Preparation method of mepivacaine and optical enantiomer of mepivacaine

A technology of mepivacaine and enantiomers, which is applied in the field of preparing mepivacaine and its optical antipodes, can solve the problems of quaternary ammonium salt by-products, expensive methyl iodide reagents, and high manufacturing costs, and achieve production costs Low cost, simple operation, less reaction steps

Active Publication Date: 2013-05-01
SHANDONG MEITAI PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Yield is lower 32%, because iodomethane reagent is expensive, and manufacturing cost is higher, also can produce quaternary ammonium salt by-product

Method used

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  • Preparation method of mepivacaine and optical enantiomer of mepivacaine
  • Preparation method of mepivacaine and optical enantiomer of mepivacaine
  • Preparation method of mepivacaine and optical enantiomer of mepivacaine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0024] Add 46g (1.0mol) of anhydrous formic acid to a 1-liter reaction flask, and add 46.46g (0.2 mol), stirred for 10 minutes, added 18g (0.6mol) of paraformaldehyde, heated in an oil bath to 90°C~95°C, and the tail gas absorption device showed gas generation. Heat preservation reaction for 8 hours. After the reaction, add 100ml (0.4mol) of 4N hydrochloric acid, evaporate the solvent to dryness under reduced pressure to obtain a light yellow slurry, dissolve it in 80ml of water, add 80ml of toluene to wash, separate the liquids, and control the temperature at 0°C~5°C in an ice bath , add 50ml of 18N sodium hydroxide to the water layer, extract with toluene 80ml×2, combine the organic phases, add 10g of anhydrous sodium sulfate and dry for 3 hours. After filtering, the filtrate was concentrated under reduced pressure with a rotary evaporator to obtain 45.1 g of mepivacaine. The yield is 91.7%. mp 149°C–151°C, MS (EI) C 15 h 22 N 2 O m / z (M +. ): 246.2.

Embodiment 2

[0026] Add 46g (1.0mol) of anhydrous formic acid to a 1-liter reaction flask, and add (S)-N-(2,6-dimethylphenyl)-2-piperidinecarboxamide at a controlled temperature of 20°C to 25°C 46.46g (0.2mol), stir for 10 minutes, add 18g (0.6mol) of paraformaldehyde, heat the oil bath to 90°C~95°C, the tail gas absorption device shows gas generation. Heat preservation reaction for 8 hours. After the reaction, add 100ml (0.4mol) of 4N hydrochloric acid, evaporate the solvent to dryness under reduced pressure to obtain a light yellow slurry, dissolve it in 80ml of water, add 80ml of toluene to wash, separate the liquids, and control the temperature at 0°C~5°C in an ice bath , add 50ml of 18N sodium hydroxide to the water layer, extract with toluene 80ml×2, combine the organic phases, add 10g of anhydrous sodium sulfate and dry for 3 hours. After filtration, the filtrate was concentrated under reduced pressure with a rotary evaporator to obtain 45.3 g of the S-mepivacaine enantiomer. Yiel...

Embodiment 3

[0028] Add 46g (1.0mol) of anhydrous formic acid to a 1-liter reaction flask, and add (R)-N-(2,6-dimethylphenyl)-2-piperidinecarboxamide at a controlled temperature of 20°C to 25°C 46.46g (0.2mol), stir for 10 minutes, add 18g (0.6mol) of paraformaldehyde, heat the oil bath to 90°C~95°C, the tail gas absorption device shows gas generation. Heat preservation reaction for 8 hours. After the reaction, add 100ml (0.4mol) of 4N hydrochloric acid, evaporate the solvent to dryness under reduced pressure to obtain a light yellow slurry, dissolve it in 80ml of water, add 80ml of toluene to wash, separate the liquids, and control the temperature at 0°C~5°C in an ice bath , add 50ml of 18N sodium hydroxide to the water layer, extract with toluene 80ml×2, combine the organic phases, add 10g of anhydrous sodium sulfate and dry for 3 hours. After filtration, the filtrate was concentrated under reduced pressure with a rotary evaporator to obtain 42.7 g of the thermal R-mepivacaine enantiome...

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Abstract

The invention discloses a novel preparation method of mepivacaine and an optical enantiomer of the mepivacaine. The method comprises the steps of taking N-(2,6-dimethyl phenyl)-2-piperidinecarboxamide or an optical enantiomer thereof as a starting material, taking formaldehyde as a methylation reagent, stirring in formic acid at 60-100 DEG C for reaction, and obtaining the mepivacaine or the optical enantiomer thereof. The raw materials adopted with the method are commercially available, extensive and sufficient in source and low in price, reaction conditions of the method are mild, a process is simple, and the disadvantages that hazardous reagents such as dimethyl sulfate and sodium cyanoborohydride are used and anhydrous reaction conditions are required are avoided.

Description

technical field [0001] The present invention relates to a kind of method for preparing mepivacaine and its optical antipodes, and the present invention especially relates to a kind of N-(2,6-dimethylphenyl)-2-piperidine carboxamide or its optical antipodes The enantiomer is used as a starting material, and formaldehyde is used as a methylating reagent to react in formic acid. The formic acid is not only a solvent for the reaction but also a reducing agent participating in the reaction. Background technique [0002] Mepivaeaine Hydrochloride (Mepivaeaine Hydrochloride), also known as carbocaine hydrochloride, the chemical name is 1-methyl-N-(2,6-dimethylphenyl)-2-piperidinecarboxamide hydrochloride, It is an amide local anesthetic, its chemical structure is similar to that of lidocaine, but its onset speed is fast, its anesthetic effect is strong, its properties are stable, its toxicity and side effects are small, and when it reaches a certain concentration, it can reduce the...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D211/60
Inventor 姚松芝梁静
Owner SHANDONG MEITAI PHARMA CO LTD
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