
- 46. The process according to claim 41, wherein the amidating step is performed for about 1 hour.
- 47. A process of preparing zonisamide, comprising the step of amidating BOS-Cl in the presence of anhydrous ammonia.
- 48. The process of claim 47, wherein the anhydrous ammonia is gas.
- 49. The process according to claim 48, wherein the anhydrous ammonia gas contains less than about 200 ppm water.
- 50. The process according to claim 48, wherein the anhydrous ammonia gas contains less than about 20 ppm water.
- 51. The process according to claim 48, wherein the amidating step is performed at a temperature of about 0 to about 25° C.
- 52. The process according to claim 48, wherein the amidating step is performed at a temperature of about 10 to about 15° C.
- 53. Zonisamide prepared according to the process of claim 48, wherein the zonisamide contains less than about 0.1% wt BOS-NH4.
- 54. Zonisamide essentially free of BOS-NH4, wherein the zonisamide contains less than about 0.1% wt BOS-NH4.
- 55. A process of preparing zonisamide, comprising the step of amidating BOS-Cl in an anhydrous solvent and in the presence of anhydrous ammonia.
- 56. The process of claim 55, wherein the solvent is toluene and ammonia is gas.
- 57. The process according to claim 56, wherein the anhydrous toluene is obtained by drying toluene with metallic sodium.
- 58. The process according to claim 56, wherein the anhydrous ammonia gas is obtained by drying ammonia gas with a drying agent selected from the group consisting of CaCl2, silica gel, metallic sodium, alumina, MgSO4, Na2SO4, and BaO.
- 59. Zonisamide prepared according to the process of claim 55, wherein the zonisamide contains less than about 5% wt BOS-NH4.
- 60. Zonisamide Zonisamide prepared according to the process of claim 55, wherein the zonisamide contains less than about 3% wt BOS-NH4.
- 61. Zonisamide Zonisamide prepared according to the process of claim 55, wherein the zonisamide contains less than about 2.4% wt BOS-NH4.
- 62. A process of preparing zonisamide, comprising the steps of:
a) chlorinating at least one compound selected from the group consisting of BOS-H and salts and esters thereof, with SOCl2; b) amidating BOS-Cl in the presence of an amidating agent selected from the group consisting of aqueous ammonia in a biphasic system, masked ammonia and dry ammonia gas; and c) isolating zonisamide.
- 63. The process of claim 62, wherein step a) further comprises chlorinating the at least one compound selected from the group consisting of BOS-H and salts and esters thereof, with SOCl2 in an inert organic solvent.
- 64. The process of claim 62, wherein step a) further comprises chlorinating the at least one compound selected from the group consisting of BOS-H and salts and esters thereof, with SOCl2 in an inert organic solvent and in the presence of a catalyst.
- 65. The process of claim 62, further comprising performing step b) under anhydrous conditions.
- 66. The process of claim 65, wherein step b) is performed in a reactor equipped with drying tubes.
- 67. The process according to claim 62, wherein the compound is BOS-H.
- 68. The process according to claim 62, wherein the compound is BOS-Na.
- 69. The process according to one of claims 62-68, wherein the inert organic solvent is selected from the group consisting of ethyl acetate, chlorobenzene, ethers, THF, MTBE, chloroform, methylene chloride, dichloroethane, dichloromethane, toluene and mixtures thereof.
- 70. The process according to claim 69, wherein the inert organic solvent is toluene.
- 71. The process according to claim 62, wherein the catalyst is di-substituted formamide.
- 72. The process according to claim 71, wherein the di-substituted formamide comprises at least one C1-C6 alkyl substituent.
- 73. The process according to claim 72, wherein the di-substituted formamide is selected from the group consisting of N,N-dimethyl formamide, N,N-dipropyl formamide, DMF and N-methylformanilide.
- 74. The process according to claim 72, wherein the di-substituted formamide is DMF.
- 75. The process according to claim 74, wherein the amidating agent is aqueous ammonia in a biphasic system, wherein the biphasic system contains a first aqueous solvent phase and a second water-immiscible solvent phase.
- 76. The process of claim 75, wherein the first aqueous solvent phase is aqueous ammonia and the second water-immiscible solvent phase is toluene.
- 77. The process according to claim 74, wherein the amidating agent is masked ammonia.
- 78. The process according to claim 77, wherein the masked ammonia is ammonium salt selected from the group consisting of ammonium carbonate, ammonium acetate and ammonium formate.
- 79. The process according to claim 74, wherein the amidating agent is anhydrous ammonia gas.
- 80. The process according to claim 74, wherein the organic solvent is anhydrous toluene and the amidating agent is anhydrous ammonia gas.
- 81. The process of claim 64, further comprising the step of crystallizing zonisamide.
- 82. The process according to claim 81, wherein the crystallizing step is performed in ethanol, absolute ethanol, methanol, isopropyl alcohol or mixtures thereof.
- 83. The process according to claim 82, wherein the ethanol is at least about 95%.
- 84. Zonisamide prepared according to the method of claim 79, wherein the zonisamide contains less than about 0.1% BOS-NH4.
- 85. Zonisamide prepared according to the method of claim 81, wherein the zonisamide contains less than about 0.02% wt BOS-NH4.
CROSS-REFERENCE TO RELATED APPLICATION
[0001] This application claims the benefit under 35 U.S.C. § 1.119(e) of Provisional Application Serial No. 60/358,916 filed Feb. 22, 2002, the disclosure of which is incorporated by reference in its entirety herein.
Provisional Applications (1)
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Number |
Date |
Country |
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60358916 |
Feb 2002 |
US |