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Method for preparing ropivacaine hydrochloride impurity (R)-N-(2, 6-dimethylphenyl) piperidine-2-formamide

A technology of ropivacaine hydrochloride and xylyl, which is applied in the field of preparing ropivacaine hydrochloride impurity-N-piperidine-2-carboxamide, which can solve the problems of less synthesis methods and no sales, and achieve chiral purity Good, solve the problem of quality control, the effect of controllable process

Pending Publication Date: 2022-05-24
SHANDONG KEYUAN PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] This impurity is not currently sold on the market, and there are few synthetic methods for this impurity reported in public information

Method used

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  • Method for preparing ropivacaine hydrochloride impurity (R)-N-(2, 6-dimethylphenyl) piperidine-2-formamide
  • Method for preparing ropivacaine hydrochloride impurity (R)-N-(2, 6-dimethylphenyl) piperidine-2-formamide
  • Method for preparing ropivacaine hydrochloride impurity (R)-N-(2, 6-dimethylphenyl) piperidine-2-formamide

Examples

Experimental program
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Effect test

Embodiment 1

[0035] The D-type dibenzoyl tartaric acid 10g was stirred with acetone 35g to heat up to dissolve; the 20gN(2,6-xylphenyl)piperidine-2-formamide was added to the reaction bottle added to acetone 35g purified water 10g stirred to heat up to 50 °C dissolved, dropwise added benzoyl tartaric acid solution to maintain 50 °C reaction for 1h, cooled to -5 °C to analyze the sperm for 1h, filtered filtrate. The filtrate was concentrated at 50 °C under reduced pressure to no condensate, the pH was adjusted to 14 with 10% potassium hydroxide, 30g of toluene was added to the system, the organic phase was separated, and the white solid was concentrated at 50 °C to give a yield of 45% of the white solid 9g and an optical purity of 99.8%.

Embodiment 2

[0037] The L-type di-p-p-methyldibenzoyl tartaric acid 100g with acetone 350g stirred to heat up to dissolve; 200gN- (2,6-xylphenyl) piperidine-2-formamide was added to the reaction bottle added to acetone 350g purified water 100g stirred to heat up to 55 °C dissolved, dropwise added benzoyl tartaric acid solution to maintain 55 °C reaction for 1h, cooled to -5 °C precipitation 2h, filtered filtrate. The filtrate was concentrated at 50 °C under reduced pressure to no condensate, the pH was adjusted to 14 with 10% sodium hydroxide, 300g of toluene was added to the system, the organic phase was separated, and the white solid was concentrated at 50 °C to give a yield of 47% of the white solid 94g and an optical purity of 99.8%.

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Abstract

The invention relates to a method for preparing a ropivacaine hydrochloride impurity (R)-N-(2, 6-dimethylphenyl) piperidine-2-formamide, which comprises the following steps of: 1, adding a resolving agent into a solvent A for dissolving; 2, adding N-(2, 6-dimethylphenyl) piperidine-2-formamide into a mixed solution of the solvent A and the solvent B, and stirring until the N-(2, 6-dimethylphenyl) piperidine-2-formamide is dissolved; 3, mixing the solutions obtained in the step 1 and the step 2, and reacting for 1 hour; 4, cooling the reacted solution to-5 DEG C to 5 DEG C, and stirring and crystallizing for 2-4 hours; 5, centrifuging or filtering, and collecting mother liquor; 6, concentrating the mother liquor under reduced pressure to evaporate the solvent A; 7, adding an alkaline neutralizer into the obtained concentrated solution to adjust the pH value to 11-14; and 8, carrying out extraction and liquid separation on the solution obtained in the step 7, collecting an organic phase, and carrying out vacuum concentration to obtain a product. The yield of the ropivacaine hydrochloride impurity (R)-N-(2, 6-dimethylphenyl) piperidine-2-formamide prepared by the method disclosed by the invention can be stabilized at 45% or above, the chiral purity is good, the post-treatment is simple, the yield is high, the process is controllable, the operability is strong, and the industrialization is easy.

Description

Technical field [0001] The present invention belongs to the field of ropivacaine hydrochloride impurities, specifically a method for preparing ropivacaine hydrochloride impurities (R)-N- (2,6-dimethylphenyl) piperidine-2-carboxamide. Background [0002] Ropivacaine hydrochloride is a novel long-acting amide local anesthetic that was marketed in 1996 and developed by the Astra Pain Control Center in Sweden. Chemical name (-)-(2S)-N-(2,6-dimethylphenyl)-1-n-propylpiperidine-2-carboxamide hydrochloride, trade name is endocarpine. Ropivacaine hydrochloride is a new generation of long-acting, safe local anesthetics for surgical anesthesia, midwifery, local or regional anesthesia, and for the treatment of acute or postoperative pain. [0003] The key intermediates in the production process of ropivacaine are (S)-2-(2,6-dimethylphenyl)-2-piperidinecarboxamide, which corresponds to the isomer (R)-2-(2,6-dimethylphenyl)-2-piperidinecarboxamide The content of this impurity will affect the ...

Claims

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Application Information

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IPC IPC(8): C07D211/60
CPCC07D211/60
Inventor 孙雪莲李树谨伦立军孙光勇郭方刚苏小勇张林陈玉玺李宁朱丽娟
Owner SHANDONG KEYUAN PHARMA
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