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Method for preparing R-ketamine and pharmaceutically acceptable salt thereof

A technology of ketamine hydrochloride and ketamine, which is applied in the field of medicinal chemistry, can solve problems such as unsatisfactory resolution and failure to obtain R-ketamine hydrochloride, and achieve good resolution, simple operation, and low content of related substances Effect

Active Publication Date: 2019-09-10
JIANGSU HENGRUI MEDICINE CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0011] After verification, the resolution effect of the method of the aforementioned prior art is unsatisfactory, and the R-ketamine hydrochloride that is qualified and higher in yield cannot be obtained

Method used

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  • Method for preparing R-ketamine and pharmaceutically acceptable salt thereof
  • Method for preparing R-ketamine and pharmaceutically acceptable salt thereof
  • Method for preparing R-ketamine and pharmaceutically acceptable salt thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0058] Embodiment 1: Preparation of R-ketamine D-DTTA salt

[0059]

[0060] Add 66.0kg of purified water into the 300L reactor, stir mechanically, then add 6.60kg (24.06mol) ketamine hydrochloride, stir until completely dissolved; slowly add NaOH solution, adjust the pH to 13-14, and continue stirring for 1-1.5 hours Then stop; the material was removed, filtered, and the filter cake was washed with purified water until it was nearly neutral, and dried to obtain 5.72 kg of ketamine.

[0061] Into a 100L reaction kettle, add acetone / water with a volume ratio of 2.5:1, mechanically stir, then add the obtained ketamine and D-DTTA 9.30kg, heat and reflux until completely dissolved; stir and crystallize; remove the material, filter, and use acetone The filter cake was washed and dried to obtain 6.34 kg of crude product of R-ketamine D-DTTA salt.

[0062] Into the 200L reaction kettle, add the prepared acetone / water solution with a volume ratio of 1:1, stir, then add the obtaine...

Embodiment 2

[0063] Embodiment 2: the preparation of R-ketamine

[0064]

[0065] Into the 300L reactor, add 75.0kg of dichloromethane, then add 5.20kg of R-ketamine D-DTTA salt, stir mechanically, slowly add NaOH solution to adjust the pH to 13-14, continue stirring; then add 100.0kg of purified water , continue to stir for 0.5 hours, stop stirring, let stand to separate layers, and separate the dichloromethane solution in the lower layer; the dichloromethane layer is washed with purified water 20.0kg×2, dried with anhydrous sodium sulfate, suction filtered, and the filtrate is concentrated to obtain The white solid was dried to obtain 1.88kg of R-ketamine.

Embodiment 3

[0066] Embodiment 3: the preparation of R-ketamine hydrochloride crude product

[0067]

[0068] Add ethyl acetate to the 100L reaction kettle, stir mechanically, then add 1.88kg R-ketamine, heat up to 30-40°C, stir until completely dissolved; stop heating, slowly add 2.5M hydrogen chloride / ethanol solution dropwise, adjust the pH The value is 2 to 3. After the addition, continue to stir for 18 to 20 hours; remove the material, filter, wash the filter cake with ethyl acetate, and dry to obtain 2.04 kg of crude product of R-ketamine hydrochloride.

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PUM

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Abstract

The invention relates to a method for preparing R-ketamine and a pharmaceutically acceptable salt thereof. More specifically, the present invention relates to a method for resolving a ketamine racemate to obtain R-ketamine, wherein a resolving agent adopted is D-DTTA, the method includes steps of resolution, purification, dissociating, and the like, and obtained R-ketamine hydrochloride is low incontent of related substances, and is suitable for use as a pharmaceutical raw material. The method is simple in operation, good in resolution effect and high in yield, and is suitable for industrialproduction.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry and relates to a preparation method of R-ketamine and a pharmaceutically acceptable salt thereof, in particular to a method for separating R-ketamine from racemic ketamine. Background technique [0002] Ketamine (racemic mixture of S- and R-enantiomers) is an NMDA receptor antagonist primarily used for induction and maintenance of general anesthesia, other uses include intensive care sedation, analgesia (especially in emergency treatment and bronchospasm treatment). Ketamine has also been shown to be effective in the treatment of depression (particularly in patients who do not respond to current antidepressant treatments), and in patients with severe depression it has also been shown to produce rapid antidepressant effect. [0003] Compared with S-ketamine, R-ketamine is more effective in fast-acting antidepressants, and may have a lower tendency to produce psychologic effects and lower risk o...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C225/20C07C221/00A61K31/135A61P25/24
CPCC07C225/20C07C221/00A61P25/24C07B2200/07C07C2601/14C07B2200/13
Inventor 葛文雷陈通郭大鹏
Owner JIANGSU HENGRUI MEDICINE CO LTD
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