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Preparation method of bupivacaine and intermediate (S)-2-piperidinecarboxylic acid thereof

A technology of piperidinecarboxylic acid and lithium hexamethyldisilazide, which is applied in the field of preparation of bupivacaine and its intermediate - 2-piperidinecarboxylic acid, can solve the problems of difficulty in obtaining starting materials, high production costs, and steps cumbersome and other problems, to achieve good market application prospects, low production costs, and good stereoselectivity

Active Publication Date: 2021-06-11
ZHEJIANG UNIV OF TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0014] In summary, the synthesis method of (S)-2-piperidinecarboxylic acid reported in the literature has the disadvantages that the starting materials are not easy to obtain, need to use expensive noble metal catalysts, the steps are cumbersome, the yield is low, and the production cost is high.

Method used

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  • Preparation method of bupivacaine and intermediate (S)-2-piperidinecarboxylic acid thereof
  • Preparation method of bupivacaine and intermediate (S)-2-piperidinecarboxylic acid thereof
  • Preparation method of bupivacaine and intermediate (S)-2-piperidinecarboxylic acid thereof

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Experimental program
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Effect test

Embodiment 1

[0055] Embodiment 1, the synthesis of compound (III)

[0056] Dissolve (R)-4-benzyl-2-oxazolidinone I (1.62g, 16mmol) in tetrahydrofuran (20mL), and add n-butyllithium in n-hexane (7.7mL , 19.2mmol, 2.5mol / L), stirred at -78°C for 30 minutes, then added compound II (3.92g, 17.6mmol) in tetrahydrofuran (25mL), continued the reaction at this temperature for 30 minutes, then naturally rose to room temperature for reaction 3 hours. After the reaction was completed, 2 mL of glacial acetic acid was added dropwise to quench the reaction, then 30 mL of water was added and stirred, extracted with dichloromethane (2×100 mL), the organic phase was collected, dried, concentrated, and the crude product was purified by silica gel column chromatography, and the eluent was petroleum Ether: ethyl acetate (volume ratio: 5:1-3:1), after concentration, 5.3 g of light yellow oily liquid Compound III was obtained, with a yield of 91%.

[0057] 1 H NMR (500MHz, Chloroform-d) δ7.92-7.74(m, 4H), 7....

Embodiment 2

[0058] Embodiment 2, the synthesis of compound (III)

[0059] (R)-4-Benzyl-2-oxazolidinone I (1 g, 10 mmol) was dissolved in tetrahydrofuran (10 mL), and sodium hydride (480 mg, 12 mmol, content 60%) was added at -5°C under nitrogen protection, After stirring at 0° C. for 1 h, a solution of compound II (2.45 g, 11 mmol) in tetrahydrofuran (15 mL) was added, and then allowed to rise to room temperature for 5 hours. After the reaction, add 1 mL of glacial acetic acid dropwise to quench the reaction, then add 20 mL of water and stir, dichloromethane extraction (2 × 80 mL), collect the organic phase, dry, concentrate, and the crude product is purified by silica gel column chromatography, and the eluent is petroleum Ether: ethyl acetate (volume ratio: 5:1-3:1), after concentration, 3.13 g of light yellow oily liquid Compound III was obtained, with a yield of 86%.

Embodiment 3

[0060] Embodiment 3, the synthesis of compound (III)

[0061] Dissolve (R)-4-benzyl-2-oxazolidinone I (1g, 10mmol) in tetrahydrofuran (10mL), add potassium tert-butoxide (1.35g, 12mmol) at 0°C under nitrogen protection, and at this temperature After stirring for 1 h, a solution of compound II (2.45 g, 11 mmol) in tetrahydrofuran (15 mL) was added, and then allowed to rise to room temperature for 5 hours. After the reaction was finished, 20 mL of water was added to quench the reaction, extracted with dichloromethane (2 × 80 mL), the organic phase was collected, dried, concentrated, and the crude product was purified by silica gel column chromatography, and the eluent was sherwood oil: ethyl acetate (volume ratio 5:1~3:1), concentrated to obtain light yellow oily liquid compound III3g with a yield of 82%.

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Abstract

The invention discloses bupivacaine and a preparation method of an intermediate (S)-2-piperidinecarboxylic acid of the bupivacaine; wherein the intermediate (S)-2-piperidinecarboxylic acid is prepared by taking (R)-4-benzyl-2-oxazolidinone as a chiral auxiliary agent through amidation, asymmetric alkylation, hydrolysis, cyclization and auxiliary group removal; wherein the prepared (S)-2-piperidinecarboxylic acid is used as a raw material to prepare the local anesthetic (S)-bupivacaine. The method utilizes cheap and easily available organic raw materials, and has the advantages of simple operation, mild reaction conditions, good stereoselectivity, high yield and the like.

Description

technical field [0001] The invention relates to the technical field of pharmaceutical chemical synthesis, in particular to a preparation method of bupivacaine and its intermediate (S)-2-piperidinecarboxylic acid. Background technique [0002] Bupivacaine was approved by Sweden for the first time in 1999, has completed clinical trials in the United States, Europe, Australia and New Zealand, and has been certified by the US FDA. Bupivacaine is a long-acting local anesthetic with dual effects of analgesia and anesthesia. It is mainly used for surgical anesthesia and epidural anesthesia. It can be used in various operations, including orthopedics, gynecology, urology and other lower limbs Surgery; it can also be used for acute pain relief after surgery or childbirth, with less toxicity to the heart, high safety, and better clinical application range. The main method of synthesizing bupivacaine at present has: (1) triphosgene synthesis bupivacaine, take 2-piperidinecarboxylic ac...

Claims

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Application Information

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IPC IPC(8): C07D211/60
CPCC07D211/60
Inventor 杨玉燕张兴贤
Owner ZHEJIANG UNIV OF TECH
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