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Preparation method of rofecoxib

A technology of ethylaniline and chloroacetyl chloride is applied in the preparation of organic compounds, chemical instruments and methods, preparation of cyanide reactions, etc., can solve the problems of heavy metal residues, expensive raw materials, etc., achieve cost saving, avoid metal organic reagents, The effect of simplifying the production process

Active Publication Date: 2012-01-11
YANGZHOU TIANHE PHARM CO LTD
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AI Technical Summary

Problems solved by technology

Currently, the synthesis methods of diarylamines mainly reported in Organic Process Research & Development 2009, 13, 1608 and Tetrahedron 2004, 60, 11571, and US 20040122254A1, in which the formation of diarylamines is mainly achieved by metal organocatalyzed coupling reactions , the coupling reaction requires harsh conditions such as anhydrous and oxygen-free, and will produce heavy metal residues, and the raw materials used are relatively expensive

Method used

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Embodiment Construction

[0014] (1) Acylation of 4-ethylaniline

[0015] Chloroacetyl chloride (55.5 mmol) was added dropwise into a solution of 4-ethylaniline (50.4 mmol) and potassium carbonate (58.0 mmol) powder in dichloromethane (100 ml). 200 ml of water, extracted with dichloromethane (2×100 ml), combined organic layers, washed with water, dried over anhydrous sodium sulfate for 2 hours, evaporated the solvent to obtain 9.798 g of white solid, yield 98%.

[0016] (2) Condensation and rearrangement of 2,3,5,6-tetrafluorophenol and halogenated amides

[0017] Add potassium carbonate powder (76 mmol) into a solution of 2,3,5,6-tetrafluorophenol (67 mmol) in isopropanol (25 ml), react at room temperature for 1 hour, and then the haloacylated product from the previous step ( 70 mmol) was added to the reaction solution in batches, and reacted at room temperature for 4 hours. Add sodium methoxide (28.4 wt% methanol solution, 73.3 mmol) dropwise and react at room temperature for 2 hours. Add water (2...

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Abstract

A preparation method of rofecoxib. The invention relates to a chemical synthesis method, especially to a novel method for synthesizing rofecoxib. With 2,3,5,6-tetrafluorophenol and 4-ethylaniline as raw materials, rofecoxib is prepared by acylation, condensation, rearrangement, acylation, alkylation and hydrolysis reactions. In comparison with a traditional method by using 2,3,5,6-tetrafluoroaniline as a raw material, the method provided by the invention is used to save cost. According to the method provided by the invention, the rearrangement method is adopted to obtain a diarylamine intermediate, thus avoiding a metal organic reagent, simplifying production technology, leading to a yield similar to the yield by traditional technologies and saving cost.

Description

technical field [0001] The invention relates to a chemical synthesis method, in particular to a new method for synthesizing robenicoxib. Background technique [0002] Robenicoxib is a selective COX-2 (cyclooxygenase 2) inhibitor, which can relieve pain by inhibiting COX-2. It is mainly used for the treatment of arthritis, but it is different from non-steroidal anti-inflammatory drugs. Bencoxib does not inhibit COX-1. COX-1 has a protective effect on the stomach, so compared with other NSAIDs (such as ibuprofen and naproxen), robenicoxib has fewer gastrointestinal adverse reactions and has a lower gastric The risk of intestinal ulcers and bleeding, and the only NSAID proven to have a lower incidence of such adverse reactions. In addition, robenicoxib was highly effective and well tolerated for a single migraine attack. The key to the preparation of Robenicoxib lies in the formation of the intermediate diarylamine. Currently, the synthesis methods of diarylamines mainly re...

Claims

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Application Information

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IPC IPC(8): C07C229/42C07C227/22
Inventor 戴振亚袁飞鹏赵云德
Owner YANGZHOU TIANHE PHARM CO LTD