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Directional preparation method and application of diaryl substituted isoxazole compound

A technology of phenylisoxazole and compounds, which is applied in the field of chemical pharmaceuticals, can solve the problems that have not been reported in the literature, and achieve the effects of improving accurate positioning and qualitative, easy control of conditions, and simple routes

Inactive Publication Date: 2018-05-18
ZHEJIANG ZHENYUAN PHARMA CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] After searching, there is no literature report on the synthesis of the impurity S

Method used

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  • Directional preparation method and application of diaryl substituted isoxazole compound
  • Directional preparation method and application of diaryl substituted isoxazole compound
  • Directional preparation method and application of diaryl substituted isoxazole compound

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0040] The preparation of embodiment 1 formula 3 compound

[0041] Mix 100g of the compound of formula 2, 300mL of concentrated sulfuric acid and 70g of anhydrous ferric chloride, mix well, and slowly add 500mL of chlorosulfonic acid dropwise at a temperature of -10°C, after the dropwise addition, stir for 0.5h; raise the temperature to 80°C for 10h; Then lower the temperature to below 30°C, slowly pour the reaction solution into 1000mL of ice-water mixture, extract with dichloromethane (500mL*2), dry the organic phase with anhydrous magnesium sulfate, filter, and concentrate the filtrate to dryness to obtain the compound containing formula 3 The product, about 80g.

Embodiment 2

[0042] The preparation of the compound of embodiment 2 formula 4

[0043] Add 400mL of dichloromethane to about 80g of the obtained product containing the compound of formula 3, lower the temperature to below 10°C, slowly add 200mL of ammonia water, keep the internal temperature at 0-5°C, after the addition is complete, keep warm for 1h; then add an appropriate amount of ammonia water , adjust the pH value of the water layer to be greater than or equal to 11; then raise the temperature to 30°C, stir and react for 10h, concentrate to remove dichloromethane, filter the obtained solid, add 200mL butanone to the obtained solid, heat to dissolve and filter, and the filtrate is in a reflux state, Slowly add 400 mL of a mixed solvent of isopropanol and water, wherein the volume ratio of isopropanol:water is 9:1, after the addition is completed, stir at 0-5°C for 8 hours, filter, and concentrate the filtrate to dryness to obtain a product containing the compound of formula 4 , about 6...

Embodiment 3

[0044] Embodiment 3 Preparation of the compound of formula 1

[0045] Add 12.8g of p-dimethylaminopyridine, 192mL of dichloromethane and 64g of triethylamine to about 62g of the obtained product containing the compound of formula 4, stir evenly, control the temperature at 10±2°C, and slowly add 64g of propionic anhydride dropwise, After the dropwise addition, react at a temperature of 25±2°C for 8 hours, monitor the completion of the reaction by TLC, cool down to 0-5°C, add 300 mL of purified water, adjust the pH of the water layer to 2-3 with hydrochloric acid solution, stir for 15 minutes, and let stand to separate layers , the organic phase was washed successively with 300 mL of purified water and 300 mL of saturated brine, dried over anhydrous magnesium sulfate, and concentrated to dryness. Add 200 mL of absolute ethanol to the obtained propionylated product, heat to 70-85°C to dissolve, and slowly add After adding 400mL of purified water, cool down to 20-30°C, stir and cr...

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Abstract

The present invention discloses a parecoxib sodium impurity S, namely, N-{3-[(5-methyl-4-phenylisoxazol-3-yl)phenyl]sulfonyl}propionamide, and an preparation method thereof, and belongs to the technical field of chemical pharmacy. The method comprises the following steps: 5-methyl-3,4-diphenylisoxazole is used as a starting raw material, and the reaction conditions and an auxiliary reagent are controlled to increase the ratio of a sulfonyl chloride group connected to the meta-position of a phenyl ring at a 3-position of an isoxazole ring; and an amination reaction is performed, a crystallization mother liquid is concentrated to dryness, the obtained product is subjected to propionylation, and finally through preparative liquid chromatography separation, the parecoxib sodium impurity S is obtained. The high-purity parecoxib sodium impurity S provided by the present invention can be used as an impurity standard product in the detection and analysis of a finished product of parecoxib sodium, so that the accurate positioning and chemical composition determination of impurities in the detection and analysis of the finished product of the parecoxib sodium are promoted, reinforcement of control of the impurities is facilitated, and the quality of the finished product of the parecoxib sodium is further improved. The method provided by the invention has the advantages of cheap and easyraw materials, simple operation, good reproducibility, and an HPLC purity of 99.5% or more.

Description

technical field [0001] The invention belongs to the technical field of chemical pharmacy, and specifically relates to a method for preparing an impurity S of a related isomer of parecoxib sodium, and using the impurity as an impurity reference substance, in terms of quality control in raw materials and preparations of parecoxib sodium the use of. Background technique [0002] It is well known that 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, it can also cause vasodilation and tissue edema, which increases the sensitivity of effectors and reduces the pain valve, resulting 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 an analgesic and anti-inflammatory effect. At the same time, it can inhibit t...

Claims

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Application Information

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IPC IPC(8): C07D261/08G01N30/02G01N30/74G01N30/86
CPCC07D261/08G01N30/02G01N30/74G01N30/8634
Inventor 郭彦飞孟祥燕袁尚董华成黄鹏张锴刘婷婷闵涛
Owner ZHEJIANG ZHENYUAN PHARMA CO LTD
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