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Preparation method of impurity in penehyclidine hydrochloride

A technology for penehyclidine hydrochloride and impurities, applied in the field of medicine, can solve problems such as small amount, complicated separation operation, etc., and achieve the effects of reducing the complexity of operation and increasing the content of impurities

Inactive Publication Date: 2017-03-22
海南欣莱医药科技股份有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0014] At present, there is no literature report on 3-[2-cyclopentyl-2-phenyl-2-(2-cyclopentyl-2-hydroxy-2-phenyl-ethoxy)ethoxy]quinuclidine The preparation method of hydrochloride, and in the process of developing penhyclidine hydrochloride, it was found that this impurity was prepared by the reaction of α-phenyl-α-cyclopentyl-1,2-oxirane and 3-quinine alcohol Produced in the process of penhyclidine free base, the amount is small and the separation operation is complicated

Method used

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  • Preparation method of impurity in penehyclidine hydrochloride
  • Preparation method of impurity in penehyclidine hydrochloride
  • Preparation method of impurity in penehyclidine hydrochloride

Examples

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Embodiment 1

[0048] A preparation method for impurities in penhyclidine hydrochloride, comprising the following steps:

[0049] (1) Add 100ml dimethyl sulfoxide and 20g 3-quinine alcohol into a 1L reaction flask, stir to dissolve the solid, add 7.5g sodium hydride (60%) in portions, stir and mix, heat up to 60°C and stir for 1 hours, in 3-quinine alcohol sodium salt. Warming up to 70°C, 113.4g dimethyl sulfoxide solution (100ml) of α-phenyl-α-cyclopentyl-α-hydroxy ethyl p-toluenesulfonate was added dropwise to the mixture, the temperature was maintained and the reaction was stirred for 6 hours, and the temperature was lowered to Below 10°C, add 150ml of purified water dropwise, after dropping, add 300ml of ethyl acetate, stir evenly, and then let stand to separate the liquid.

[0050] (2) The organic phase was extracted with 300ml 10% citric acid aqueous solution, and the organic phase was separated, and the aqueous phase was adjusted to pH 8-9 with saturated sodium bicarbonate solution, ...

Embodiment 2

[0058] A preparation method for impurities in penhyclidine hydrochloride, comprising the following steps:

[0059] (1) Add 120ml of dimethyl sulfoxide and 24g of 3-quinine alcohol into a 2L reaction flask, stir to dissolve the solid, add 9.8g of sodium hydride (60%) in portions, stir and mix, heat up to 50°C and stir for 1 hour , in 3-quinine alcohol sodium salt. Warming up to 70°C, 204.2g of dimethyl sulfoxide solution (200ml) of α-phenyl-α-cyclopentyl-α-hydroxy ethyl p-toluenesulfonate was added dropwise to the mixture, the temperature was maintained and the reaction was stirred for 8 hours, and the temperature was lowered to Below 10°C, add 300ml of purified water dropwise, after dropping, add 400ml of ethyl acetate, stir evenly, then let stand to separate the liquid.

[0060] (2) The organic phase was extracted with 370 ml of 10% citric acid aqueous solution, and the organic phase was separated. The aqueous phase was adjusted to pH 8-9 with saturated sodium bicarbonate s...

Embodiment 3

[0066] A preparation method for impurities in penhyclidine hydrochloride, comprising the following steps:

[0067] (1) Add 60ml dimethyl sulfoxide and 12.7g 3-quinuclidinol to a 1L reaction flask, stir to dissolve the solid, add 5g sodium hydride (60%) in portions, stir and mix, heat up to 50°C and stir for 1 hours, in 3-quinine alcohol sodium salt. The temperature was raised to 80° C., 90 g of dimethyl sulfoxide solution (90 ml) of ethyl α-phenyl-α-cyclopentyl-α-hydroxy p-toluenesulfonate was added dropwise, and the temperature was maintained and the reaction was stirred for 7 hours. Cool down to below 10°C, add 100ml of purified water dropwise, add 200ml of ethyl acetate, stir evenly, and then let stand to separate the liquid.

[0068] (2) The organic layer was extracted with 230 ml of 10% citric acid aqueous solution, and the organic layer was separated. The aqueous layer was adjusted to pH 8-9 with saturated sodium bicarbonate solution, and 100ml of ethyl acetate was add...

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Abstract

The invention discloses a preparation method of an impurity in penehyclidine hydrochloride. The preparation method comprises the following steps: taking alpha-phenyl-alpha-cyclopentyl-alpha-hydroxyl ethyl p-toluene sulfonate and 3-quinuclidinol as the raw materials, carrying out reactions for a while under an alkaline condition, performing a post treatment to obtain 3-[2-cyclopentyl-2-phenyl-2-(2-cyclopentyl-2-hydroxyl-2-phenyl-ethyoxyl)ethyoxyl] quinuclidine hydrochloride free alkali, carrying out salt forming reactions between the free alkali and hydrogen chloride, and performing refinement to obtain hydrochloride of the free alkali. The preparation method can prominently increase the impurity content during the preparation process, the operation difficulty is reduced, moreover, the preparation method is suitable for massive production and is capable of obtaining a qualified high purity impurity; and the impurity purity measured by HPLC is 100%.

Description

technical field [0001] The invention relates to the technical field of medicines, in particular to a method for preparing impurities in penhyclidine hydrochloride. Background technique [0002] Penehyclidine Hydrochloride, whose chemical name is 3-(2-cyclopentyl-2-hydroxy-2-phenylethoxy)quinuclidine hydrochloride, was approved by the State Drug Administration in 1999 Approved (Academy of Military Medical Sciences), and later produced by Chengdu Lisite Pharmaceutical Co., Ltd. under the trade name of Chang Tuoning, it is used for the first-aid treatment of organophosphorus poison (pesticide) poisoning and the late stage of poisoning or after aging of cholinesterase (ChE) Maintain atropinization. The chemical structural formula is shown in (1). [0003] [0004] This strain is a new type of selective anticholinergic drug, which can bind to M and N choline receptors, inhibit the physiological functions of smooth muscles and glands innervated by postganglionic cholinergic n...

Claims

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Application Information

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IPC IPC(8): C07D453/02
CPCC07D453/02
Inventor 邝少轶陈年根陈明文范学杠肖华健
Owner 海南欣莱医药科技股份有限公司
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