Dexmedetomidine hydrochloride intermediate resolution method

A technology for dexmedetomidine hydrochloride and intermediates, which is applied in the field of enantiomeric separation and detection, can solve problems such as unsatisfactory direct separation of medetomidine, and achieve favorable raw material supply guarantee, huge market potential, and high efficiency. Yield effect

Inactive Publication Date: 2017-05-10
XUZHOU MEDICAL UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

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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  • Dexmedetomidine hydrochloride intermediate resolution method

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Effect test

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 Ring, then slowly be warming up to 90 ℃, add sulfur trioxide 10.2ml (240mmol) dropwise under stirring, dripping is finished, continue to react for 2 hours, monitor the reaction to finish, concentrate the reaction solution under reduced pressure, the concentrate uses 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 Ring, then slowly be warming up to 80 ℃, add sulfur trioxide 6.4ml (150mmol) dropwise under stirring, dripping is completed, continue to react for 2 hours, monitor the reaction to finish, concentrate the reaction solution under reduced pressure, and the concentrate uses 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 Ring, then slowly heat up to 60 ° C, add 5.1 ml (120 mmol) of sulfur trioxide dropwise under stirring, and continue to react for 6 hours after dropping, and concentrate the reaction solution under reduced pressure, and the concentrate is washed with cold ethanol (0 ~ 5 ° C) to obtain Sulfonated 4-[1-(2,3-dimethylphenyl)ethyl]-1H-imidazole 25.1 g, yield 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 invention relates to the technical field of enantiomeric separation and detection, in particular to a separation method of a dexmedetomidine hydrochloride intermediate. Background technique [0002] Dexmedetomidine hydrochloride is an α2-adrenergic receptor agonist developed by Orion Pharma in Finland and Abott in the United States. It was first marketed in the United States in March 2000. Dexmedetomidine hydrochloride has antisympathetic, sedative and analgesic effects. Compared with metomidine, it has stronger selectivity and short half-life. It can be clinically used for intubation and ventilator patients during intensive care treatment. At the same time, the drug can also reduce the amount of anesthesia, 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 hydrochloride, and its specific struct...

Claims

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Application Information

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