Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
  • C07D261/20—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings condensed with carbocyclic rings or ring systems
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/08—Antiepileptics; Anticonvulsants

Definitions

• the present invention relates to a process for the preparation of crystals of zonisamide (chemical name: 1,2-benzisoxazole-3-methanesulfonamide), which is useful as an antiepileptic agent. More particularly, the present invention relates to a process for efficiently preparing crystals of zonisamide containing residual 1,2-dichloro-ethane of not more than 5 ppm.
• Zonisamide has widely been used as an antiepileptic agent in Japan and Unite States. Zonisamide and processes for the preparation thereof are disclosed in JP-A-53-77057, U.S. Pat. No. 4,172,896 and JP-A-54-163823. In addition, Yakugaku-Zasshi, vol. 116, p. 533-547 (1996) discloses that zonisamide has actually been prepared using as an intermediate 1,2-benzisoxazole-3-methanesulfonyl chloride, which is obtained by sulfonation and decarboxylation of 1,2-benzisoxazol-3-acetic acid.
• the solvent for the above sulfonation and decarboxylation is dichloro-methane in the process disclosed in Yakugaku-Zasshi, vol. 116, p. 533-5-47 (1996), and 1,2-dichloroethane in the process disclosed in JP-A-53-77057.
• a solvent may play an important role in increasing the yield rate or in determination of physical properties of drug substance such as crystal form, purity, solubility, etc., even if such a solvent is known to be toxic, there may be many cases that the use thereof in the preparation of drug substance cannot be avoided in terms of risk-benefits. In such cases, this guideline decrees that a concentration of a residual solvent in drug substance should be not more than a value of limit, which is toxicologically acceptable.
• a solvent for the preparation of the intermediate for zonisamide, 1,2-benzisoxazole-2-methansulfonyl chloride is rather 1,2-dichloroethane than dichloromethane. Because, during the decarboxylation, which is carried out after the sulfonation of 1,2-benzisoxazole-3-acetic acid, the reaction mixture requires to be heated at about 60° C., which is higher than the boiling point of dichloromethane. In addition, 1,2-dichloroethane can be used as well in the step of preparation of zonisamide by reacting 1,2-benzisoxazole-3-methanesulfonyl chloride with ammonia.
• zonisamide when zonisamide is prepared using 1,2-dichloro-ethane, the residual concentration thereof should be not more than 5 ppm as defined in the above-mentioned guideline “IMPURITIES: GUIDELINE FOR RESIDUAL SOLVENTS”.
• This guideline is not applied to the drugs, which are already on market, but it is very important to prepare a drug substance complying with this guideline in terms of safety of drugs.
• U.S. Pat. No. 4,533,746 discloses a method of removing the solvent by distillation in purification of bisphenols, wherein the solvent occluded in bisphenols is released and removed from bisphenol melted in water. This method utilizes the characteristic of bisphenol, which melts in water by heating, and thereby the occluded solvent is released.
• zonisamide cannot melt even by heating in water, and hence, this method cannot be applied for removal of the solvent occluded in crystals of zonisamide.
• the present inventors have intensively studied a process for the preparation of crystals of zonisamide having a high safety and complying with the above-mentioned guideline, and have found that the desired crystals of zonisamide containing residual 1,2-dichloroethane of not more than 5 ppm can easily be obtained even from crystals of zonisamide containing 1,2-dichloroethane in a high concentration, by using an aqueous C 2-4 alcohol, i.e., by the steps of adding an aqueous C 2-4 alcohol to said crystals and distillating the resulting mixture, followed by crystallization, without equipping any additional apparatus to existing ones, or without repetition of recrystal-lization, and further there are no affects on the yield thereof, and finally the present inventors have accomplished the present invention.
• the present invention provides a process for the preparation of crystals of zonisamide containing residual 1,2-dichloroethane of not more than 5 ppm, which comprises adding an aqueous C 2-4 alcohol to crystals of zonisamide containing residual 1,2-dichloroethane of more than 5 ppm, usually more than 5 ppm to 200000 ppm, removing said 1,2-dichloroethane by azeotropic distillation, followed by collecting the crystals from the residual mixture.
• the present invention provides a process for the preparation of crystals of zonisamide containing residual 1,2-dichloroethane of not more than 5 ppm, which comprises the following steps (a), (b), (c) and (d):
• the present invention also provides a process for the preparation of crystals of zonisamide containing residual 1,2-dichloroethane of not more than 5 ppm, which comprises the above steps (a) and (b), and the following steps (c1) and (d1):
• the “aqueous C 2-4 alcohol” means a mixture of water and a C 2-4 alcohol, and the “C 2-4 alcohol” includes, for example, ethanol, propanol, isopropanol, and 2-butanol.
