A kind of resolution method of dexmedetomidine hydrochloride intermediate

A technology for dexmedetomidine hydrochloride and intermediates, which is applied in the field of enantiomer resolution and detection, can solve problems such as unsatisfactory direct resolution of medetomidine, and achieve favorable raw material supply guarantee and high resolution yield , the effect of high yield

Inactive Publication Date: 2019-01-08
XUZHOU MEDICAL UNIV
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0007] The purpose of the present invention is to overcome the unsatisfactory defect of the direct resolution of existing medetomidine, and provide a resolution method with high resolution efficiency and high resolution yield

Method used

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  • A kind of resolution method of dexmedetomidine hydrochloride intermediate

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Embodiment 1

[0023] Preparation of sulfonated 4-[1-(2,3-dimethylphenyl)ethyl]-1H-imidazole;

[0024] In a 250ml three-necked flask, add 40g (200mmol) racemic 4-[1-(2,3-dimethylphenyl)ethyl]-1H-imidazole, 4g sodium sulfate and 120ml 1,4-dioxane Then slowly increase the temperature to 90°C, add 10.2ml (240mmol) of sulfur trioxide dropwise under stirring, and continue the reaction for 2 hours. Monitor the end of the reaction. Concentrate the reaction solution under reduced pressure. Use cold ethanol (0~5 (°C) washing to obtain 55.4 g of sulfonated 4-[1-(2,3-dimethylphenyl)ethyl]-1H-imidazole with a yield of 98.7%.

Embodiment 2

[0026] Preparation of sulfonated 4-[1-(2,3-dimethylphenyl)ethyl]-1H-imidazole;

[0027] In a 250ml three-necked flask, add 20g (100mmol) racemic 4-[1-(2,3-dimethylphenyl)ethyl]-1H-imidazole, 3g sodium sulfate and 80ml 1,4-dioxane Then slowly increase the temperature to 80°C, add 6.4ml (150mmol) of sulfur trioxide dropwise with stirring, continue the reaction for 2 hours, monitor the end of the reaction, concentrate the reaction solution under reduced pressure, and use cold ethanol (0~5 (°C) washing to obtain 27.7 g of sulfonated 4-[1-(2,3-dimethylphenyl)ethyl]-1H-imidazole with a yield of 98.9%.

Embodiment 3

[0029] Preparation of sulfonated 4-[1-(2,3-dimethylphenyl)ethyl]-1H-imidazole;

[0030] In a 250ml three-necked flask, add 20g (100mmol) racemic 4-[1-(2,3-dimethylphenyl)ethyl]-1H-imidazole, 2g sodium sulfate and 80ml 1,4-dioxane Then slowly warm up to 60°C, add 5.1ml (120mmol) of sulfur trioxide dropwise with stirring, continue the reaction for 6 hours, concentrate the reaction solution under reduced pressure, and wash the concentrate with cold ethanol (0~5°C). Sulfonated 4-[1-(2,3-dimethylphenyl)ethyl]-1H-imidazole was 25.1 g, and the yield was 89.4%.

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Abstract

The invention discloses a dexmedetomidine hydrochloride intermediate resolution method. The resolution method includes: (1) subjecting salt racemized 4-[1-(2,3-dimethyl phenyl)ethyl]-1H-imidazole to sulfonation reaction with a sulfonating agent; (2) subjecting a product obtained in the step (1) to stirring salt-forming reaction with lysine ethyl ester in absolute ethyl alcohol, standing, and performing suction filtration to obtain (S)-salt; (3) allowing reaction of the (S)-salt obtained in the step (2) in sodium hydroxide aqueous solution to obtain (S)-4-[1-(2,3-dimethyl phenyl)ethyl]-1H-imidazole. According to the resolution method, sulfonation is performed prior to adoption of chiral compound lysine ethyl ester for resolution, high resolution efficiency and resolution yield can be achieved. By providing of the dexmedetomidine hydrochloride intermediate resolution method, a beneficial raw material supply guarantee can be provided for dexmedetomidine hydrochloride, and great market potential is realized.

Description

Technical field [0001] The present invention relates to the technical field of enantiomer resolution and detection, in particular to a method for resolution of dexmedetomidine hydrochloride intermediates. Background technique [0002] Dexmedetomidine hydrochloride is an α2-adrenergic receptor agonist jointly developed by Orion Pharma of Finland and Abott of the United States. It was first marketed in the United States in March 2000. Dexmedetomidine hydrochloride has anti-sympathetic, sedative and analgesic effects. Compared with metopilidine, it is more selective and has a short half-life. It can be clinically used for patients who start intubation and use ventilator during intensive care treatment. At the same time, the drug can also reduce the amount of anesthetics, improve the stability of hemodynamics during surgery and reduce the incidence of myocardial ischemia. The chemical name of dexmedetomidine hydrochloride is (S)-4-[1-(2,3-dimethylphenyl)ethyl]-1H-imidazole hydrochlo...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D233/58
CPCC07B2200/07C07D233/58
Inventor 张洋吕燕华
Owner XUZHOU MEDICAL UNIV
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