CN111848538A

CN111848538A - Synthesis method of parecoxib sodium impurity

Info

Publication number: CN111848538A
Application number: CN201910337699.3A
Authority: CN
Inventors: 曹慧敏; 钱林艺; 任霞
Original assignee: Shandong Mohai Biotechnology Co ltd
Current assignee: Shandong Mohai Biotechnology Co ltd
Priority date: 2019-04-25
Filing date: 2019-04-25
Publication date: 2020-10-30

Abstract

The invention discloses a synthesis method of parecoxib sodium impurity N-ethyl-5- [4- (5-methyl-3-phenyl-4-isoxazolyl) phenyl ] sulfamide, which takes 5-methyl-3, 4-diphenyl isoxazole as a raw material, and obtains parecoxib sodium impurity through sulfonation and ammoniation reaction, wherein the impurity can be used as an impurity standard substance in detection and analysis of parecoxib sodium finished products. The method provided by the invention has the advantages of cheap and easily available raw materials, simple operation and high HPLC product purity of more than 98%.

Description

Synthesis method of parecoxib sodium impurity

Technical Field

The invention relates to a method for synthesizing parecoxib sodium impurity N-ethyl-5- [4- (5-methyl-3-phenyl-4-isoxazolyl) phenyl ] sulfamide.

Background

Parecoxib sodium is used as a valdecoxib soluble prodrug and is the first COX-2 inhibitor which can be intravenously and intramuscularly administered. After intravenous or intramuscular injection, the valdecoxib is hydrolyzed in the viscera and quickly converted into the valdecoxib with pharmacological activity, specifically inhibits COX-2, plays the role of analgesia, can also prevent central and peripheral sensitization, and is used for advanced analgesia. The curative effect of parecoxib sodium on treating postoperative pain is proved in various types of operations, the parecoxib sodium is definite in effect and high in safety, can be injected and administered, and is widely applied to clinic.

The parecoxib sodium has the chemical name of N- [ [4- (5-methyl-3-phenyl-4-isoxazolyl) phenyl ] sulfonyl ] propionamide sodium salt, is a high-selectivity cyclooxygenase-2 inhibitor, can be used for short-term treatment of postoperative pain, and has ideal water-soluble physicochemical properties.

The impurity N-ethyl-5- [4- (5-methyl-3-phenyl-4-isoxazolyl) phenyl ] sulfamide is generated by the reaction of N- [4- (5-methyl-3-phenyl-4-isoxazolyl) phenyl ] sulfonyl chloride and ethylamine in ammonia water during the synthesis of the parecoxib sodium in the synthesis process of the parecoxib sodium, and may remain in the parecoxib sodium final product to influence the product quality. Through searching, no report about the synthesis of the impurity exists. The structural formula is shown as (I).

Disclosure of Invention

The invention aims to provide a method for preparing impurity N-ethyl-5- [4- (5-methyl-3-phenyl-4-isoxazolyl) phenyl ] sulfamide of parecoxib sodium, which has the advantages of simple operation, cheap and easily obtained raw materials, high yield and high purity.

The purpose of the invention is realized by the following technical scheme: the synthesis route of the impurity N-ethyl-5- [4- (5-methyl-3-phenyl-4-isoxazolyl) phenyl ] sulfonamide is as follows:

the specific synthetic process comprises the following steps:

S1: and (3) sulfonation reaction: adding 5-methyl-3, 4-diphenyl isoxazole, dichloromethane and chlorosulfonic acid into a reaction bottle, reacting for 4-5 hours at 34-45 ℃, and performing post-treatment to obtain N- [4- (5-methyl-3-phenyl-4-isoxazolyl) phenyl ] sulfonyl chloride;

s2, ammoniation reaction: adding the obtained N- [4- (5-methyl-3-phenyl-4-isoxazolyl) phenyl ] sulfonyl chloride into a reaction bottle, adding dichloromethane and ethylamine, reacting at 0-5 ℃ for 2-3 hours, and performing post-treatment to obtain parecoxib sodium impurity N-ethyl-5- [4- (5-methyl-3-phenyl-4-isoxazolyl) phenyl ] sulfonamide;

in an embodiment, the molar ratio of 5-methyl-3, 4-diphenylisoxazole to chlorosulfonic acid in step S1 is 1:4 to 8;

in an embodiment, the post-processing in step S1 is: after the reaction is finished, cooling to 0-5 ℃, dropwise adding into ice water, separating liquid, and concentrating to obtain N- [4- (5-methyl-3-phenyl-4-isoxazolyl) phenyl ] sulfonyl chloride;

in an embodiment, the molar ratio of N- [4- (5-methyl-3-phenyl-4-isoxazolyl) phenyl ] sulfonyl chloride to ethylamine in step S2 is 2-3;

in an embodiment, the post-processing in step S2 is: after the reaction is finished, washing, layering, drying an organic phase by using anhydrous sodium sulfate, and concentrating under reduced pressure to obtain a product, and recrystallizing the product by using anhydrous ethanol to obtain parecoxib sodium impurity N-ethyl-5- [4- (5-methyl-3-phenyl-4-isoxazolyl) phenyl ] sulfamide;

In an embodiment, the post-processing in step S1 is: after the reaction is finished, washing, layering, drying an organic phase by using anhydrous sodium sulfate, and concentrating under reduced pressure to obtain a product, and recrystallizing the product by using anhydrous ethanol to obtain parecoxib sodium impurity N-ethyl-5- [4- (5-methyl-3-phenyl-4-isoxazolyl) phenyl ] sulfamide;

in an embodiment, the product is recrystallized by absolute ethyl alcohol, and the mass-to-volume ratio of the N-ethyl-5- [4- (5-methyl-3-phenyl-4-isoxazolyl) phenyl ] sulfonamide to the absolute ethyl alcohol is 4-6;

the invention has the following advantages: according to the invention, 5-methyl-3, 4-diphenyl isoxazole is used as a raw material, N-ethyl-5- [4- (5-methyl-3-phenyl-4-isoxazolyl) phenyl ] sulfamide as an impurity is obtained through sulfonation reaction and ammoniation reaction, a high-purity sample can be obtained, the control on the impurity is enhanced, the product quality of parecoxib sodium is improved, the raw material is easy to obtain, the operation is simple, and the purity HPLC of the obtained product is more than or equal to 98.

