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

The invention discloses a method for synthesizing Erecoxib, which belongs to the technical field of pharmaceutical chemical synthesis. Step: Synthesis of 2-n-propylamino-1-p-methylsulfonyl acetophenone: N-propyl-β-hydroxyl-4-methylsulfonyl phenethylamine in a system composed of oxidation reagent, solvent and water Carry out oxidation reaction in, obtain 2-n-propylamino-1-p-methylsulfonyl acetophenone; Synthetic Erecoxib: the 2-n-propylamino-1-p-methylsulfonyl acetophenone obtained and p- Cresyl acetate undergoes condensation cyclization reaction in a system of alkali reagent and solvent to obtain Erecoxib. The reaction steps are significantly simplified and optimized, and the process operation is simple, which helps to reduce the cost; the reaction has less impurities and is controllable, and no pollutants are produced, reflecting the effect of environmental protection; the starting materials and reagents used are easily available and can be produced in large quantities To meet the use requirements of raw materials and 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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