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Preparation method of bupivacaine hydrochloride

A technology of bupivacaine hydrochloride and potassium carbonate, which is applied in the field of preparation of bupivacaine hydrochloride, can solve the problems of long reaction time, low reaction yield and high production cost, and achieves high product quality, low operating cost and stable operation. good effect

Inactive Publication Date: 2017-12-22
JIANGXI YONGTONG TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Levobupivacaine is mainly used for surgical epidural anesthesia, its chemical name is 1-butyl-N-(2,6-dimethylphenyl)-piperidine-2-carboxamide, and its English name is Levobupivacaine, molecular formula is C18H32ClN2O, and its structural formula is: in the prior art, piperidine amide is commonly used as starting material and bromobutane reaction, uses salt of wormwood as acid-binding agent, and DMF is made reaction solvent and obtains bupivacaine, and this reaction is obtained The rate is low, the reaction time is long, about 40 hours, and the purity is low, and then D-tartaric acid is used as a resolving agent to resolve levobupivacaine to obtain bupivacaine, and the resolution effect is not good, and the yield Low, resulting in cumbersome process and high production costs
[0003] At present, lack the preparation method of the high bupivacaine hydrochloride of a kind of productive rate

Method used

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  • Preparation method of bupivacaine hydrochloride

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Embodiment 1

[0020] A kind of preparation method of bupivacaine hydrochloride of invention comprises the steps:

[0021] (1) Preparation of N-(2,6-xylyl)-2-piperidinecarboxamide:

[0022]

[0023] Add 2-piperidinecarboxylic acid into a three-necked flask, pass hydrogen chloride gas through toluene at room temperature for 1 hour, heat the mixture to 55°C, add the toluene solution of bis(trichloromethyl)carbonate BTC dropwise within 2 hours, and keep the temperature for reaction For 5 hours, add a toluene solution of 2,6-dimethylaniline dropwise, react at 55°C for 2 hours, filter, wash with toluene, dissolve the filter cake in water, adjust the pH to 5.5 with 20% NaOH, extract with toluene, and recover the organic 2,6-dimethylaniline in the phase, adjust the water phase to pH 11, extract with toluene, separate layers, and evaporate the solvent to obtain a white solid, which is then washed with petroleum ether, filtered, and dried to obtain N-(2, 6-xylyl)-2-piperidinecarboxamide BBKY-2; ...

Embodiment 2

[0031] The difference between embodiment 2 and embodiment 1 is: a kind of preparation method of bupivacaine hydrochloride of invention, comprises the steps:

[0032] In step (1), 6.5 g of 2-piperidinecarboxylic acid was added to a three-necked flask, 100 ml of toluene was passed through hydrogen chloride gas at room temperature for 1 hour, the mixture was heated to 55° C., and 5 g of bis(tri) was added dropwise within 2 hours. Chloromethyl)carbonate BTC toluene (20ml) solution, keep warm for 5 hours, add 2,6-dimethylaniline 32.5ml toluene (10ml) solution dropwise, react at 60°C for 2 hours; filter, wash with toluene, filter Dissolve the cake in water, adjust the pH to 4.5 with 20% NaOH, extract with toluene, and recover 26ml of 2,6-dimethylaniline in the organic phase; adjust the pH of the aqueous phase to 11.5, extract with toluene, separate layers, and evaporate solvent to obtain a white solid; then washed with petroleum ether, filtered, and dried to obtain 5.8 g of N-(2,6-x...

Embodiment 3

[0034] The difference between embodiment 3 and embodiment 1 is:

[0035] A kind of preparation method of bupivacaine hydrochloride of the present invention comprises the steps:

[0036] In step (1), 6.5 g of 2-piperidinecarboxylic acid was added to a three-necked flask, 100 ml of toluene was passed through hydrogen chloride gas at room temperature for 1 hour, the mixture was heated to 58 ° C, and 5 g of bis(tri Chloromethyl)carbonate BTC in toluene (20ml) solution, keep warm for 5 hours, add dropwise 2,6-dimethylaniline 32.5ml in toluene (10ml) solution, react at 55-60°C for 2 hours; filter, wash with toluene , the filter cake was dissolved in water, adjusted to pH 4.8 with 20% NaOH, extracted with toluene, and 26ml of 2,6-dimethylaniline in the organic phase was recovered; the aqueous phase was adjusted to pH 12, extracted with toluene, and separated. The solvent was evaporated to obtain a white solid; it was washed with petroleum ether, filtered, and dried to obtain 5.8 g o...

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Abstract

The invention discloses a preparation method of bupivacaine hydrochloride. The preparation method includes the steps of: 1) preparing N-(2,6-xylyl)-2-piperidineformamide; 2) preparing the bupivacaine hydrochloride. The reaction routes in the two steps are described in the specification. The method has high yield, high product quality and low operation cost, allows automation operation of equipment, has good stability, and can satisfy industrial demands.

Description

technical field [0001] The invention relates to the technical field of chemical synthesis, in particular to a preparation method of bupivacaine hydrochloride. Background technique [0002] Bupivacaine hydrochloride is a drug used for local anesthesia in surgery and postoperative pain relief. Levobupivacaine is mainly used for surgical epidural anesthesia, its chemical name is 1-butyl-N-(2,6-dimethylphenyl)-piperidine-2-carboxamide, and its English name is Levobupivacaine, molecular formula is C18H32ClN2O, and its structural formula is: in the prior art, piperidine amide is commonly used as starting material and bromobutane reaction, uses potassium carbonate as acid-binding agent, and DMF is made reaction solvent to obtain bupivacaine, and this reaction is obtained The rate is low, the reaction time is long, about 40 hours, and the purity is low, and then D-tartaric acid is used as a resolving agent to resolve levobupivacaine to obtain bupivacaine, and the resolution effect ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D211/60
CPCC07D211/60
Inventor 刘忠春
Owner JIANGXI YONGTONG TECH
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