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Preparation and refining method of parecoxib and intermediate thereof

A technology for parecoxib and a synthesis method, applied in the field of medicinal chemistry, can solve problems such as substandard material purity, and achieve the effects of shortening working hours and saving consumption

Pending Publication Date: 2021-12-28
NANJING CHIA TAI TIANQING PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

And it is all recrystallized with absolute ethanol after the acylation reaction, but the finished product prepared through this step, the purity of the relevant substances is not up to the standard, and it needs to be further refined after forming a salt

Method used

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  • Preparation and refining method of parecoxib and intermediate thereof
  • Preparation and refining method of parecoxib and intermediate thereof
  • Preparation and refining method of parecoxib and intermediate thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0074] Embodiment 1 sulfonation step

[0075] Add 15.6kg of dichloromethane and 6.0kg of SM1 into the reactor, stir and cool down to 0-15°C. Slowly add 26.64kg of chlorosulfonic acid dropwise, and control the internal temperature to 0-15°C. After dropping, rise to 40-45°C to reflux for 4 hours. Lower the temperature to 0-15°C, slowly add the reaction solution dropwise to 72kg of purified water, and control the internal temperature to 0-30°C. Stand and separate the layers, separate the organic phase, extract the aqueous phase with 18 kg of ethyl acetate (no emulsification, no need to stand), separate the organic phase, and extract and wash with 5.0 kg of purified water. After concentrating the organic phase of dichloromethane, adding ethyl acetate, the organic phase was concentrated again until the remaining mass of the system was 15kg±1kg. Control the temperature at 30-40°C and add 33kg of n-hexane dropwise, slowly lower the temperature to 10-20°C, stir and crystallize for ...

Embodiment 2

[0076] Embodiment 2 sulfonation step

[0077] Add 15.6kg of dichloromethane and 6.0kg of SM1 into the reactor, stir and cool down to 0-15°C. Slowly add 26.64kg of chlorosulfonic acid dropwise, and control the internal temperature to 0-15°C. After dropping, rise to 40-45°C to reflux for 4 hours. Lower the temperature to 0-15°C, slowly add the reaction solution dropwise to 72kg of purified water, and control the internal temperature to 0-30°C. Stand to separate the layers, separate the organic phase, extract with 10kg*2 dichloromethane, and let stand for no less than 2 hours (repeat the extraction operation once). The organic phases were combined, washed twice with 2.0kg*2 purified water, dried over anhydrous sodium sulfate, and concentrated. Add 7.2kg of ethyl acetate, heat up to 30-30°C and stir to dissolve, slowly add 32.4kg of n-hexane dropwise, slowly cool down to 10-20°C, stir and crystallize for 1 hour, centrifuge, rinse with 6kg of n-hexane, 60-65 °C and dried under ...

Embodiment 3

[0082] Embodiment 3 amination step

[0083] Add 20kg of ammonia water into the reactor, and add 6.0kg of intermediate I (prepared in Example 2) in dichloromethane solution (dissolve 6.0kg of intermediate I in 9.1kg of dichloromethane) dropwise under temperature control at 0-15°C. After dropping, the temperature was raised to 25-30°C to react for 1 hour. Add 28kg of purified water, and continue stirring at 25-30°C for 1 hour. Centrifuge, wash with purified water, and dry to obtain 6 kg of crude product. Add 30kg of ethanol with a water content of 5%, heat up to 70-80°C to dissolve, cool down to 20-25°C for crystallization for 1 hour, centrifuge, rinse with 1.2kg of absolute ethanol, and dry to obtain 5.73kg of white solid, namely for valdecoxib. Purity 99.6% (see attached figure 2 ).

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Abstract

The invention provides a preparation and refining method of parecoxib and an intermediate thereof, wherein the parecoxib can be prepared with high efficiency, high yield and high purity through sulfonation, amination and acylation steps, and the method is more suitable for industrial large-scale production.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and in particular relates to a preparation method and a refining method of parecoxib and an intermediate thereof. Background technique [0002] Parecoxib sodium is a specific COX-2 inhibitor, mainly used for the treatment of postoperative pain. Its chemical structure is as follows: [0003] [0004] Parecoxib sodium (trade name: Dynastat) is mainly used for the short-term treatment of postoperative pain, and it can be used clinically for the treatment of moderate or severe postoperative acute pain. [0005] WO2003029230A discloses a method for synthesizing parecoxib sodium, which uses 1,2-benzophenone as a raw material, and 5-methyl-3,4-diphenyl-isoxazole reacts with chlorine in the presence of trifluoroacetic acid Sulfonic acid reaction, the reaction mixture is repeatedly treated with toluene and water, and then concentrated ammonium hydroxide is added to obtain valdecoxib, which is repea...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D261/08
CPCC07D261/08
Inventor 张洁卢翔张静松许建良王曙东王华萍徐丹朱春霞
Owner NANJING CHIA TAI TIANQING PHARMA
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