Method for preparing etoricoxib

A technology of etoricoxib and hydrohalide salt, which is applied in the field of preparation of etoricoxib, can solve the problems of poor product purity, difficulty in purification, unsuitability for industrial production, and high production cost, and achieve low cost and avoid column chromatography separation operation , the effect of mild reaction conditions

Active Publication Date: 2017-05-10
SHANGHAI BOCIMED PHARMA CO LTD
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] The technical problem to be solved by the present invention is to overcome the shortcomings of the prior art preparation method of etoricoxib, such as cumbersome operation, low yield, poor purity of the obtained product, difficulty in purification, high production cost, and unsuitability for industrialized production. A kind of preparation method of etoricoxib

Method used

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  • Method for preparing etoricoxib
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  • Method for preparing etoricoxib

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0046] Example 1: Preparation method of etoricoxib intermediate II (prepared according to the method described in patent CN01810137)

[0047]

[0048] Add tetrahydrofuran (6L) to 4-methylsulfonylphenylacetic acid (3.0Kg), add dropwise 1M solution of tert-butylmagnesium chloride in tetrahydrofuran (40L), heat at 70-80°C, and slowly add methyl 6-methylnicotinate ( 1.7kg) of tetrahydrofuran (5L) solution, drop it in about 2 to 3 hours. Reflux was maintained for 1 hour after the addition was complete. Cool to 20~25 DEG C, add water, be adjusted to pH=7~8 with mass concentration as 20% sodium hydroxide aqueous solution (the described mass concentration refers to the percentage that the quality of sodium hydroxide accounts for the total mass of sodium hydroxide aqueous solution), A large amount of solid precipitated out. After centrifugation, the filter cake was rinsed with water and then vacuum-dried at 50° C. for 16 hours to obtain about 3.6 kg of a yellow solid. Recrystalli...

Embodiment 2

[0049] Example 2: Preparation method of etoricoxib intermediate III (prepared according to the method described in patent CN01810137)

[0050]

[0051] N,N-Dimethylformamide (8.8L) was heated to 50~55℃, slowly added dropwise 2.0kg of chloroacetyl chloride, the temperature was raised to 65~70℃, and phosphorus oxychloride (2.8kg) was added dropwise, at 65~ After stirring at 70°C for 12 hours, cool to 20-30°C. Add dropwise in rapidly stirring ice water (40L), wherein the ice water contains hexafluorophosphoric acid (7.75kg) and sodium hydroxide (1.6kg), adjust the pH with 50% (wt%) sodium hydroxide aqueous solution after adding 1~2. After stirring for 30 minutes, it was centrifuged, the filter cake was rinsed with water (2 L), and air-dried at 60° C. for 12 hours to obtain 3.2 kg of etoricoxib intermediate III.

Embodiment 3

[0052] Embodiment 3: the preparation method of etoricoxib I hydrochloride

[0053]

[0054] Add 2.6 Kg of etoricoxib crude product (HPLC purity 85.17%) into 4 L of isopropanol to dissolve. Add dropwise 1.7L of 4mol / L isopropanol hydrochloride solution below 15°C under stirring, and then stir at 10-20°C for 2 hours to precipitate hydrochloride. After filtration, the filter cake was washed twice with isopropanol (1 L) at -0.08 MPa to 0.01 MPa, and vacuum-dried at 60° C. for 16 hours to obtain 2.25 kg of a yellow solid as etoricoxib I hydrochloride. Yield 91.5%.

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Abstract

The invention discloses a method for preparing etoricoxib, and provides a method for preparing etoricoxib I. The method comprises the following step: performing neutralization reaction on hydrohaloride of the etoricoxib I and alkali in a halogenated hydrocarbon solvent to obtain the etoricoxib I, wherein X is halogen. The preparation method is mild in reaction condition, simple and safe in operation and high in yield, no special purification equipment is required, column chromatography separation operation in a posttreatment process is avoided, and the prepared etoricoxib is high in purity (the purity is equal to or higher than 99.5 percent, the content of all impurities is equal to or lower than 0.10 percent, and a raw medicament standard can be met), low in cost and suitable for industrial production.

Description

technical field [0001] The invention relates to a preparation method of etoricoxib. Background technique [0002] Etoricoxib Tablets (trade name: Ankangxin), is a selective COX-2 inhibitor, has anti-inflammatory, analgesic and antipyretic effects, and is suitable for the treatment of symptoms and signs of osteoarthritis in the acute and chronic stages. Can treat acute gouty arthritis. Developed and produced by Merck, it is currently on the market in 84 countries and regions around the world, including China. Etoricoxib has been recommended by the American College of Rheumatology guidelines for the diagnosis and treatment of gout for the treatment of acute gouty arthritis. The guidelines for the diagnosis and treatment of osteoarthritis in my country and the orthopedic pain management expert opinion of the Orthopedic Branch of the Chinese Medical Association recommend that patients with gastrointestinal risk choose selective COX-2 inhibitors, and etoricoxib can be used. Th...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D213/61
CPCC07D213/61
Inventor 刘胜辉陈健黄鹿
Owner SHANGHAI BOCIMED PHARMA CO LTD
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