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Preparation method of levobupivacaine hydrochloride

A technology of levobupivacaine hydrochloride and alcoholic hydrochloride solution is applied in the field of preparation of levobupivacaine hydrochloride, can solve the problems of harsh reaction conditions, prolonged preparation process route, increased production cycle and the like, and achieves mild reaction conditions and synthetic The route is short and avoids the effect of strong corrosiveness

Active Publication Date: 2017-08-29
SHANDONG BESTCOMM PHARMA CO LTD
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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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  • Preparation method of levobupivacaine hydrochloride
  • Preparation method of levobupivacaine hydrochloride
  • Preparation method of levobupivacaine hydrochloride

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0042] Embodiment 1: Preparation of S configuration 1-butylpiperidine-2-carboxylic acid

[0043] Add 20g (0.155mol) of S-configuration 2-piperidinecarboxylic acid and 11.17g (0.155mol) of n-butyraldehyde into 200ml of methanol solvent, stir for about 1 hour, weigh 1g of palladium carbon with a mass fraction of 10%, and add it to the reaction solution , into hydrogen, after 3 times of gas exchange, the pressure rose to 20 atm, kept the pressure at room temperature for 1 to 2 hours, and terminated the reaction after testing that the reaction was complete. The reaction solution was filtered and the filtrate was collected. After the filtrate was spin-dried, 200 ml of petroleum ether was added to make a slurry, and the filter cake was filtered and collected. After drying, 27.5 g of S-configuration 1-butylpiperidine-2-carboxylic acid was obtained. Yield 95.7%. MS:184[M-H]

Embodiment 2

[0044] 1H-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), 1.38-1.35(m, 1H), 1.29-1.23(m, 2H), 0.89-0.86(t, J=7.2Hz, 3H) Example 2: Preparation of S configuration 1-butyl Piperidine-2-carboxylic acid

[0045] Add 20g (0.155mol) of S-configuration 2-piperidinecarboxylic acid and 33.53g (0.465mol) of n-butyraldehyde to 200ml of isopropanol solvent, stir for about 1 hour, weigh 10g of Raney nickel and add it to the reaction solution, Hydrogen gas was introduced, and the pressure rose to 5 atm after three gas exchanges, and the reaction was maintained at room temperature for 5 to 6 hours, and the reaction was terminated after testing that the reaction was complete. The reaction solution was filtered and the filtrate was collected. After the filtrate was spin-dried, 200ml of petroleum ether was added to make a slurry, and the filter cake was filtered and collected. After drying, 27.3g of S-configuration 1-butylpiperidine-2-ca...

Embodiment 3

[0046] Example 3: Preparation of racemic 1-butylpiperidine-2-carboxylic acid

[0047]Add 20g (0.155mol) of 2-piperidinecarboxylic acid and 16.8g (0.233mol) of n-butyraldehyde to 200ml of ethanol solvent, stir for about 1 hour, weigh 2g of palladium carbon with a mass fraction of 5%, and add it to the reaction solution. Introduce hydrogen and exchange gas three times, then continue to infuse hydrogen, react at room temperature and normal pressure for 8 to 10 hours, and terminate the reaction after testing that the reaction is complete. The reaction solution was filtered and the filtrate was collected. After the filtrate was spin-dried, 200ml of petroleum ether was added to make a slurry, and the filter cake was filtered and collected. After drying, 27.8g of 1-butylpiperidine-2-carboxylic acid was obtained. Yield 96.8%.

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Abstract

The invention belongs to the technical field of chemical synthesis and particularly relates to a preparation method of levobupivacaine hydrochloride. The preparation method comprises the steps of carrying out catalytic hydrogenation on racemic or S-form 2-piperidinecarboxylicacid as a raw material and n-butanal so as to obtain 1-butylpiperidine-2-carboxylic acid, carrying out condensation reaction on 1-butylpiperidine-2-carboxylic acid and 2,6-dimethylaniline so as to generate bupivacaine or levobupivacaine, and carrying out subsequent treatment, so as to obtain a final product, namely levobupivacaine hydrochloride. Compared with existing synthetic routes, the preparation method has the advantages that the synthetic route is short, the method is simple, convenient in operation, low in cost and easy for industrial production, reaction conditions of each step are relatively mild, the process is stable, a strong-corrosion chlorinated reagent is not used, and the environmental pollution is reduced.

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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IPC IPC(8): C07D211/60
Inventor 甄宜战张志强赵显栋马燕青邱欣
Owner SHANDONG BESTCOMM PHARMA CO LTD
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