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Simple preparation method of prostaglandin D2 receptor inhibitor compound

A receptor inhibitor, prostaglandin technology, applied in the field of medicinal chemistry, can solve the problems of high price of 2-amino-3-bromopyridine, unfavorable green industrial production, large metal residues, etc., and achieves less generation of three wastes and cost. Low, high yield and purity effects

Active Publication Date: 2019-11-19
XINFA PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0011] However, the raw material 2-amino-3-bromopyridine used in this route is expensive and difficult to obtain; the amount of catalyst and cocatalyst used in the Ullmann ring closure reaction is large, the reaction temperature is high, the time is long (120 ° C, 12 hours), and the operation requirements are high. The resulting product has heavy color, large metal residues, large yield range, and large amount of three wastes, which is not conducive to green industrial production

Method used

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  • Simple preparation method of prostaglandin D2 receptor inhibitor compound
  • Simple preparation method of prostaglandin D2 receptor inhibitor compound
  • Simple preparation method of prostaglandin D2 receptor inhibitor compound

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0054] Embodiment 1: the preparation of Fevipiprant (Ⅰ)

[0055] In the 500 milliliter four-necked flask that is connected with stirring, thermometer, water trap and reflux condenser, add 200 grams of toluene, 25.3 grams (0.1 mole) 4-methanesulfonyl-2-trifluoromethylbenzylamine (Ⅱ) , 21.0 g (0.1 mol) dimethyl 3-acetylglutarate (III 1 ), 0.5 g of p-toluenesulfonic acid, stirred and reacted at 45 to 50° C. for 2 hours, and stirred and reacted at 82 to 85° C. for 4 hours, while separating the water separated by azeotropy. Cool to 20-25° C., add 1.0 g DBU, 10.0 g (0.11 mole) 2-chloroacrolein, and stir at 40-45° C. for 4 hours. Add 40.0 g (0.4 mol) of 17 wt% ammonia methanol solution, and stir the reaction at 50 to 55°C for 4 hours. Cool to 20 to 25°C, add 250 grams of water, 30 grams of 20wt% sodium hydroxide aqueous solution, stir and react at 25 to 30°C for 2 hours, separate layers, add 0.5 grams of activated carbon to the separated water layer, and set the temperature at 25 t...

Embodiment 2

[0059] Embodiment 2: the preparation of Fevipiprant (Ⅰ)

[0060] To a 500 ml four-neck flask connected with stirring, thermometer, water separator and reflux condenser, add 200 g of 1,2-dichloroethane, 25.3 g (0.1 mole) of 4-methylsulfonyl-2-trifluoro Methylbenzylamine (II), 23.0 g (0.1 mol) diethyl 3-acetylglutarate (III 2 ), 0.5 gram of 98wt% concentrated sulfuric acid, stirred and reacted at 45 to 50° C. for 2 hours, and stirred and reacted at 70 to 75° C. for 5 hours, while separating the water separated by azeotropy. Cool to 20 to 25°C, add 1.2 g of DBU, 13.5 g (0.1 mole) of 2-bromoacrolein, and react with stirring at 35 to 40°C for 4 hours. Add 40.0 g (0.4 mol) of 17 wt% ammonia methanol solution, and stir the reaction at 50 to 55°C for 4 hours. Cool to 20 to 25°C, add 250 grams of water, 30 grams of 20wt% sodium hydroxide aqueous solution, stir and react at 20 to 25°C for 2 hours, separate layers, add 0.5 grams of activated carbon to the separated water layer, and set...

Embodiment 3

[0061] Embodiment 3: the preparation of Fevipiprant (Ⅰ)

[0062] In the 500 milliliter four-necked flask that is connected with stirring, thermometer, water trap and reflux condenser, add 200 grams of toluene, 25.3 grams (0.1 mole) 4-methanesulfonyl-2-trifluoromethylbenzylamine (Ⅱ) , 21.0 g (0.1 mol) dimethyl 3-acetylglutarate (III 1 ), 0.5 g of p-toluenesulfonic acid, stirred and reacted at 40 to 45° C. for 3 hours, and stirred and reacted at 82 to 85° C. for 4 hours, while separating the water separated by azeotropy. Cool to 20-25°C, add 1.2g of DBU, 13.5g (0.1 mole) of 2-bromoacrolein, and react with stirring at 40-45°C for 4 hours. Add 40.0 g (0.4 mol) of 17 wt% ammonia methanol solution, and stir the reaction at 50 to 55°C for 4 hours. Cool to 20 to 25°C, add 250 grams of water, 35 grams of 20wt% potassium hydroxide aqueous solution, stir and react at 20 to 25°C for 2 hours, separate layers, add 0.5 grams of activated carbon to the separated water layer, and set the tem...

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Abstract

The invention provides a simple preparation method of a prostaglandin D2 receptor inhibitor compound. The compound is obtained by using 4-methylsulfonyl-2-trifluoromethylbenzylamine (II) and 3-acetylglutaric acid diester (III) as raw materials, carrying out condensation and cyclization, carrying out an addition reaction with 2-halogenated acrolein, carrying out a pyridine cyclization reaction withammonia and finally carrying out hydrolysis and hydrochloric acid acidification. The method of the invention has the advantages of simple operation, mild reaction conditions, less three wastes, environmental protection, cheap and easily available raw materials, low cost, high reaction selectivity, less by-products, simple purification and high yield and purity, and facilitates the industrial production of the prostaglandin D2 receptor inhibitor compound Fevipiprant.

Description

technical field [0001] The invention relates to a convenient preparation method of Fevipiprant, a prostaglandin D2 receptor inhibitor compound, and belongs to the technical field of medicinal chemistry. Background technique [0002] Fevipiprant (Ⅰ), CAS number is [872365-14-5], chemical name is [1-(4-methylsulfonyl-2-trifluoromethylphenyl)methyl-2-methyl-1H-pyrrolo [2,3-b]pyridin-3-yl]acetic acid, a prostaglandin D2 receptor (DP2 / CRTh2) inhibitor developed by Novartis, is mainly used for the treatment of asthma. According to clinical trials, the candidate molecule has excellent safety and tolerance, and has great potential for clinical development. It is currently undergoing phase III clinical trials in the United States. It is a very promising treatment for mild to moderate persistence Asthma, moderate to severe atopic dermatitis and allergic rhinitis drug candidates. [0003] The chemical structural formula of Fevipiprant is as follows: [0004] [0005] There have b...

Claims

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Application Information

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IPC IPC(8): C07D471/04
CPCC07D471/04
Inventor 戚聿新王保林徐欣腾玉奇李新发
Owner XINFA PHARMA
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