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A kind of synthetic method of Erecoxib

A synthesis method and p-methylphenyl technology, applied in the field of erecoxib synthesis, can solve the problems of many impurities and by-products, unfavorable post-processing and purification, and difficulty in meeting the quality requirements of raw materials, and achieve cost reduction, The effect of less impurities

Active Publication Date: 2021-11-23
SUZHOU FUSHILAI PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0014] where R 1 , R 2 Chlorine or bromine, this process route needs to use a strong base as a condensing agent to carry out the cyclization reaction. Since there are many impurities and by-products continuously produced in each step, it is not conducive to post-treatment and purification, and it is difficult to meet the quality requirements of the raw material drug

Method used

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  • A kind of synthetic method of Erecoxib
  • A kind of synthetic method of Erecoxib
  • A kind of synthetic method of Erecoxib

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0040] A) Synthesis of 3-p-methylphenyl-4-p-methylsulfonylphenylpyrrole-2-carboxylic acid methyl ester:

[0041] (E)-1-p-methylsulfonylphenyl-1-nitro-2-p-tolylethylene (21.0g) was dissolved in isopropanol (300mL), sodium hydroxide (4.0g) was added, stirred and ice-bathed Cool to 5-10°C, add a solution of methyl isocyanoacetate (7.2g) in isopropanol (12mL) dropwise, rise to 30°C and react for 18h until the reaction is complete. After post-treatment, the obtained crude product is recrystallized with ethanol, To obtain methyl 3-p-methylphenyl-4-p-methylsulfonylphenylpyrrole-2-carboxylate, 23.2 g of off-white solid, yield 95%.

[0042] B) Synthesis of 3-p-methylphenyl-4-p-methylsulfonylphenylpyrrole-2-carbaldehyde:

[0043]3-p-methylphenyl-4-p-methylsulfonylphenylpyrrole-2-carboxylic acid methyl ester (23.0g) was dissolved in dichloromethane (350mL), cooled to -78°C, and bis(2-methyl Oxyethoxy) sodium aluminum hydride (13.8g) in n-hexane solution, heat preservation reaction for ...

Embodiment 2

[0049] A) synthesis of 3-p-methylphenyl-4-p-methylsulfonylphenylpyrrole-2-carboxylic acid ethyl ester:

[0050] (E)-1-p-methylsulfonylphenyl-1-nitro-2-p-tolylethylene (12.0g) was dissolved in tetrahydrofuran (180mL), potassium carbonate (9.4g) was added, stirred and cooled to 5 ~10°C, add a solution of ethyl isocyanoacetate (5.6g) in tetrahydrofuran (10mL) dropwise, rise to 35°C and react for 12h until the reaction is complete. Ethylphenyl-4-p-methylsulfonylphenylpyrrole-2-carboxylate, off-white solid 13.5g, yield 93%.

[0051] B) Synthesis of 3-p-methylphenyl-4-p-methylsulfonylphenylpyrrole-2-carbaldehyde:

[0052] 3-p-methylphenyl-4-p-methylsulfonylphenylpyrrole-2-carboxylic acid ethyl ester (13.0g) was dissolved in toluene (180mL), cooled to -78°C, diisobutylaluminum hydride ( 6.3 g) of n-hexane solution, keep it warm for 4 hours until the reaction is complete, add dilute hydrochloric acid dropwise at low temperature to quench the reaction solution, rise to room temperatu...

Embodiment 3

[0058] A) Synthesis of 3-p-methylphenyl-4-p-methylsulfonylphenylpyrrole-2-carboxylic acid methyl ester:

[0059] (E)-1-p-methylsulfonylphenyl-1-nitro-2-p-tolylethylene (5.6g) was dissolved in methanol (100mL), and 1,8-diazabicyclo[5.4.0]deca was added One-carb-7-ene (5.4g), stirred and cooled in an ice bath to 5-10°C, added dropwise a solution of methyl isocyanoacetate (2.6g) in methanol (6mL), raised to 20°C and reacted for 24h until the reaction was complete , after post-treatment, the obtained crude product was recrystallized from ethanol to obtain 3-p-methylphenyl-4-p-methylsulfonylphenylpyrrole-2-carboxylic acid methyl ester, 6.3 g of off-white solid, yield 96%.

[0060] B) Synthesis of 3-p-methylphenyl-4-p-methylsulfonylphenylpyrrole-2-carbaldehyde:

[0061] 3-p-methylphenyl-4-p-methylsulfonylphenylpyrrole-2-carboxylic acid methyl ester (6.2g) was dissolved in chloroform (100mL), cooled to -78°C, diisobutylaluminum hydride ( 3.6 g) of n-hexane solution, heat preservati...

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Abstract

A kind of synthetic method of Erecoxib, step: with (E)-1-p-methylsulfonylphenyl-1-nitro-2-p-tolylethylene and isocyanoacetate in the mixture of alkali reagent and solvent The condensation cyclization reaction is carried out in the system; the obtained 3-p-methylphenyl-4-p-methylsulfonylphenylpyrrole-2-carboxylate is reduced at -78°C in a system of reducing agent and solvent Reaction; The obtained 3-p-methylphenyl-4-p-methylsulfonylphenylpyrrole-2-formaldehyde is oxidized in the system of hydrogen peroxide and solvent; the obtained 3-p-methylphenyl-4- Perform substitution reaction between p-methylsulfonylphenyl-3-pyrrolidin-2-one and 1-halopropane or hydrocarbon sulfonate propyl ester derivatives in a system of alkali reagent and solvent to obtain Erecoxib. The reaction steps are simplified and optimized, and the process operation is simple, which helps to reduce the cost; the impurities in the reaction are less and controllable, reflecting green environmental protection; the starting materials and the reagents used are easily available.

Description

technical field [0001] The invention belongs to the technical field of pharmaceutical chemical synthesis, and in particular relates to a synthesis method of Erecoxib. Background technique [0002] The new COX-2 selective inhibitor Imrecoxib (Imrecoxib) is the first class 1.1 new drug independently developed by Jiangsu Hengrui Company. It is used to treat and relieve the pain symptoms of osteoarthritis and postoperative inflammation. It has been approved by the National FDA listed. Its chemical name is N-n-propyl-3-p-methylphenyl-4-p-methylsulfonylphenyl-3-pyrrolidin-2-one, and its chemical structure is: [0003] [0004] The first-line medication for osteoarthritis will change somewhat in the future, and specific inhibitors of COX-2 (a cyclooxygenase that causes joint pain and inflammation) may replace the current acetaminophen as an osteoarthritis drug. first-line medication. In the changing pattern of first-line drugs for osteoarthritis in the future, Irexix has a go...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D207/38
CPCC07D207/38
Inventor 莫国宁
Owner SUZHOU FUSHILAI PHARMA CO LTD
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