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The synthetic method of Erecoxib

A synthesis method and n-propylamino technology, applied in the field of pharmaceutical chemical 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 the effects of less impurities and lower costs.

Active Publication Date: 2021-08-31
SUZHOU FUSHILAI PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

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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  • The synthetic method of Erecoxib
  • The synthetic method of Erecoxib
  • The synthetic method of Erecoxib

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0031] A) Synthesis of 2-n-propylamino-1-p-methylsulfonyl acetophenone:

[0032] N-n-propyl-β-hydroxy-4-methylsulfonylphenethylamine (14.0g) was dissolved in 1,2-dichloroethane (280mL), potassium permanganate (9.5g) and water (1080mL) were added , raised to 20°C and reacted for 8 hours until the reaction was complete. After post-treatment, the obtained crude product was recrystallized with ethanol to obtain 2-n-propylamino-1-p-methylsulfonylacetophenone, off-white solid 12.4g, yield 89 %.

[0033] B) Synthesis of Erecoxib:

[0034] Dissolve 2-n-propylamino-1-p-methylsulfonylacetophenone (10.0g) in isopropanol (200mL), add sodium isopropoxide (6.4g), stir and cool to 5-10°C in an ice bath, Add a solution of ethyl p-tolyl acetate (10.5g) in isopropanol (15mL) dropwise, rise to 20°C and react for 12h until the reaction is complete. After post-treatment, the obtained crude product is recrystallized with ethanol to obtain Erecoxib, white Solid 13.6g, yield 94%.

Embodiment 2

[0036] A) Synthesis of 2-n-propylamino-1-p-methylsulfonyl acetophenone:

[0037] Dissolve N-propyl-β-hydroxy-4-methylsulfonylphenethylamine (27.0g) in acetonitrile (500mL), add hydrogen peroxide (0.105mol) and water (1500mL), raise the temperature to 40°C for 4h until the reaction is complete , after post-treatment, the resulting crude product was recrystallized from ethanol to obtain 2-n-propylamino-1-p-methylsulfonylacetophenone, 25.4 g of an off-white solid, with a yield of 95%.

[0038] B) Synthesis of Erecoxib:

[0039] Dissolve 2-n-propylamino-1-p-methylsulfonylacetophenone (22.0g) in ethanol (450mL), add sodium ethoxide (10.6g), stir and cool in an ice bath to 5-10°C, add p-toluene dropwise Methyl acetate (18.4g) in ethanol (25mL) was raised to 70°C for 9h until the reaction was complete. After post-treatment, the resulting crude product was recrystallized with ethanol to obtain Erecoxib, a white solid of 30.2g, yield 95%.

Embodiment 3

[0041] A) Synthesis of 2-n-propylamino-1-p-methylsulfonyl acetophenone:

[0042] Dissolve N-propyl-β-hydroxy-4-methylsulfonylphenethylamine (100.0g) in ethanol (1800mL), add pyridinium chlorochromate (96.3g) and water (3900mL), and heat up to 60°C for reaction After 2 hours to complete the reaction, after post-treatment, the obtained crude product was recrystallized from ethanol to obtain 2-n-propylamino-1-p-methylsulfonylacetophenone, 92.3 g of off-white solid, with a yield of 93%.

[0043] B) Synthesis of Erecoxib:

[0044] 2-n-propylamino-1-p-methylsulfonylacetophenone (91.5g) was dissolved in tetrahydrofuran (1500mL), sodium hydroxide (21.5g) was added, stirred and cooled to 5-10°C in an ice bath, and p- A solution of ethyl tolyl acetate (70.3g) in tetrahydrofuran (125mL) was raised to 90°C for 6h until the reaction was complete. After post-treatment, the obtained crude product was recrystallized with ethanol to obtain Erecoxib, a white solid of 125.8g. The rate is 95%.

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Abstract

A method for synthesizing ericoxib belongs to the technical field of pharmaceutical chemical synthesis. Steps: Synthesis of 2-n-propylamino-1-p-methanesulfonyl acetophenone: N-n-propyl-β-hydroxy-4-methanesulfonyl phenethylamine in a system composed of oxidizing reagent, solvent and water The oxidation reaction is carried out to obtain 2-n-propylamino-1-p-methylsulfonyl acetophenone; synthesis of Irecoxib: combine the obtained 2-n-propylamino-1-p-methylsulfonyl acetophenone with p-methylsulfonyl acetophenone. Tolylacetate undergoes a condensation cyclization reaction in a system of alkali reagents and solvents to obtain ericoxib. The reaction steps are significantly simplified and optimized, and the process operation is simple, which helps to reduce costs; the impurities in the reaction are less, controllable, and no pollutants are produced, reflecting the green and environmentally friendly effect; the starting materials and reagents used are easy to obtain, and can be mass-produced To meet the demand for raw materials and be suitable for industrial production.

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 drug COX-2 selective inhibitor Imrecoxib (Imrecoxib) is used to treat and relieve the pain symptoms of osteoarthritis and postoperative inflammation. p-methylphenyl-4-p-methylsulfonylphenyl-3-pyrrolidin-2-one, the 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 osteoarthritis drugs in the future, Erecoxib has a good market prospect. [0005] There have been many patent reports on the preparation method of Erecoxib. Patent CN1134413C and US20040029951 disclose a synthetic route for ...

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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