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Synthesis method of parecoxib sodium impurity

A technology of parecoxib sodium and its synthesis method, which is applied in the field of chemical pharmacy to achieve the effects of cheap raw materials, simple operation and improved quality of finished products

Inactive Publication Date: 2015-05-06
CHENGDU CLIMB PHARMA TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] After retrieval, there is no bibliographical report about the synthesis of this impurity, therefore, it is of great practical significance to provide a synthetic method of parecoxib sodium impurity E for the preparation of impurity standard

Method used

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  • Synthesis method of parecoxib sodium impurity
  • Synthesis method of parecoxib sodium impurity
  • Synthesis method of parecoxib sodium impurity

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0022] Example 1: Synthesis of Parecoxib Sodium Impurity E N-[4-(5-methyl-3-phenyl-4-isoxazolyl)phenyl]sulfonic acid

[0023] Add 3g of 5-methyl-3,4-diphenylisoxazole, 9g of dichloromethane, and 6g of chlorosulfonic acid into the reaction flask, reflux at 40°C for 4 hours, add the reaction solution dropwise to 50g of water, and add 12g of dichlorosulfonic acid Extracted with methyl chloride, concentrated to dryness, added 3g of ethyl acetate, crystallized 12g of petroleum ether for 1.5 hours, and filtered to obtain 3.24g of intermediate I, with a yield of 76.1%.

[0024] Add 2g of intermediate I to the reaction flask, add 4g of water, 4g of acetonitrile, reflux at 85°C for 12h, reduce the pressure to -0.07MPa and concentrate to obtain 1.78g of white solid, with a yield of 94.2%.

[0025] Parecoxib sodium impurity E purity detection HPLC spectrum is as follows figure 1 As shown, the purity is 99.0%. ;

[0026] Parecoxib Sodium Impurity E Mass Spectrum figure 2 As shown, MS...

Embodiment 2

[0028] Example 2: Synthesis of Parecoxib Sodium Impurity E N-[4-(5-methyl-3-phenyl-4-isoxazolyl)phenyl]sulfonic acid

[0029] Add 3g of 5-methyl-3,4-diphenylisoxazole, 18g of dichloromethane, and 15g of chlorosulfonic acid into the reaction flask, reflux at 50°C for 8 hours, add the reaction solution dropwise to 50g of water, and add 12g of dichlorosulfonic acid Extract with methyl chloride, concentrate to dryness, add 3g of ethyl acetate, crystallize 12g of petroleum ether for 2.5 hours, filter to obtain 3.17g of intermediate I, yield 74.5%.

[0030] Add 2g of intermediate I to the reaction flask, add 10g of water, 10g of acetonitrile, reflux at 95°C for 20h, depressurize to -0.08MPa and concentrate to obtain 1.82g of white solid, yield 96.3%, HPLC purity 98.7%.

Embodiment 3

[0031] Example 3: Synthesis of Parecoxib Sodium Impurity E N-[4-(5-methyl-3-phenyl-4-isoxazolyl)phenyl]sulfonic acid

[0032] Add 5g of 5-methyl-3,4-diphenylisoxazole, 20g of dichloromethane, and 20g of chlorosulfonic acid into the reaction flask, reflux at 42°C for 6 hours, add the reaction solution dropwise to 85g of water, and add 20g of dichlorosulfonic acid Extract with methyl chloride, concentrate to dryness, add 5g of ethyl acetate, crystallize 20g of petroleum ether for 2 hours, and filter to obtain 5.80g of intermediate I, with a yield of 81.7%.

[0033] Add 5g of intermediate I to the reaction flask, add 15g of water, 15g of acetonitrile, reflux at 90°C for 16h, depressurize to -0.10MPa and concentrate to obtain 4.45g of white solid, yield 94.2%, HPLC purity 98.8%.

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Abstract

The invention discloses a synthesis method of a parecoxib sodium impurity, namely N-[4-(5-methyl-3-phenyl-4-isoxazolyl)phenyl]sulfonic acid, belonging to the technical field of chemical pharmacy. The synthesis method comprises the step of carrying out sulfonation reaction and hydrolysis reaction by taking 5-methyl-3, 4-diphenylisoxazole as a raw material to obtain the parecoxib sodium impurity. The synthesized high-purity parecoxib sodium impurity can be used as a standard impurity in parecoxib sodium finished product detection and analysis, so that the accurate impurity location and qualification realized through the parecoxib sodium finished product detection and analysis are improved, the impurity can be better controlled, and furthermore the quality of a parecoxib sodium finished product is improved. The synthesis method disclosed by the invention is simple in operation; the raw material is cheap and available; and the yield of the obtained product is up to 95+ / -5%, and the HPLC purity is larger than or equal to 98%.

Description

technical field [0001] The invention belongs to the technical field of chemical pharmacy, in particular to a method for synthesizing parecoxib sodium impurity E N-[4-(5-methyl-3-phenyl-4-isoxazolyl)phenyl]sulfonic acid . Background technique [0002] The inflammatory response after noxious stimuli such as surgery and trauma can lead to the release of inflammatory mediators and pain-causing substances. In addition to directly causing pain, they can also cause blood vessels to dilate, tissue edema, increase the sensitivity of effector receptors, and reduce the pain threshold. This results in peripheral hyperalgesia. Selective COX-2 inhibitors can effectively inhibit the expression of peripheral COX-2 and reduce the synthesis of peripheral prostaglandins, thereby exerting analgesic and anti-inflammatory effects. At the same time, they can inhibit the expression of central COX-2, inhibit the synthesis of central prostaglandins and inhibit pain hypersensitivity Give full play t...

Claims

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Application Information

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IPC IPC(8): C07D261/08
CPCC07D261/08
Inventor 蒋明勇刘芍利叶丁林蓉莹
Owner CHENGDU CLIMB PHARMA TECH
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