Drawings

FIG. 1 is a mass spectrum of parecoxib sodium impurity N-ethyl-5- [4- (5-methyl-3-phenyl-4-isoxazolyl) phenyl ] sulfamide;

FIG. 2 shows the NMR spectrum of parecoxib sodium impurity N-ethyl-5- [4- (5-methyl-3-phenyl-4-isoxazolyl) phenyl ] sulfamide.

Detailed Description

The present invention will be further described with reference to the following examples, but the scope of the present invention is not limited to the following.

Example (b): adding 50g of 5-methyl-3, 4-diphenyl isoxazole, 250ml of dichloromethane and 198g of chlorosulfonic acid into a reaction bottle, carrying out reflux reaction at 40 ℃ for 5 hours, cooling to 0-5 ℃ after the reaction is finished, dropwise adding into 800g of ice water, stirring for 30 minutes, standing for layering, separating liquid, washing 400ml of dichloro phase with water once, and directly feeding into the next step.

And (3) cooling the dichloromethane solution of the product to 0-5 ℃, dropwise adding 21g of ethylamine, keeping the temperature and stirring for 2 hours after the dropwise adding is finished, adding 200ml of water for washing, washing an organic phase with 200ml of water twice, drying the organic phase with anhydrous sodium sulfate, and concentrating the solid at 30 ℃ under reduced pressure to obtain 51.6g of solid, namely the crude product of the N-ethyl-5- [4- (5-methyl-3-phenyl-4-isoxazolyl) phenyl ] sulfonamide with the yield of 71.1%.

50g of crude N-ethyl-5- [4- (5-methyl-3-phenyl-4-isoxazolyl) phenyl ] sulfonamide and 250ml of absolute ethanol were added to a reaction flask and reacted at 80 ℃ under reflux. After dissolving and cleaning, slowly cooling to 0-5 ℃, stirring for two hours, carrying out suction filtration, leaching a filter cake with 50ml of absolute ethyl alcohol, and carrying out forced air drying at 80 ℃ to obtain 34.5g of white solid, namely N-ethyl-5- [4- (5-methyl-3-phenyl-4-isoxazolyl) phenyl ] sulfamide with the yield of 69%.

Claims

1. A method for synthesizing parecoxib sodium impurity, wherein the impurity is N-ethyl-5- [4- (5-methyl-3-phenyl-4-isoxazolyl) phenyl ] sulfamide, is characterized in that the synthetic route is as follows:

the specific synthesis method comprises the following steps:

s1, sulfonation reaction: adding 5-methyl-3, 4-diphenyl isoxazole, dichloromethane and chlorosulfonic acid into a reaction bottle, reacting for 4-5 hours at 34-45 ℃, and performing post-treatment to obtain N- [4- (5-methyl-3-phenyl-4-isoxazolyl) phenyl ] sulfonyl chloride;

s2, ammoniation reaction: adding the obtained N- [4- (5-methyl-3-phenyl-4-isoxazolyl) phenyl ] sulfonyl chloride into a reaction bottle, adding dichloromethane and ethylamine, reacting at 0-5 ℃ for 2-3 hours, and performing post treatment to obtain parecoxib sodium impurity N-ethyl-5- [4- (5-methyl-3-phenyl-4-isoxazolyl) phenyl ] sulfonamide.

2. The method for synthesizing parecoxib sodium impurity of claim 1 wherein the molar ratio of 5-methyl-3, 4-diphenylisoxazole to chlorosulfonic acid in step S1 is 1: 4-8.

3. The method for synthesizing parecoxib sodium impurity of claim 1 wherein said post-treatment in step S1 is: and after the reaction is finished, cooling to 0-5 ℃, dropwise adding into ice water, separating liquid, and concentrating to obtain the N- [4- (5-methyl-3-phenyl-4-isoxazolyl) phenyl ] sulfonyl chloride.

4. The method for synthesizing parecoxib sodium impurity of claim 1, wherein the molar ratio of N- [4- (5-methyl-3-phenyl-4-isoxazolyl) phenyl ] sulfonyl chloride to ethylamine in step S2 is 2-3.

5. The method for synthesizing parecoxib sodium impurity of claim 1 wherein said post-treatment in step S1 is: and after the reaction is finished, washing, layering, drying an organic phase by using anhydrous sodium sulfate, and concentrating under reduced pressure to obtain a product, and recrystallizing the product by using anhydrous ethanol to obtain parecoxib sodium impurity N-ethyl-5- [4- (5-methyl-3-phenyl-4-isoxazolyl) phenyl ] sulfamide.

6. The method according to claim 5, wherein the mass/volume ratio of N-ethyl-5- [4 (-5-methyl-3-phenyl-4-isoxazolyl) phenyl ] sulfonamide to absolute ethyl alcohol is 4 to 6.