• the “aqueous C 2-4 alcohol” is preferably aqueous ethanol, aqueous propanol, and aqueous isopropanol, among them aqueous isopropanol is most preferable.
• crystals of zonisamide containing residual 1,2-dichloroethane of more than 5 ppm mean crystals of zonisamide containing residual 1,2-dichloroethane in the range of more than 5 ppm to 200000 ppm, although the higher limit of the concentration of said 1,2-dichloroethane is not necessarily specified.
• “crystals of zonisamide containing residual 1,2-dichloroethane of more than 5 ppm” are crystals of zonisamide containing residual 1,2-dichloro-ethane in the range of 8 ppm to 150000 ppm.
• the steps from dissolving the starting crystals of zonisamide in an aqueous C 2-4 alcohol to removing 1,2-dichloroethane by azeotropic distillation are usually carried out subsequently.
• the temperature for dissolving the starting crystals of zonisamide is necessarily specified, but it is usually in the range of from 30° C. to a boiling point of the C 2-4 alcohol to be used.
• the starting crystals of zonisamide are mixed with an aqueous C 2-4 alcohol in an amount of 5 to 15 parts by volume per 1 part by weight of the starting crystals of zonisamide.
• 1 g of dry weight of zonisamide is mixed with 5 to 15 ml of an aqueous C 2-4 alcohol.
• the starting crystals of zonisamide are preferably mixed with an aqueous C 2-4 alcohol in an amount of 5.2 to 10.4 parts by volume per 1 part by weight of the starting crystals of zonisamide.
• aqueous C 2-4 alcohol is usually a C 2-4 alcohol containing water in 35 to 65% by volume, and more preferable one is a C 2-4 alcohol containing water in 40 to 60% by volume, and further preferable one is a C 2-4 alcohol containing water in 45 to 55% by volume.
• the 55% by volume aqueous C 2-4 alcohol means a mixture of water in 55 parts by volume and a C 2-4 alcohol in 45 parts by volume.
• the distillation may be carried out either under atmospheric pressure or under reduced pressure, but preferably carried out under atmospheric pressure.
• the temperature at which the distillation is started is usually an azeotropic point of 1,2-dichloroethane-an C 2-4 alcohol-water.
• the azeotropic point of 1,2-dichloro-ethane-ethanol-water is 66.7° C.
• the azeotropic point of 1,2-dichloroethane-isopropanol-water is 69.7° C., but these azeotropic points may vary under the influences of barometric pressure when the distillation is carried out or of molar elevation of boiling point, etc.
• the temperature at which the distillation is stopped may vary according to the kinds of the aqueous C 2-4 alcohol to be used, and it is usually in the range of from 78° C. to 100° C., preferably in the range of from 85° C. to 100° C., and more preferably in the range of 90° C. to 100° C.
• the residual mixture is cooled in situ to precipitate crystals of zonisamide containing residual 1,2-dichloroethane of not more than 5 ppm.
• crystals of zonisamide may be precipitated in the middle of the distillation procedure. Therefore, in cases that crystals are precipitated in the residual mixture after the distillation is stopped, the same C 2-4 alcohol as that to be used in the distillation procedure and/or water are added to the residual mixture after the distillation is stopped, and the resulting mixture is heated again to dissolve the crystals, and then cooled to precipitate crystals of zonisamide containing residual 1,2-dichloroethane of not more than 5 ppm.
• water and/or isopropanol are added to the residual mixture after the distillation in such an amount that the ratio of water and isopropanol in the residual mixture after the distillation becomes in the range of 35:65 to 65:35, preferably in the range of 40:60 to 60:40, more preferably in the range of 45:55 to 55:45, and the total volume of water and isopropanol becomes 2 to 20 parts by volume, preferably 8 to 14 parts by volume, per 1 part by weight of the starting crystals (in dry state) of zonisamide, and the resulting mixture is heated again and then cooled.
• This step is preferably carried out together with the purification using activated carbon.
• the crystallized zonisamide is collected by filtration and dried by a conventional method to give crystals of zonisamide containing residual 1,2-dichloroethane of not more than 5 ppm, and in many cases, there are obtained crystals of zonisamide containing residual 1, 2-dichloro-ethane of less than detection limit.
• the crystals of zonisamide to be collected by filtration are dried at a temperature of from 60 to 100° C., preferably at a temperature of from 70 to 90° C., for 8 to 24 hours, preferably for 12 to 18 hours. Vacuum drying is more preferable.
