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A kind of preparation method of levobupivacaine hydrochloride

A technology of levobupivacaine hydrochloride and carboxylic acid, which is applied in the field of preparation of levobupivacaine hydrochloride, can solve the problems of harsh reaction conditions, prolonging the preparation process route, increasing the production cycle, etc., and achieves mild reaction conditions and synthetic route Short, avoid strong corrosive effects

Active Publication Date: 2019-09-20
SHANDONG BESTCOMM PHARMA CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0012] In this synthetic route, the starting material piperidinecarboxylic acid is protected by Cbz, and the protective group needs to be removed in the later stage, the preparation process route is extended, the production cycle is increased, and the generation of three wastes is increased, resulting in a substantial increase in industrial production costs, which is not conducive to Industrial production
[0013] In summary, there are long synthetic routes in the synthetic route of levobupivacaine hydrochloride in the prior art, complicated operation, harsh reaction conditions, high production cost, and disadvantages of industrialized production

Method used

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  • A kind of preparation method of levobupivacaine hydrochloride
  • A kind of preparation method of levobupivacaine hydrochloride
  • A kind of preparation method of levobupivacaine hydrochloride

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0043] Example 1: Preparation of S configuration-1-butylpiperidine-2-carboxylic acid

[0044] Add 5g (38.7mmol) of S-configuration 2-piperidinecarboxylic acid and 3.07g (42.6mmol) of n-butyraldehyde to 50ml of methanol, add 234mg (3.9mmol) of glacial acetic acid, stir at room temperature for about 1 hour, then add 1.6g (42.6mmol) sodium borohydride, slowly warming up to 30~40 ℃ and continue stirring reaction at this temperature for 5 hours; Stop reaction, adjust reaction solution pH to 7~8 with 1N sodium hydroxide solution, add 100ml ethyl acetate, The organic layer was collected by extraction and liquid separation, and the organic phase was concentrated by distillation under reduced pressure. The obtained crude product was purified by column chromatography to obtain 4.3 g of S-configuration 1-butylpiperidine-2-carboxylic acid with a yield of 60%. MS:184[M-H]

[0045] 1 H-NMR(400MHz,DMSO-d6),ppm:3.26-3.23(m,1H),3.12-3.08(m,1H),3.0-2.9(m,2H),1.91-1.87(m,1H),1.63 -1.50(m,6H),...

Embodiment 2

[0046] Example 2: Preparation of S configuration-1-butylpiperidine-2-carboxylic acid

[0047]Add 5g (38.7mmol) of S-configuration 2-piperidinecarboxylic acid, 8.37g (116.1mmol) of n-butyraldehyde, and 878mg (7.7mmol) of p-trifluoroacetic acid into 50ml of methanol, stir at room temperature for about 1h, then add 7.3g ( 116.1mmol) sodium cyanoborohydride, continue to stir and react at 30-40°C for 6h; adjust the pH of the reaction solution to 7-8 with 1mol / L sodium hydroxide solution, add 100ml ethyl acetate to extract and separate the liquid, and subtract the organic phase After evaporation and concentration, the resulting crude product was purified by column chromatography to obtain 4.6 g of S-configuration 1-butylpiperidine-2-carboxylic acid with a yield of 65%.

Embodiment 3

[0048] Example 3: Preparation of racemic 1-butylpiperidine-2-carboxylic acid

[0049] Add 5g (38.7mmol) racemic 2-piperidinecarboxylic acid, 4.2g (58.1mmol) n-butyraldehyde, 344mg (2.0mmol) p-toluenesulfonic acid to 50ml ethanol, stir at room temperature for 1h, then add 49.2g (232.2mmol) ) sodium triacetylborohydride, continue to stir and react at 30-40°C for 6h; use 1mol / L sodium hydroxide solution to adjust the pH of the reaction solution to 7-8, add 100ml ethyl acetate to extract and separate the liquid, and evaporate and concentrate the organic phase to obtain The crude product was purified by column chromatography to obtain 4.5 g of racemic 1-butylpiperidine-2-carboxylic acid with a yield of 62.8%.

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Abstract

The invention belongs to the technical field of chemical synthesis and in particular relates to a preparation method of levobupivacaine hydrochloride. The preparation method takes racemic or S-configuration 2-piperidinecarboxylic acid as a starting raw material and comprises the following steps: taking the starting raw material and n-butylaldehyde to react and carrying out borohydride reduction reaction to obtain 1-butylpiperidine-2-carboxylic acid; taking the 1-butylpiperidine-2-carboxylic acid and 2,6-dimethylaniline to be subjected to condensation reaction, so as to generate bupivacaine or levobupivacaine; carrying out subsequent treatment to obtain a final product levobupivacaine hydrochloride. Compared with an existing synthesis route, the preparation method has the advantages of short synthesis route, simple method, convenience for operation, low cost and easiness for industrial production; reaction conditions of each step are relatively moderate, a process is stable, a strong-corrosion chlorination reagent is not used, the pollution to environment is reduced and the like.

Description

technical field [0001] The invention belongs to the technical field of chemical synthesis, and in particular relates to a preparation method of levobupivacaine hydrochloride. Background technique [0002] Levobupivacaine is a single isomer of racemic bupivacaine, developed by British Chiroscience Company (now UCB Company), it is a long-acting amide local anesthetic, suitable for peripheral nerve block and epidural block and subarachnoid block. As of February 2010, levobupivacaine has been marketed in more than 60 countries around the world. [0003] The structural formula of levobupivacaine hydrochloride is as follows: [0004] [0005] The main synthetic route of levobupivacaine hydrochloride reported in existing literature is as follows: [0006] Synthetic Route 1 (CN 104003930 and Hunan University master's thesis "Synthetic Technology Research of Ropivacaine Hydrochloride and Bupivacaine Hydrochloride") [0007] [0008] In this reaction route, the salt-forming ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D211/60
Inventor 陈敬金张志强甄宜战张绪猛邱欣
Owner SHANDONG BESTCOMM PHARMA CO LTD
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