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Preparation method of parecoxib sodium impurity

A technology of parecoxib sodium and impurities, applied in the direction of organic chemistry, etc., can solve problems such as shortage, and achieve the effects of improving product quality, easy access to raw materials, and simple operation

Inactive Publication Date: 2019-09-17
ZHEJIANG ZHENYUAN PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] The technical problem to be solved by the present invention is to overcome the lack of a large-scale preparation method of N-﹝4-(5-methyl-4-phenylisoxazol-3-yl)benzenesulfonyl﹞propanamide in the prior art However, a method for preparing parecoxib sodium impurities is provided. The synthesis method has the advantages of accurate positioning, simple operation, easy access to raw materials, and high yield and high purity.

Method used

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  • Preparation method of parecoxib sodium impurity
  • Preparation method of parecoxib sodium impurity
  • Preparation method of parecoxib sodium impurity

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0049] Preparation of step 1, 5-methyl-4-phenylisoxazole-3-boronic acid (Ⅳ)

[0050] Put 3-bromo-5-methyl-4-phenylisoxazole (10g, 42mmol) into the reaction flask, add 100ml of tetrahydrofuran, protect with high-purity nitrogen, stir, cool down to -70°C, and then dropwise add 2.5M normal Butyllithium n-hexane solution (18.5ml, 46.25mmol), react for about 1.5hr, add triisopropyl borate (16.6g, 88.25mmol) dropwise at around -70°C, after the dropwise completion, react for 30min, then slowly heat up to At room temperature, react for about 4 hours, cool down to about -10°C, slowly add 50ml of water dropwise, after the drop is complete, adjust the pH to 2-3 with 6mol / L hydrochloric acid aqueous solution, extract with ethyl acetate, wash with saturated saline, dry over magnesium sulfate, filter, Concentrate and crystallize to obtain compound IV (4.3 g, yield 59.87%).

[0051] The preparation of step 2, 4-(5-methyl-4-phenyl-3-isoxazole) benzenesulfonamide (Ⅱ)

[0052] Compound IV (5g...

Embodiment 2

[0081] Preparation of N-﹝4-(5-methyl-4-phenylisoxazol-3-yl)benzenesulfonyl﹞propanamide

[0082] Put compound II (5g, 15.9mmol) into a round-bottomed flask, then add 50ml of tetrahydrofuran, 0.5g of 4-dimethylaminopyridine, 10ml of triethylamine, stir, control the temperature at -5~0°C, add propionic anhydride (5ml, 38.4mmol), the dropwise addition was completed, and the temperature was slowly raised to about 35°C, reacted for 4 to 5 hours, monitored by TLC, until the end of the reaction, the reaction time was about 16 hours, the reaction solution was poured into ice water, dichloromethane extracted, 3mol / Washed with L hydrochloric acid, dried over sodium sulfate, filtered, concentrated, and the crude product was dissolved and crystallized in 50ml of methanol for purification to obtain the target compound I as a white crystalline powder (5.4g, 14.6mmol). TLC conditions: dichloromethane:methanol:concentrated ammonia water=90:10 :0.5 (volume ratio). Yield 95.1%; HPLC purity: 99...

Embodiment 3

[0084] Preparation of N-﹝4-(5-methyl-4-phenylisoxazol-3-yl)benzenesulfonyl﹞propanamide

[0085] Put compound II (5g, 15.9mmol) into a round bottom flask, then add 50ml of tetrahydrofuran, 0.5g of 4-dimethylaminopyridine, 15ml of triethylamine, stir, control the temperature at -5~0°C, add propionic anhydride (10ml, 76.8mmol), the dropwise addition was completed, and the temperature was slowly raised to about 40°C, and the reaction was carried out for 4 to 5 hours (hr), monitored by TLC until the end of the reaction, the reaction time was about 8 hours, the reaction solution was poured into ice water, extracted with dichloromethane , washed with 3mol / L hydrochloric acid, dried over sodium sulfate, filtered, concentrated, and the crude product was dissolved and crystallized in 50ml of methanol for purification to obtain the target compound I white crystalline powder (5.5g, 14.8mmol), TLC conditions: dichloromethane: methanol: concentrated ammonia water = 90:10:0.5 (volume ratio)....

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Abstract

The invention discloses a preparation method of a parecoxib sodium impurity. The preparation method of the parecoxib sodium impurity as shown in a formula I is provided, and comprises the following step of in tetrahydrofuran, at 30-50 DEG C, in the presence of 4-dimethylaminopyridine and triethylamine, subjecting propionic anhydride and a compound as shown in a formula II to amidation reaction to obtain a compound I, namely the parecoxib sodium impurity, wherein a molar ratio of the triethylamine to the propionic anhydride is 1 to (0.5 to 2). The synthesis method is simple to operate, the yield can reach 90% or above, after purification is conducted, a white competitive product can be obtained, and the purity can reach 99% or above.

Description

technical field [0001] The invention relates to a preparation method of parecoxib sodium impurity. Background technique [0002] Although non-steroidal anti-inflammatory drugs (NSAIDs) have antipyretic, analgesic, anti-inflammatory and anti-rheumatic effects, their adverse reactions involve the systemic system, especially the most serious adverse reactions in the gastrointestinal tract, mainly gastric mucosal ulcers, bleeding and even perforation. Vane et al first proposed in 1971 that the efficacy and side effects of NSAIDs stem from their inhibition of cyclooxygenase (COX). The COX theory was discovered in the early 1990s, indicating that COX has two isoenzymes, namely COX-1 and COX-2. COX-1 exists in most human tissues (especially stomach, kidney and platelets), and regulates the normal physiological activities of cells by synthesizing prostaglandins (PG) that are physiologically required, such as inhibiting gastric acid secretion, protecting gastric mucosa, and maintai...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D261/08
CPCC07D261/08
Inventor 董华成郝琳孙亚萍孟祥燕张锴封潇琦谢华丽
Owner ZHEJIANG ZHENYUAN PHARMA CO LTD