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Celecoxib preparation method

A technology of celecoxib and ethanol, applied in the field of drug synthesis, can solve the problems of low yield and poor purity, and achieve the effects of high purity, uniform distribution and fine particle size

Inactive Publication Date: 2015-12-09
SUZHOU ERYE PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0017] Aiming at the problems of low yield and poor purity generally existing in the preparation method of celecoxib, the present invention provides a kind of preparation method of celecoxib with high yield and high purity:

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1 3

[0042] The preparation of embodiment 1 ethyl trifluoroacetate

[0043]

[0044] Add 300mL of trifluoroacetic acid in batches to 1.4L of absolute ethanol, then add 100g of D072 strongly acidic cation exchange resin as a catalyst, heat and stir under reflux for 8 hours, filter out the resin under reduced pressure, and rectify to obtain 340mL of ethyl trifluoroacetate with a boiling point of 60 ~62°C, the yield was 94.2%.

Embodiment 2

[0045] The preparation of embodiment 2 p-hydrazinobenzenesulfonamide hydrochloride

[0046]

[0047] P-aminobenzenesulfonamide is first reacted with sodium nitrite to obtain diazonium salt, and then reduced by sodium nitrite to obtain hydrazine.

[0048] Table 1, preparation of feed intake and proportioning of p-hydrazinobenzenesulfonamide hydrochloride

[0049]

[0050] Operation process:

[0051] A. Put (41kg hydrochloric acid and 60kg purified water) mixture into a 200L (208#) reaction tank, put 20kg p-aminobenzenesulfonamide under stirring, and cool down to below -4~-10°C. spare.

[0052] B. Weigh 8.84kg of sodium nitrite in a 50L barrel, add 24.8kg of purified water, and stir until completely dissolved.

[0053] C. Drop the sodium nitrite solution into the 208# reaction tank, control the temperature during the process at -4~-10°C, and stir for 10 minutes after the drop is completed.

[0054] D. Add 96.8kg of purified water into a 500L (204#) reaction tank, add 3...

Embodiment 3

[0068] Example 3 Preparation of 1-(4-methylphenyl)-4,4,4-trifluoro-1,3-butanedione

[0069]

[0070] Table 5, the preparation of 1-(4-methylphenyl)-4,4,4-trifluoro-1,3-butanedione feeding and ratio

[0071]

[0072] Operation process:

[0073] A. Put 47.6kg of absolute ethanol into 208# reaction tank (need to be dried), add 7.62kg of sodium ethoxide, and stir until completely dissolved.

[0074] B. Control the temperature below 40°C, add 16.1 kg of ethyl trifluoroacetate, and stir for 5 minutes. Add 11.42 kg of p-methylacetophenone, raise the temperature to 50±2°C, and keep stirring for 2 hours. spare.

[0075] Optimization of reaction conditions:

[0076] Table 6. Research on the reaction conditions for the preparation of 1-(4-methylphenyl)-4,4,4-trifluoro-1,3-butanedione

[0077]

[0078] According to the analysis results, if the reaction temperature is lower than 40°C, the reaction of the raw materials will not be completed; if the reaction temperature is high...

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Abstract

The present invention relates to a celecoxib preparation method, wherein 4'-methylacetophenone and ethyl trifluoroacetate are adopted as raw materials, Claisen condensation is performed to obtain a beta-diketone intermediate, the beta-diketone intermediate and p-hydrazinobenzenesulfonamide hydrochloride are subjected to condensation cyclization in ethanol to obtain celecoxib, and refining and crystallization are performed to obtain the celecoxib crystal. According to the present invention, with the preparation method, the celecoxib can be obtained in the high yield manner, the purity of the obtained product is high, the single impurity can be controlled to be less than or equal to 0.5%, and the obtained celecoxib crystal has characteristics of fine particle size and uniform distribution, and is suitable for bulk drug production.

Description

technical field [0001] The invention relates to a synthesis method of celecoxib, which belongs to the field of drug synthesis. Background technique [0002] Celecoxib (celecoxib) is the first specific cyclooxygenase-2 (COX-2) inhibitor developed by Searle, USA, for the treatment of osteoarthritis and rheumatoid arthritis. [0003] [0004] The main synthetic route of existing celecoxib is as follows: [0005] Route 1: [0006] [0007] [0008] Carry out Claisen condensation under the effect of 25% sodium methylate-methanol with p-methyl acetophenone and ethyl trifluoroacetate to obtain β-diketone intermediate, this intermediate is not separated and purified, directly with p-hydrazinobenzenesulfonamide The hydrochloride is obtained by condensation and cyclization in ethanol, and then recrystallized from ethyl acetate-n-octane, with a total yield of 46%. The disadvantages of this method are: the yield is low and the reaction time is long; since the intermediat...

Claims

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Application Information

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IPC IPC(8): C07D231/12
CPCC07D231/12
Inventor 张健姚婵艳钟玫陈学文刘志
Owner SUZHOU ERYE PHARMA CO LTD
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