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Green and environment-friendly zonisamide synthesis method

A zonisamide, green and environmental protection technology, applied in the fields of medical technology and organic synthesis, can solve the problems of strong irritating odor, corrosiveness, inconvenience, difficulty and the like, and achieves the effects of low cost, convenience and low volatility

Active Publication Date: 2017-06-09
珠海市海瑞德生物科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0013] In order to solve the risks brought by the use of the highly toxic reagent phosphorus oxychloride in the preparation of zonisamide sulfonyl chloride (VII), the world patent WO2003072552 discloses a method of using thionyl chloride under the catalysis of dimethylformamide (DMF) to complete A method for the synthesis of 1,2-benzisoxazole-3-methanesulfonic acid sodium acid chloride, which is of great significance for improving the production environment of zonisamide and reducing the harm to human health, but there are still many deficiencies Solution: 1. The use of thionyl chloride will bring a lot of waste gas and waste acids such as hydrogen chloride and sulfur dioxide, hydrochloric acid and sulfurous acid; 2. Due to the existence of a large amount of waste acid, it will bring many difficulties to the next amidation, such as a large amount of inorganic The production of ammonium salts brings inconvenience to operations such as stirring and filtering; 3. Strong pungent odor and corrosiveness will inevitably put forward high requirements for equipment and production safety

Method used

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Embodiment 1

[0038] Embodiment 1 A kind of green environmental protection synthetic method of zonisamide

[0039] The synthetic reaction formula of the green environment-friendly synthesis method of zonisamide of the present embodiment is as follows, comprising the following steps:

[0040]

[0041]1), add 235.20 grams (1.0MOL) 1,2-benzisoxazole-3-sodium methanesulfonate and 1500 grams of toluene in the there-necked flask with thermometer, mechanical stirring and reflux water separator, heat and reflux After 2 hours of water, take a sample to detect the moisture content of the reaction solution. When the moisture content of the reaction solution is less than 0.1%, cool the reaction solution to 25-30°C, add 105 grams of solid phosgene (0.354MOL) and 25 grams of DMF, complete and heat up After reaching 35°C and stirring the reaction at this temperature for 4 hours, when the remaining raw material of 1,2-benzisoxazole-3-methanesulfonate sodium is less than 1.0%, the reaction is terminated;...

Embodiment 2

[0045] Embodiment 2 A kind of green environmental protection synthetic method of zonisamide

[0046] The synthetic reaction formula of the green environment-friendly synthesis method of zonisamide of the present embodiment is as follows, comprising the following steps:

[0047]

[0048] 1), add 228.20 grams (1.0MOL) 1,2-benzisoxazole-3-ammonium methanesulfonate and 1500 grams of toluene in the there-necked flask with thermometer, mechanical stirring and reflux water separator, heat and reflux After 2 hours of water, take a sample to detect the moisture content of the reaction solution. When the moisture content of the reaction solution is less than 0.1%, cool the reaction solution to 25-30°C, add 105 grams of solid phosgene (0.354MOL) and 25 grams of DMF, complete and heat up After reaching 35°C and stirring the reaction at this temperature for 4 hours, when the remaining raw material of 1,2-benzisoxazole-3-methanesulfonate sodium is less than 1.0%, the reaction is terminat...

Embodiment 3

[0052] Embodiment 3 A kind of green environmental protection synthetic method of zonisamide

[0053] The synthetic reaction formula of the green environment-friendly synthesis method of zonisamide of the present embodiment is as follows, comprising the following steps:

[0054]

[0055] 1), add 235.20 grams (1.0MOL) 1,2-benzisoxazole-3-sodium methanesulfonate and 1500 grams of toluene in the there-necked flask with thermometer, mechanical stirring and reflux water separator, heat and reflux After 2 hours of water, take a sample to detect the moisture content of the reaction solution. When the moisture content of the reaction solution is less than 0.1%, the reaction solution is cooled to 25-30° C., and 105 grams (0.354 MOL) of solid phosgene and 25 grams of triethylamine are added to complete the reaction. 1. After raising the temperature to 35°C and stirring and reacting at this temperature for 4 hours, when the remaining raw material of 1,2-benzisoxazole-3-methanesulfonate...

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Abstract

The invention discloses a green and environment-friendly zonisamide synthesis method which includes the steps: adding 1, 2-sulfamethoxazole-3-sodium methanesulfonate or 1, 2-sulfamethoxazole-3-ammonium methanesulfonate into methylbenzene, heating, reflowing and reducing temperature to 10-35 degrees, adding triphosgene and catalysts, heating, stirring and reacting mixture; pumping in a vacuum manner to remove redundant unreacted triphosgene, leading anhydrous ammonia until pH (potential of hydrogen) to be 9-10; centrifuging out solids, leaching the solids by the aid of methylbenzene, adding water to stir mixture, centrifuging and drying the solids, and performing recrystallization for the dried solids by the aid of methyl alcohol to obtain zonisamide crystal. The zonisamide synthesis method is safe, reliable, green, environmentally friendly, high in yield, low in cost, simple in post-processing and suitable for mass industrial production, and raw materials are easily obtained.

Description

technical field [0001] The invention belongs to the technical fields of medical technology and organic synthesis, and specifically relates to a green and environment-friendly synthesis method of zonisamide, an anti-epileptic and anti-Parkinson's disease drug. Background technique [0002] The chemical name of Zonisamide (Zonisamide) is 1,2-benzisoxazole-3-methanesulfonamide. It is a new type of broad-spectrum antiepileptic drug developed by Dainippon Pharmaceutical Company. It was launched in Japan under the trade name Zonegran in 1989. It was approved for marketing for the first time and was launched in the United States in 2000. It is clinically used for the treatment of epileptic grand mal seizures, petit mal seizures, partial seizures, status epilepticus and psychomotor seizures, with few side effects. In January 2009, the new indication of Zonisamide Tablets approved by Dainippon Sumitomo Pharmaceutical Co., Ltd. is used to treat patients with progressive Parkinson's di...

Claims

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Application Information

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IPC IPC(8): C07D261/20
CPCC07D261/20
Inventor 戴新荣
Owner 珠海市海瑞德生物科技有限公司
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