New crystal form of penehyclidine hydrochloride and preparation method of new crystal form

A technology for penehyclidine hydrochloride and crystal form, applied in the field of new crystal forms of medicines, can solve the problem of no penehyclidine hydrochloride, etc., and achieve the effects of good stability, guarantee of clinical efficacy, and avoidance of drug impurities

Active Publication Date: 2012-10-03
CHENGDU ZIHAO PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] However, there is no solid raw material sales of penehyclidine hydrochloride on the market at present, and it is not convenient to research and develop new non-injection dosage forms of penehyclidine hydrochloride

Method used

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  • New crystal form of penehyclidine hydrochloride and preparation method of new crystal form
  • New crystal form of penehyclidine hydrochloride and preparation method of new crystal form
  • New crystal form of penehyclidine hydrochloride and preparation method of new crystal form

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Embodiment 1

[0030] Embodiment 1 Preparation of penhyclidine hydrochloride crystal form of the present invention

[0031] Take 49.5 g of penehyclidine hydrochloride, add 150 ml of isopropanol to reflux to dissolve, then add 200 ml of petroleum ether while it is hot and let it cool down naturally.

[0032] Wherein, raw material penhyclidine hydrochloride is prepared by the following method:

[0033] Add 350ml of dimethyl sulfoxide to a 1L three-necked flask, then add 25.4g (0.20mol) of 3-quinuclidinol and 8.4g (0.21mol) of 60% sodium hydride, stir at room temperature for two hours until no bubbles are generated, then drop Add 39.0g (0.201mol) of 1-phenyl-1-cyclopentyl oxirane, react at 50°C for 30 hours after the addition is complete, stop the reaction, remove impurities after acid and alkali treatment, and then use 500ml ethyl acetate Extract, wash with brine until neutral, concentrate and add 400ml ether hydrochloric acid solution to obtain 49.5g of penhyclidine hydrochloride.

[0034] ...

Embodiment 2

[0035] Embodiment 2 Preparation of penhyclidine hydrochloride crystal form of the present invention

[0036] Add 600ml of dimethyl sulfoxide to a 1L three-necked flask, then add 50.8g (0.40mol) of 3-quinuclidinol and 17g (0.42mol) of 60% sodium hydride, stir at room temperature for two hours until no bubbles are generated, and then add dropwise 80g (0.41mol) of 1-phenyl-1-cyclopentyl oxirane, react at 35°C for 45 hours after the addition is complete, stop the reaction, treat with acid and alkali, extract with 800ml ethyl acetate, wash with brine until neutral, After concentrating, add 800ml of ethyl acetate hydrochloric acid solution to form hydrochloride, and obtain 101.8g of solid, add 300ml of isopropanol to reflux to dissolve, then add 300ml of ethyl acetate while it is hot, and naturally cool to precipitate crystals, in order to ensure complete crystallization, then lower the temperature to Further crystallization was carried out at 0-5°C. After the crystallization was co...

Embodiment 3

[0037] Embodiment 3 Preparation of penhyclidine hydrochloride crystal form of the present invention

[0038] Add 500ml of dimethyl sulfoxide into a 1L three-necked flask, then add 25.4g (0.20mol) of 3-quinuclidinol and 8.4g (0.21mol) of 60% sodium hydride, stir at room temperature for two hours until no bubbles are generated, then drop Add 39.0g (0.201mol) of 1-phenyl-1-cyclopentyl oxirane, react at 40°C for 40 hours after the addition is complete, stop the reaction, treat with acid and alkali, extract with 500ml ethyl acetate, wash with brine to medium After concentration, add 100ml of ethanol hydrochloric acid solution, then add 300ml of petroleum ether, after natural cooling, then cool down to 0-5°C to crystallize, and filter to obtain 32.9g of the product, with a yield of 46.74%.

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Abstract

The invention provides a crystal form of penehyclidine hydrochloride. Absorption peaks with diffraction angles (2 theta) at 8.96+ / -0.2, 13.28+ / -0.2, 15.68+ / -0.2, 16.61+ / -0.2, 18.17+ / -0.2, 19.27+ / -0.2, 21.379+ / -0.2, 22.38+ / -0.2 and 25.97+ / -0.2 are available in a powder X-ray diffraction diagram of the crystal form. The invention also provides a preparation method of the crystal form and a medicinal composition based on the crystal form. The crystal form of the penehyclidine hydrochloride has good stability, the increase in medicinal impurities can be effectively avoided without special package and storage conditions, so that the high cost brought by special storage conditions is reduced, long-term research of a non-injection new dosage form of the penehyclidine hydrochloride is facilitated, and effective guarantee is brought to the safety and the clinical therapeutic effect of a final product.

Description

technical field [0001] The present invention relates to a new crystal form of medicine, in particular to a new crystal form of penhyclidine hydrochloride, and to a preparation method of the crystal form. Background technique [0002] Penehyclidine hydrochloride is 3-(2-hydroxy-2-cyclopentyl-2-phenylethoxy)quinuclidane hydrochloride, the molecular formula is: C 20 h 29 NO 2 .HCl [0003] [0004] The compound is a potent anticholinergic drug designed and developed by the Chinese Academy of Military Medical Sciences, with selective M 1 , M 3 and N 1 , N 2 Receptor antagonism, showing a strong anticholinergic effect on the central and peripheral, but on M 2 The receptor has no obvious effect, which can avoid the tachycardia caused by atropine lack of M receptor subtype selectivity and block the presynaptic membrane M 2 Receptor regulation function, so long-acting and less side effects, in 1999, Chengdu Lisite Pharmaceutical Co., Ltd. exclusively marketed under the tr...

Claims

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Application Information

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IPC IPC(8): C07D453/02A61K31/439A61P39/02A61P23/00
Inventor 刘忠荣余建红叶兵严强
Owner CHENGDU ZIHAO PHARMA
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