Preparation method of high-purity esketamine hydrochloride ketone body

A technology for esketamine hydrochloride ketone body and acyl chloride, which is applied in the field of preparation of high-purity esketamine hydrochloride ketone body, can solve problems such as low yield, long reaction time, and high toxicity, and achieve high yield and reaction Effects in short duration and mild conditions

Active Publication Date: 2021-02-02
YANGTZE RIVER PHARM GRP CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] In the above-mentioned synthetic method (1), the product actually contains more (2-chlorophenyl)-1-cyclopenten-1-yl ketone , the 81.62% yield contains a lot of (2-chlorophenyl)-1-cyclopenten-1-yl ketone; the synthetic method (2) has a long reaction time and the yield is not high; moreover, the above two Both synthetic methods use a class of organic solvents, which are more toxic

Method used

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  • Preparation method of high-purity esketamine hydrochloride ketone body
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  • Preparation method of high-purity esketamine hydrochloride ketone body

Examples

Experimental program
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Effect test

Embodiment 1

[0060] Embodiment 1 - the preparation of cyclopentacarbonyl chloride

[0061] Add 262.7g of thionyl chloride into the reaction flask, stir, and add 210g of cyclopentanoic acid dropwise at 40-50°C. After the dropwise addition, keep warm at 40-50°C for 2 hours. After treatment, concentrated under reduced pressure to remove excess thionyl chloride to obtain 237.5 g of cyclopentanoyl chloride with a yield of 97.4%.

Embodiment 2

[0062] Embodiment 2 - the preparation of o-chlorophenyl magnesium chloride

[0063] Under the protection of nitrogen, add 1306ml tetrahydrofuran solution of isopropylmagnesium chloride and lithium chloride with a concentration of 1.3mol / L into the reaction bottle, stir, cool down to 0-10°C, add 250g of o-chlorobromobenzene dropwise, after the dropwise addition, keep the temperature React at 0-10°C for 4 hours and set aside.

Embodiment 3

[0064] Embodiment 3 - the preparation of o-chlorophenyl cyclopentyl ketone

[0065] Under the protection of nitrogen, stir, and cool down the reaction solution in Example 2 to -10~0°C, add 225.1 g of cyclopentanoyl chloride in Example 1 dropwise, after the dropwise addition, keep warm at -10~0°C for reaction 2 Hours, after treatment, add 450ml of 2mol / L dilute hydrochloric acid dropwise, divide and remove the lower layer, wash the upper organic layer with 13% aqueous sodium chloride solution, then wash with 10% sodium hydroxide, wash with saturated sodium chloride, and concentrate under reduced pressure to remove the low boiling point solvent, and then distilled to obtain 208 g of o-chlorophenyl cyclopentyl ketone, with a yield of 76.3% and a purity of 98.0%.

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Abstract

The invention discloses a preparation method of a high-purity esketamine hydrochloride ketone body. The structure of the esketamine hydrochloride ketone body is shown as a formula (I). The preparationmethod comprises the following steps of: by taking cyclopentanoic acid and o-chlorobromobenzene as starting materials, carrying out acylating chlorination reaction, metallization reaction and Grignard reaction to synthesize the esketamine hydrochloride ketone body. The esketamine hydrochloride ketone body obtained by the method has the characteristics of high purity, high yield, capability of being applied to preparation of esketamine hydrochloride bulk drugs and the like.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and in particular relates to a preparation method of high-purity esketamine hydrochloride ketone body. Background technique [0002] Esketamine hydrochloride (Esketamine hydrochloride), the chemical name is (2S)-2-(2-chlorophenyl)-2-(methylamino)cyclohexanone hydrochloride; first listed in Germany in 1997, it can be used alone or Combined with other anesthetics, it is used for the induction and maintenance of general anesthesia; it is used for anesthesia and pain relief in emergency; it is used as an auxiliary for local or regional anesthesia. [0003] Esketamine hydrochloride ketone body, the chemical name is o-chlorophenyl cyclopentyl ketone, is an important intermediate for the synthesis of esketamine hydrochloride, and there are currently two main synthetic methods: [0004] (1) Using o-chlorobenzoyl chloride as a raw material, anhydrous aluminum trichloride as a catalyst, cyclohexane and ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C45/46C07C49/813C07C51/60C07C61/06C07F3/02
CPCC07C45/46C07C45/004C07C51/60C07F3/02C07C2601/08C07C61/06C07C49/813
Inventor 申新程徐浩宇朱晶梁慧兴李浩冬曹兵鲍鹤龄张利军常晓敏
Owner YANGTZE RIVER PHARM GRP CO LTD
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