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Preparation method for impurities in penehyclidine hydrochloride

A technology for penehyclidine hydrochloride and penehyclidine hydrochloride is applied in the field of preparation of impurities in penehyclidine hydrochloride, can solve the problems of incomplete reaction, complicated operation, many side reactions, etc., and achieves easy operation and simple process steps. , the effect of less side effects

Active Publication Date: 2019-05-31
山东博洛德生物科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] In this method, 2-cyclopentyl-2-hydroxyl-2-phenyl-ethoxy is continuously connected twice in the reaction by feeding once, the reaction is incomplete, and there are many side reactions, post-treatment is through column chromatography, and the operation Complicated and too low yield

Method used

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  • Preparation method for impurities in penehyclidine hydrochloride
  • Preparation method for impurities in penehyclidine hydrochloride
  • Preparation method for impurities in penehyclidine hydrochloride

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0022] 3-[2-Cyclopentyl-2-phenyl-2-(2-cyclopentyl-2-hydroxy-2-phenyl-ethoxy)ethoxy]quinuclidane free base

[0023] Add 18.90g (0.06mol) of penehyclidine into a 500ml three-neck flask, add 150mL of DMSO, heat to 60°C, add 2.40g (0.06mol, 1eq) of NaH with a content of 60% after dissolving, and continue heating at this temperature after adding After reacting for 1 hour, add 40 mL of DMSO solution of 11.80 g (0.063 mol, 1.05 eq) of α-phenyl-α-cyclopentyl-oxirane into it, continue heating and reacting at this temperature for 6 hours, cool down to 10°C, add 100ml of water was extracted three times with methyl tert-butyl ether, the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure to obtain 27.41 g of light yellow viscous oil.

[0024] 3-[2-Cyclopentyl-2-phenyl-2-(2-cyclopentyl-2-hydroxy-2-phenyl-ethoxy)ethoxy]quinuclidine hydrochloride

[0025] 27.00 g of 3-[2-cyclopentyl-2-phenyl-2-(2-cyclopentyl-2-hydroxy-2-pheny...

Embodiment 2

[0027] 3-[2-Cyclopentyl-2-phenyl-2-(2-cyclopentyl-2-hydroxy-2-phenyl-ethoxy)ethoxy]quinuclidane free base

[0028] Add 18.90g (0.06mol) of penehyclidine into a 500ml three-necked flask, add 150mL of DMSO, heat to 60°C, add 2.52g (0.063mol, 1.05eq) of NaH with a content of 60% after the addition is complete, and continue at this temperature After heating and reacting for 1 hour, add 11.80g (0.063mol, 1.05eq) of α-phenyl-α-cyclopentyl-oxirane in 40mL of DMSO solution, continue heating and reacting at this temperature for 4 hours, then lower the temperature to 10°C, Add 100 ml of water, extract three times with methyl tert-butyl ether, combine the organic phases, dry over anhydrous sodium sulfate, and concentrate to dryness under reduced pressure to obtain 27.86 g of light yellow viscous oil.

[0029] 3-[2-Cyclopentyl-2-phenyl-2-(2-cyclopentyl-2-hydroxy-2-phenyl-ethoxy)ethoxy]quinuclidine hydrochloride

[0030] Add 27.00 g of 3-[2-cyclopentyl-2-phenyl-2-(2-cyclopentyl-2-hydroxy-...

Embodiment 3

[0032] Add 18.90g (0.06mol) of penehyclidine into a 500ml three-necked flask, add 150mL of DMSO, heat to 60°C, add 2.52g (0.063mol, 1.05eq) of NaH with a content of 60% after the addition is complete, and continue at this temperature After heating and reacting for 1 hour, add 12.36g (0.066mol, 1.1eq) of α-phenyl-α-cyclopentyl-oxirane in 40mL of DMSO solution, continue heating and reacting at this temperature for 4 hours, then lower the temperature to 10°C, Add 100ml of water, extract three times with methyl tert-butyl ether, combine the organic phases, dry over anhydrous sodium sulfate, and concentrate to dryness under reduced pressure to obtain 28.12 g of light yellow viscous oil.

[0033] 3-[2-Cyclopentyl-2-phenyl-2-(2-cyclopentyl-2-hydroxy-2-phenyl-ethoxy)ethoxy]quinuclidine hydrochloride

[0034] Add 27.50 g of 3-[2-cyclopentyl-2-phenyl-2-(2-cyclopentyl-2-hydroxy-2-phenyl-ethoxy)ethoxy]quinuclidane free base to 15 ml Methanol and 135ml of ethyl acetate, stirred and mixed ...

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Abstract

The invention relates to the technical field of organic synthesis, in particular to a preparation method for impurities in penehyclidine hydrochloride. The method comprises the steps that penehyclidine and alpha-phenyl-alpha-cyclopentyl-oxirane are adopted as raw materials, under the alkali compound effect, a reaction is performed to obtain 3-[2-cyclopentyl-2-phenyl-2-(2-cyclopentyl-2-hydroxyl-2-phenyl-ethyoxyl)ethyoxyl]quinuclidine free alkali, and after salt formation of hydrogen chloride, free alkali hydrochloride is obtained. The preparation method has the advantages that the technologicalsteps are simple, side reactions are few, operation is simple and convenient, post treatment is simple, raw materials are cheap and easy to obtain, and the yield is high, and the method is suitable for large-batch preparation.

Description

technical field [0001] The invention relates to the technical field of organic synthesis, in particular to a method for preparing impurities in penhyclidine hydrochloride as follows. [0002] Background technique [0003] Penehyclidine Hydrochoride, whose chemical name is 3-(2-cyclopentyl-2-hydroxy-2-phenylethoxy)quinuclidine hydrochloride, is a new type of selective anticholinergic drug. Approved by the State Drug Administration (Academy of Military Medical Sciences) in 2009, it is used for the first-aid treatment of organophosphorus poison (pesticide) poisoning and the maintenance of atropine in the late stage of poisoning or after cholinesterase (ChE) aging. [0004] Impurity research is an important link in the drug development process. At the same time, the establishment of quality standards requires a certain amount of standard products. After searching, a major impurity will be produced in all known production routes of penhyclidine hydrochloride: 3- [2-cyclopenty...

Claims

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Application Information

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IPC IPC(8): C07D453/02
Inventor 蔡连辉
Owner 山东博洛德生物科技有限公司
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