Medetomidine industrial splitting method

A technology of medetomidine and imidazole, which is applied in the field of industrial separation of medetomidine, can solve the problem of low resolution yield and achieve the effect of simple industrial operation and high efficiency

Active Publication Date: 2014-11-19
安庆生命科技园发展有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0018] In order to solve the problem of medetomidine in the prior art [ie (±) 4-[1-(2,3-xylyl)-ethyl]-1H -imidazole] The problem that the resolution yield is n

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0027] Example 1: Preparation of (S)-medetomidine L-(-)camphorsulfonate

[0028] Add 400g (2.0mol) of medetomidine, 10L of absolute ethanol, 233g (1.0mol) of L-(-)camphorsulfonic acid into a 20L reactor, stir and heat up, dissolve and reflux at 75±5°C for 20min, and the temperature will drop naturally Crystallize at 5±2°C for 18h. Suction filtration, 300% absolute ethanol slurry washing, filter drying, the filter cake was dried under vacuum at 50°C for 5h to obtain 415g of white solid (S)-medetomidine L-(-)camphorsulfonate, yield 46%, optical purity 99.6%.

Embodiment 2

[0029] Example 2: Preparation of (S)-medetomidine L-(-)camphorsulfonate

[0030] Add 400g (2.0mol) of medetomidine, 12L of absolute ethanol, and 345g (1.5mol) of L-(-) camphorsulfonic acid into a 20L reactor, stir and heat up, dissolve and reflux at 75±5°C for 20min, and the temperature will drop naturally Crystallize at 5±2°C for 18h. Suction filtration, 350% ethanol slurry washing, filter drying, filter cake 50 ℃ vacuum drying for 5h to obtain white solid (S)-medetomidine L-(-)camphorsulfonate 419g, yield 46.7%, optical purity 99.8%.

Embodiment 3

[0031] Example 3: The preparation of dexmedetomidine hydrochloride

[0032] Put 3500ml of dichloromethane, 2000ml of water, and 200g of the compound of Example 1 into a 10L reaction bottle, stir and dissolve, adjust the pH value to 9±1 with concentrated ammonia water, let it stand and separate after the pH value is stable, wash the organic phase with 700ml×2 water, Stir with anhydrous sodium sulfate until clear, dry for 3 hours, filter with suction, rinse the filter cake with 500ml of dichloromethane, combine the mother liquors, and evaporate to dryness under reduced pressure at 40±5°C to obtain a white solid. The obtained white solid was dissolved in 1500ml of dichloromethane, 87ml of 10N ethanol hydrochloric acid solution was added dropwise, stirred for 20min, and then 6000ml of anhydrous ether was quickly dropped into, stirred and crystallized for 5h. Suction filtration, wash the filter cake with anhydrous diethyl ether slurry, and dry the filter cake at 60°C for 6 hours ...

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PUM

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Abstract

The invention discloses a medetomidine industrial splitting method which takes L-(-) camphorsulfonic acid as a chiral reagent and C1-C5 alcohol as a chiral auxiliary. According to the method disclosed by the invention, the splitting yield reaches up to over 40% and the splitting optical purity reaches over 99.5%. The method is simple in industrialized operation and can be used for industrialized and commercialized production.

Description

technical field [0001] The invention relates to the technical field of medicinal chemistry, in particular to an industrial resolution method of medetomidine. Background technique [0002] At present, dexmedetomidine hydrochloride injection has been listed both at home and abroad. As a short-acting, powerful and highly selective α 2 - Adrenergic receptor agonist, which has the characteristics of sedation, analgesia, anti-anxiety and no inhibition of breathing; high selectivity makes it rarely have the adverse reactions of clonidine. Sedation while maintaining wakeability. The drug does not induce clinically significant respiratory depression, making extubation safer, and may enable patients to be extubated and weaned as soon as possible; at the same time, it is widely used in clinical practice as a preoperative and intraoperative sedative for various operations. Therefore, hydrochloric acid Dexmedetomidine injection has become the first-line choice of sedation for clinician...

Claims

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Application Information

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IPC IPC(8): C07D233/58
CPCC07D233/58
Inventor 徐奎刘丽
Owner 安庆生命科技园发展有限公司
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