Purification of 3-(2-cyclopentyl-2-hydroxy-2-phenylethoxy)quinuclidine and preparation method of penehyclidine hydrochloride

A technology of phenylethoxy and purification method, which is applied in the field of purification of 3-quinuclidine and penehyclidine hydrochloride preparation, can solve the problem of lack of target product impurity removal and purification process, low purity and yield, and poor product quality. Complex operation and other problems, to achieve the effect of low cost, simple purification method and easy availability of raw materials

Active Publication Date: 2020-09-18
北京鑫开元医药科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, the existing preparation of this intermediate often lacks a good impurity removal and purification process for the target product, which makes the operation of the product complicated, low in purity and yield, and high in cost.

Method used

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  • Purification of 3-(2-cyclopentyl-2-hydroxy-2-phenylethoxy)quinuclidine and preparation method of penehyclidine hydrochloride
  • Purification of 3-(2-cyclopentyl-2-hydroxy-2-phenylethoxy)quinuclidine and preparation method of penehyclidine hydrochloride
  • Purification of 3-(2-cyclopentyl-2-hydroxy-2-phenylethoxy)quinuclidine and preparation method of penehyclidine hydrochloride

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Embodiment 1

[0036] Embodiment 1-a kind of purification method of 3-(2-cyclopentyl-2-hydroxyl-2-phenylethoxy)quinuclidine, comprises the steps:

[0037] (1) Mix 3-quinuclidinol with dimethyl sulfoxide solution, and add sodium hydride in turn to stir the reaction, add dropwise 1,1-phenylpentyl oxirane solution to react and add dropwise saturated sodium chloride The solution terminates the reaction to obtain a reaction solution; wherein, the mol ratio of 1,1-phenylpentyl oxirane solution, 3-quinuclidinol and sodium hydride is 1:1:1;

[0038] (2) Add purified water to the reaction solution and stir, add ethyl acetate for extraction, separate the ethyl acetate layer, and collect the organic phase; after the organic phase is washed with pure water and saturated sodium chloride solution successively, back-extract with hydrochloric acid solution, collect the water layer;

[0039] (3) Adjust the pH value of the aqueous layer to 5-7 with an alkaline solution, wash with ethyl acetate, adjust the pH...

Embodiment 2

[0041] Embodiment 2-a kind of purification method of 3-(2-cyclopentyl-2-hydroxyl-2-phenylethoxy)quinuclidine, comprises the steps:

[0042] (1) Stir and mix 3-quinuclidinol and dimethyl sulfoxide solution at room temperature at 145-155 rpm for 5-10 minutes, add sodium hydride at room temperature and stir for 25-35 minutes, then heat up Continue constant temperature stirring at 60°C for 1~1.5h; and control the temperature below 20°C, add 1,1-phenylpentyl oxirane solution dropwise, after the dropwise addition is completed within 25~35min, raise the temperature to 70°C for reaction 3.5 to 4.5 hours; lower the temperature to below 20°C, add a saturated sodium chloride solution dropwise to terminate the reaction, and obtain a reaction liquid; among them, 1,1-phenylpentyl oxirane solution, 3-quinuclidinol and sodium hydride The molar ratio is 1:2.5:1.5;

[0043] (2) Add purified water to the reaction solution and stir, add ethyl acetate for extraction, separate the ethyl acetate la...

Embodiment 3

[0046] Embodiment 3-a kind of penhyclidine hydrochloride preparation method comprises the steps:

[0047] (1) Add tert-butyl methyl ether to the oil of 3-(2-cyclopentyl-2-hydroxy-2-phenylethoxy)quinuclidane prepared in Example 2, and heat to 55-65°C After dissolving, cool down to -5~0°C, add hydrogen chloride ethyl acetate solution dropwise under stirring condition until the pH value of the solution is 2~3, slowly add tert-butyl methyl ether, and stir at room temperature to precipitate a solid;

[0048] (2) Filter the precipitated solid, wash it with tert-butyl methyl ether, and dry it under vacuum at 65-75° C. for 2-3 hours to obtain penhyclidine hydrochloride.

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Abstract

The invention provides a method for purifying 3-(2-cyclopentyl-2-hydroxy-2-phenylethoxy) quinuclidine and preparing penehyclidine hydrochloride. The method comprises the following steps: (1) mixing 3-quinuclidinol with a dimethyl sulfoxide solution, and reacting with sodium hydride and a 1,1-phenyl amyl oxirane solution; (2) adding purified water and ethyl acetate to carry out extraction, collecting the organic phase, washing, carrying out back extraction with a hydrochloric acid solution, and collecting the water layer; (3) adjusting the pH value of the water layer to 5-7, washing the water layer by ethyl acetate, adjusting the pH value to 9-12 again, extracting the water layer by ethyl acetate, and collecting the organic phase; and (4) filtering, and carrying out reduced pressure concentration to obtain 3-(2-cyclopentyl-2-hydroxy-2-phenylethoxy) quinuclidine oil. According to the method, by separating and purifying 3-(2-cyclopentyl-2-hydroxy-2-phenylethoxy) quinuclidine, the yield and quality of a target product are improved, and a penehyclidine hydrochloride finished product with a high yield and high purity is obtained through one-step salifying crystallization.

Description

technical field [0001] The invention relates to the technical field of medicinal chemistry, in particular to a method for purifying 3-(2-cyclopentyl-2-hydroxy-2-phenylethoxy)quinuclidine and preparing penhyclidine hydrochloride. Background technique [0002] Penehyclidine hydrochlordie is a new anticholinergic drug developed by the Academy of Military Medical Sciences in my country. The chemical name is 3-(2-cyclopentyl-2-hydroxy-2-phenylethoxy)quinuclidine hydrochloride, which is the bioisostere analog of diphenylglycolic acid-3-quinuclidinol thing. Studies have shown that penehyclidine hydrochloride is a selective anticholinergic drug. At present, vardenafil hydrochloride has been successfully used in the clinical treatment of organophosphorus pesticide poisoning, with high antitoxic potency, long-lasting antitoxic effect and small adverse effects. At the same time, penehyclidine hydrochloride has anticholinergic effects on gastrointestinal diseases, eye diseases, respi...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D453/02
CPCC07D453/02
Inventor 夏中宁赵宇夏兵
Owner 北京鑫开元医药科技有限公司
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