Synthetic method of non-steroidal antiinflammatory drug pain killing

A technology for a non-steroidal anti-inflammatory drug and a synthetic method, applied in the field of drug synthesis, can solve the problems of poor commercialization, unsuitable storage, high price, etc., and achieve the effects of reducing process cost, cheap process raw materials, and simple process

Active Publication Date: 2021-04-16
HANGZHOU DIKE TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, in this method, N-methylpyrrole is used as a raw material, and the process cost is high
[0009] (6) U.S. Patent US4363918 protects the preparation of 2-(2-acetoxy)-1-methyl-1H-pyrrole-3-carboxylic acid using acetone dicarboxylic acid, methylamine and chloroacetaldehyde, but does not give specific implementation method
Moreover, acetone dicarboxylic acid is a very unstable crystal, which is easily decomposed by heating, is not suitable for storage, is expensive, and has a poor degree of commercialization. Using acetone dicarboxylic acid as a starting material cannot realize the industrialized production of pemetidine
[0010] Most of the existing published synthetic routes of pemetidine rely on N-methylpyrrole, and the sharp rise in the market price of N-methylpyrrole has significantly reduced the economic benefits of the pemethadine process

Method used

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  • Synthetic method of non-steroidal antiinflammatory drug pain killing
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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0042] Synthesis of Acetone Dicarboxylic Acid

[0043]Add 1000g of concentrated sulfuric acid and 192g of citric acid into a 2000ml three-neck flask, stir and react at 50°C for 15h, add the reaction liquid to 1000ml of ice water for cooling and crystallization, and filter at low temperature to obtain 161.2g of crude acetone dicarboxylic acid containing sulfuric acid. Liquid chromatography detected that the crude product contained 123.5 g of acetone dicarboxylic acid, and the yield was 84.5%.

[0044] Synthesis of 2-(2-acetoxy)-1-methyl-1H-pyrrole-3-carboxylic acid

[0045] 95.4g crude acetone dicarboxylic acid containing sulfuric acid (containing 73.1g acetone dicarboxylic acid), 60.0g 26% methylamine aqueous solution and 100g 40% chloroacetaldehyde aqueous solution were mixed, and stirred and reacted for 12h under an ice-water bath, and the reaction Afterwards, unreacted methylamine and chloroacetaldehyde were distilled off under reduced pressure, the temperature of the solu...

Embodiment 2

[0056] Synthesis of Acetone Dicarboxylic Acid

[0057] Add 2000g of concentrated sulfuric acid and 192g of citric acid into a 2000ml three-neck flask, stir and react at 10°C for 15h, add the reaction liquid to 1000ml of ice water for cooling and crystallization, and filter at low temperature to obtain 103.5g of crude acetone dicarboxylic acid containing sulfuric acid. Liquid chromatography detected that the crude product contained 77.9 g of acetone dicarboxylic acid, and the yield was 53.3%.

[0058] Synthesis of 2-(2-acetoxy)-1-methyl-1H-pyrrole-3-carboxylic acid

[0059] Mix 97.0 g of crude acetone dicarboxylic acid containing sulfuric acid (containing 73.0 g of acetone dicarboxylic acid), 360.0 g of 40% aqueous solution of methylamine and 200.0 g of 40% aqueous solution of chloroacetaldehyde, and stir the reaction in an ice-water bath for 12 h, After the reaction, the unreacted methylamine and chloroacetaldehyde were distilled off under reduced pressure, the temperature of...

Embodiment 3

[0069] Synthesis of Acetone Dicarboxylic Acid

[0070] Add 500g of concentrated sulfuric acid and 192g of citric acid into a 2000ml three-necked flask, stir and react at 70°C for 15h, add the reaction liquid to 1000ml of ice water for cooling and crystallization, and filter at low temperature to obtain 142.8g of crude acetone dicarboxylic acid containing sulfuric acid. Liquid chromatography detected that the crude product contained 111.4 g of acetone dicarboxylic acid, and the yield was 76.2%.

[0071] Synthesis of 2-(2-acetoxy)-1-methyl-1H-pyrrole-3-carboxylic acid

[0072] 93.8g of crude acetone dicarboxylic acid containing sulfuric acid (containing 73.2 g of acetone dicarboxylic acid), 770 g of 40% methylamine aqueous solution and 295.0 g of 40% chloroacetaldehyde aqueous solution were mixed, and stirred and reacted in an ice-water bath for 12 h, the reaction Afterwards, the unreacted methylamine and chloroacetaldehyde were distilled off under reduced pressure, the tempera...

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Abstract

The invention discloses a synthesis method of non-steroidal anti-inflammatory drug tolmetin. The methodcomprises the following steps: sequentially preparing a sulfuric acid-containing acetonedicarboxylic acid crude product, 2-(2-acetoxy)-1-methyl-1H-pyrrole-3-formic acid and 2-(2-alkyl acetate)-1-methyl-1H-pyrrole-3-formic acid by taking citric acid or citric acid monohydrate as a raw material; and carrying out decarboxylation, acylation, hydrolysis and acidification to obtain tolmetin. The synthetic method provided by the invention overcomes the defect that the existing tolmetin preparation process depends on N-methylpyrrole, and is a low-cost, low-pollution and high-yield synthetic method of non-steroidal anti-inflammatory drug tolmetin.

Description

technical field [0001] The invention belongs to the field of drug synthesis, in particular to a method for synthesizing a non-steroidal anti-inflammatory drug acetidine. Background technique [0002] Tolmetin, chemical name: 1-methyl-5-(p-methylbenzoyl)pyrrole-2-acetic acid, is a non-steroidal anti-inflammatory analgesic, developed by McNeil Company of the United States, in 1976 Approved by the US FDA for marketing. Its effect is similar to that of other non-steroidal anti-inflammatory drugs such as aspirin, but the side effects are relatively mild, and it is easier to be tolerated by patients. Animal experiments have proved that its anti-arthritis effect is stronger than that of aspirin, but weaker than indomethacin and phenylbutazone. Its analgesic effect is equivalent to that of ibuprofen, and its antipyretic effect is also strong. It can be absorbed quickly and safely after oral administration. [0003] At present, the synthetic route of Pamonadine mainly contains the ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D207/337
CPCY02P20/55
Inventor 俞迪虎王权包磊侯大鹏
Owner HANGZHOU DIKE TECH CO LTD
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