• the starting crystals of zonisamide to be used in the present process may be prepared according to the method disclosed in Reference Example 3 and Example 1 of JP-A-53-77057. That is, it is prepared by reacting 1,2-benz-isoxazole-3-methanesulfonyl chloride with ammonia in 1,2-dichloroethane as a solvent, concentrating the reaction mixture, adding water to the resulting residue, followed by collecting the precipitated crystals to give wet crystals containing zonisamide in an amount of about 85% by weight.
• the wet crystals containing zonisamide in an amount of about 85% by weight obtained in the above process are recrystallized from 50% aqueous isopropanol in usual manner, and the resulting crystals are dried under reduced pressure at a temperature of from 40 to 80° C. for 18 hours to give crystals of zonisamide containing residual 1,2-dichloroethane in a concentration of from 8 to 14 ppm.
• Example 2 Water content in aqueous 65 50 isopropanol (vol %) Amount of aqueous 450 310 isopropanol (ml) Evaporation temperature 76-100 80-100 (° C.) Amount of evaporated solvent (ml) 250 205 Yield of crystals (g) 49.0 47.8 Content of residual 1,2- ⁇ 1 ⁇ 1 dichloroethane (ppm) (less than DL) (less than DL) (DL: detection limit)
• Example 2 To the same wet crystals (60 g) containing zonisamide in an amount of about 85% by weight as used in Example 1 were added 50 vol % aqueous isopropanol (300 ml), water (7.5 ml) and 1,2-dichloroethane (8.8 g), and 210 ml of the solvent was removed by evaporation at a temperature of from 79 to 100° C. under stirring. The residual mixture was cooled, and the precipitated crystals were collected by filtration to give wet crystals of zonisamide (56.7 g). The content of 1,2-dichloroethane in the wet crystals of zonisamide was less than 1 ppm (less than detection limit). The wet crystals were dried at 80° C. for 16 hours to give dried crystals of zonisamide (49.9 g).
• the activated carbon was separated by filtration, and washed with 50% aqueous isopropanol (175 ml). The filtrate and the washing were combined and cooled. After cooled to about 8° C., the precipitated crystals were collected by filtration and washed with water (136 ml). The crystals were dried with air blowing at 100° C. for 16 hours to give the dried crystals of zonisamide (47.1 g).
• crystals of zonisamide containing residual 1,2-dichloro-ethane of not more than 5 ppm could not be obtained from the starting crystals of zonisamide prepared using 1,2-dichloroethane.
• the content of the residual 1,2-dichloroethane in the crystals of zonisamide prepared by the present process is less than 1 ppm (less than detection limit), which is far lower than required 5 ppm.
• the present process is effective and applicable even if a large amount of 1,2-dichloroethane resides in the starting crystals of zonisamide.
• the yield of crystals of zonisamide is not so reduced even by subjecting to the present process.
• crystals of zonisamide containing residual 1,2-dichloroethane of not more than 5 ppm can effectively be obtained from the starting crystals of zonisamide prepared using 1,2-dichloroethane as the solvent.

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• 2003
  • 2003-07-28 ES ES03815138T patent/ES2338871T3/es not_active Expired - Lifetime
  • 2003-07-28 AU AU2003249010A patent/AU2003249010A1/en not_active Abandoned
  • 2003-07-28 EP EP03815138A patent/EP1583748B1/en not_active Expired - Lifetime
  • 2003-07-28 DE DE60331257T patent/DE60331257D1/de not_active Expired - Lifetime
  • 2003-07-28 KR KR1020057012737A patent/KR101004187B1/ko active IP Right Grant
  • 2003-07-28 DK DK03815138.7T patent/DK1583748T3/da active
  • 2003-07-28 AT AT03815138T patent/ATE457304T1/de active
  • 2003-07-28 PT PT03815138T patent/PT1583748E/pt unknown
  • 2003-07-28 SI SI200331754T patent/SI1583748T1/sl unknown
  • 2003-07-28 WO PCT/JP2003/009530 patent/WO2004063174A1/en active Application Filing
  • 2003-07-28 CN CNB038257890A patent/CN100528849C/zh not_active Expired - Lifetime
  • 2003-07-29 TW TW092120721A patent/TWI331035B/zh not_active IP Right Cessation
  • 2003-08-08 US US10/636,593 patent/US20050080269A1/en not_active Abandoned
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• 2005
  • 2005-06-29 IL IL169451A patent/IL169451A/en active IP Right Grant
• 2006
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• 2010
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