A kind of preparation method of ropivacaine hydrochloride impurity f

A technology for ropivacaine hydrochloride and impurities, which is applied in the field of chemical synthesis, can solve the problems such as the synthetic method of impurity F that is not reported in public data, and achieves the effects of high product purity, short synthesis route and simple operation

Active Publication Date: 2017-05-31
山东诚汇双达药业有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] Ropivaca hydrochloride impurity F is not sold on the market, and there is no public information on the synthesis method of impurity F

Method used

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  • A kind of preparation method of ropivacaine hydrochloride impurity f

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0022] 100g of acetone and 20g of (S)-N-(2',6'-xylyl)-2-piperidinecarboxamide were added to a 250ml clean three-necked flask equipped with mechanical stirring, and the solids were completely dissolved by stirring and heating. Then add 5 g of acetic acid, continue to heat up to reflux, and after 5 hours of reaction, the thin-layer detection of the raw materials basically completes the reaction (TLC conditions: dichloromethane: methanol = 10:1). The solvent was slowly evaporated under normal pressure, and after the solvent distillation was completed, 300 g of deionized water at 50° C. was added to the residue, and a solid was slowly precipitated, and the pH value was adjusted to 9 with sodium hydroxide solution. After filtration, the filter cake was washed with deionized water and dried to obtain 19 g of crude product with a liquid phase purity greater than 97%. 19g of crude product was added to 76g of ethanol, heated to reflux for 30 minutes to dissolve the solid; cooled to roo...

Embodiment 2

[0024] 200g of acetone and 25g of (S)-N-(2',6'-xylyl)-2-piperidinecarboxamide were added to a 500ml clean three-necked flask equipped with mechanical stirring, and the solids were completely dissolved by stirring and heating. Then add concentrated hydrochloric acid 15g, continue to heat up to reflux, after 10 hours of reaction, the thin layer detects that the raw material has basically reacted (TLC conditions methylene chloride: methanol=10:1). The solvent was slowly evaporated under normal pressure. After the solvent was distilled, 375 g of deionized water at 50° C. was added to the residue, and the solid was slowly precipitated, and the pH was adjusted to 9 with sodium hydroxide solution. After filtration, the filter cake was washed with deionized water and dried to obtain 24 g of crude product with a liquid phase purity greater than 96%. 24g of crude product was added to 168g of methyl isobutyl ketone, heated to reflux for 30 minutes to dissolve the solid; cooled to room te...

Embodiment 3

[0026] 75g of acetone and 25g of (S)-N-(2',6'-xylyl)-2-piperidinecarboxamide were added to a 250ml clean three-necked flask equipped with mechanical stirring, and the solid was dissolved by stirring and heating. Then add sulfuric acid 2.5g, continue to heat up to reflux, after 8 hours of reaction, the thin layer detects that the raw material is basically reacted (TLC conditions methylene chloride: methanol=10:1). The solvent was slowly evaporated under normal pressure, and after the solvent distillation was completed, 375 g of deionized water at 50°C was added to the residue, and a solid was slowly precipitated, and the pH value was adjusted to 9 with sodium hydroxide solution. Filtration, the filter cake was washed with deionized water, and dried to obtain 25 g of crude product with a liquid phase purity greater than 96%. 25g of crude product was added to 50g of acetonitrile, heated to reflux for 30 minutes to dissolve the solid; cooled to room temperature, filtered, and the ...

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Abstract

The invention belongs to the field of chemical synthesis technology, and concretely relates to a preparation method of a ropivacaine hydrochloride impurity F (8aS)-2-(2,6-dimethylphenyl)-3,3-dimethyl-imidazo[1,5-a]pyridine-1(5H)-ketone. (S)-N-(2',6'-dimethylphenl)-2-piperidine carboxamide and acetone are used as raw materials, a condensation reaction is carried out with an acidic condition in order to remove one water molecule, a solution is distilled, treatment is adjusted with alkaline, the impurity F crude product is obtained, then refining is carried out, and the high-purity ropivacaine hydrochloride impurity F is obtained. The method has the advantages of short synthetic route, simple operation, and high product purity; and a qualified impurity reference substance is provided for quality control of ropivacaine hydrochloride.

Description

technical field [0001] The invention belongs to the technical field of chemical synthesis, in particular to a ropivacaine hydrochloride impurity F(8aS)-2-(2,6-dimethylphenyl)-3,3-dimethyl-imidazo[1, Method for the preparation of 5-a]pyridin-1(5H)-one. Background technique [0002] Ropivacaine hydrochloride is a new long-acting amide local anesthetic, which was launched in 1996 and developed by the Astra Pain Control Center in Sweden. The chemical name is (-)-(2S)-N-(2,6-dimethylphenyl)-1-n-propylpiperidine-2-carboxamide hydrochloride, and the trade name is Nailepin. Ropivacaine hydrochloride is a new generation of long-acting, safe local anesthetic; used for surgical anesthesia, midwifery procedures, local or regional anesthesia, and the treatment of acute or post-operative pain. [0003] The impurities of ropivaca hydrochloride are mainly its degradation products, which have certain toxicity, so its content should be strictly controlled. There are 8 impurities in the qua...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D471/04
CPCC07D471/04
Inventor 孙宝亮李跃东赵会清周艳艳宋爱玲
Owner 山东诚汇双达药业有限公司
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