Preparation and purification method of ropivacaine hydrochloride intermediate

A technology of ropivacaine hydrochloride and an intermediate, which is applied in the field of preparation of pharmaceutical compounds and can solve problems such as complicated processes

Active Publication Date: 2019-03-22
HEBEI YIPIN PHARMA +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The resulting intermediate needs to be subjected to chiral resolution to obtain the target compound, and the process is cumbersome

Method used

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  • Preparation and purification method of ropivacaine hydrochloride intermediate
  • Preparation and purification method of ropivacaine hydrochloride intermediate
  • Preparation and purification method of ropivacaine hydrochloride intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0047] Preparation of Example 1 Intermediate (-)-(2S)-N-(2,6-dimethylphenyl)piperidine-2-carboxamide

[0048] Add L-piperidine formic acid hydrochloride (30.00g, 0.18mol) and toluene (300ml) successively into a clean 500ml three-necked reaction flask, stir, add N,N-dimethylformamide (1ml), chlorinated ethylene Sulfone (25.85g, 0.22mol). After the addition was completed, the temperature was raised to 50-55°C and the reaction was maintained for 3 hours. Add a buffer absorption device to vacuum for 1 hour. A toluene solution of 2,6-dimethylaniline (2,6-dimethylaniline (109.75 g, 0.91 mol) mixed with toluene (60 ml)) was added dropwise. After the addition was completed, the reaction was incubated at 60°C for 2.0h. Cool down to 20-30°C, add purified water (300ml), separate layers, collect the water phase; add fresh toluene (300ml) to the water phase, adjust the pH of the system to 6-7 with 10% sodium hydroxide, separate layers, and collect the water phase Water phase is adjuste...

Embodiment 2

[0049] The refining of embodiment 2 intermediate (-)-(2S)-N-(2,6-dimethylphenyl)piperidine-2-carboxamide

[0050] The intermediate (-)-(2S)-N-(2,6-dimethylphenyl)piperidine-2-carboxamide (5.00g, 21.52mmol) obtained in Example 1 was sequentially added to a 100ml clean three-necked reaction flask , diethyl ether (50ml), stir and heat up to reflux, reflux for 1 hour and keep stirring for 1 hour, cool down to room temperature, keep stirring for 1 hour, filter with suction, diethyl ether (10ml) rinse the filter cake, and dry the filter cake in a 50°C blast oven for 2 hours 2.66g (yield 53.2%, calculate HPLC purity 99.837% according to peak area normalization method), spectrum sees attached figure 1 .

Embodiment 3

[0051] The purification of embodiment 3 intermediate (-)-(2S)-N-(2,6-dimethylphenyl)piperidine-2-carboxamide

[0052]The intermediate (-)-(2S)-N-(2,6-dimethylphenyl)piperidine-2-carboxamide (5.00g, 21.52mmol) obtained in Example 1 was sequentially added to a 100ml clean three-necked reaction flask , isopropyl ether (50ml), stir and heat up to reflux, reflux and heat preservation and stirring for 1 hour, cool to room temperature, heat preservation and stirring for 1 hour, suction filtration, isopropyl ether (10ml) rinse the filter cake, and blow the filter cake at 50 ° C Dry in a drying oven for 2 hours to 3.45 g (yield 69.0%, HPLC purity 99.332% calculated by peak area normalization method). See attached figure 2 .

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Abstract

The invention relates to a preparation and purification method of a ropivacaine hydrochloride intermediate. According to the method, single chiral intermediate (-)-(2S)-N-(2,6-dimethylphenyl)piperidine-2-carboxamide is prepared from single chiral raw material L-pipecolic acid hydrochloride and 2,6-dimethylaniline, and a resolution step can be omitted; a nonpolar solvent is further adopted to refine the intermediate (-)-(2S)-N-(2,6-dimethylphenyl)piperidine-2-carboxamide, and related impurities are reduced. The preparation method is simple in aftertreatment, product purity is high, purity reaches 99.5% or higher after beating refining, content of single impurities is lower than 0.1%, the total yield is higher than 80%, and the method is suitable for large-scale industrial production.

Description

technical field [0001] The invention relates to a preparation method of a pharmaceutical compound, in particular to a preparation and purification method of a ropivacaine hydrochloride intermediate. Background technique [0002] Ropivacaine hydrochloride is a long-acting local anesthetic developed and marketed by Astra, Sweden; it is used for surgical anesthesia, midwifery, local or regional anesthesia, and the treatment of acute pain or postoperative pain. Ropivacaine hydrochloride, the chemical name is (-)-(2S)-N-(2,6-dimethylphenyl)-1-n-propylpiperidine-2-carboxamide hydrochloride monohydrate, The structural formula is as follows: [0003] [0004] The preparation of ropivacaine hydrochloride involves a key intermediate (1), chemical name: (-)-(2S)-N-(2,6-dimethylphenyl) piperidine-2-carboxamide, the structural formula is as follows : [0005] [0006] The prior art discloses the relevant synthetic method of the following intermediate (1): [0007] route one ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D211/60
CPCC07B2200/07C07D211/60
Inventor 张辑陈文辉吕帅刘雪松段士宝刘佳兴李铭皓程瑶赵翠然张永然马福民
Owner HEBEI YIPIN PHARMA
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