Enzalutamide intermediate preparation method

A technology of enzalutamide and intermediates, applied in the field of chemical synthesis, can solve the problems of expensive, limited application, and not very common sources of raw materials, and achieve the effect of low price, simple operation, and large-scale industrial application value

Inactive Publication Date: 2016-02-17
FERGUSON WUHAN BIOTECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Because 2-acetylcyclohexanone and isopropyl acetate are relatively expensive, and the sources of raw materials are not very common, w...

Method used

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  • Enzalutamide intermediate preparation method

Examples

Experimental program
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Effect test

Embodiment 1

[0024] The molar ratio of 4-bromo-2-fluoro-N-methylbenzamide, 2-amino-isobutyric acid, catalyst, auxiliary catalyst, acid binding agent, and water is 1:1.5:0.1:0.1:4:2.3 .

[0025] Add 4-bromo-2-fluoro-N-methylbenzamide (10g, 43.1mmol), 2-amino-isobutyric acid (6.7g, 64.7mmol), potassium carbonate (23.8g, 172.4mmol) in a single-necked flask ), proline (0.7g, 4.31mmol), water (1.8ml, 100mmol) were dissolved in DMF (60ml), replaced with nitrogen under stirring, then added CuCl (0.45g, 4.31mmol), heated to 100℃, reacted for 24h . After the completion of the reaction, first add water (120ml) to dilute the mixture, then add dichloromethane for extraction, remove the organic phase, adjust the pH to 4 for the aqueous phase with 1mol / L citric acid solution, and filter the precipitated solid. The solid was washed three times with a mixed solution of water and ethanol (100:1) to obtain 9.5 g of pure white solid. Yield 87%, product melting point: 210-211°C, HPLC purity 99.5%, HRMS[M+1] +...

Embodiment 2

[0029] The molar ratio of 4-bromo-2-fluoro-N-methylbenzamide, 2-amino-isobutyric acid, catalyst, auxiliary catalyst, acid binding agent, and water is 1:1:0.02:0.02:3:1.3 .

[0030] Add 4-bromo-2-fluoro-N-methylbenzamide (10g, 43.1mmol), 2-amino-isobutyric acid (4.7g, 43.1mmol), sodium carbonate (13.7, 129.3mmol) in a single-necked flask , N,N-Dimethyl-2-aminopyridine (0.105g, 0.862mmol), water (1ml, 55.6mmol) were dissolved in DMSO (60ml), replaced with nitrogen under stirring, and then added CuI (0.163g, 0.862mmol) , Heat to 110°C, react for 20h. After the reaction is completed, water (120ml) is added to dilute the mixture, and then ethyl acetate is added for extraction to remove the organic phase. The water phase was adjusted to pH=3 with 1 mol / L hydrochloric acid solution, and the precipitated solid was filtered; the solid was washed three times with a mixed solution of water and ethanol (100:1) to obtain 9.3 g of pure product. Yield 85%, product melting point: 210-212°C, H...

Embodiment 3

[0032] The molar ratio of 4-bromo-2-fluoro-N-methylbenzamide, 2-amino-isobutyric acid, catalyst, auxiliary catalyst, acid binding agent, and water is 1:2:0.25:0.25:6:2.6 .

[0033] Add 4-bromo-2-fluoro-N-methylbenzamide (10g, 43.1mmol), 2-amino-isobutyric acid (9.4g, 86.2mmol), triethylamine (26.1g, 258.6 mmol), 8-hydroxyquinoline (1.57g, 10.8mmol), and water (2ml, 111mmol) were dissolved in DMF (60ml), replaced with nitrogen under stirring, and then added CuBr (1.54g, 10.8mmol), heated to 120°C and refluxed , Reaction for 24h. After the reaction is completed, first add water (120ml) to dilute the mixture, and then add chloroform for extraction. The aqueous phase is adjusted to pH=5 with 1mol / L citric acid solution, and the precipitated solid is filtered; the solid is washed three times with a mixed solution of water and ethanol (100:1). The pure product is 9.1g. The yield is 83%, the product melting point: 209-210°C, the HPLC purity is 99.2%, HRMS[M+1] + :255.1076.

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Abstract

The present invention discloses an enzalutamide intermediate preparation method, wherein 2-bromo-4-fluoro-N-methylbenzamide and 2-amino-isobutyric acid are subjected to a substitution reaction under catalysis of cuprous halide, assisted catalysis of a nitrogen-containing ligand and the effect of an acid-binding agent, and the nitrogen-containing ligand is proline, o-phenanthroline, 8-hydroxy quinoline, metformin or 1,8-diazabicycloundec-7-ene. According to the present invention, the method has characteristics of safety, environmental protection, simple operation, low cost, high product yield, and great production use value.

Description

Technical field [0001] The invention belongs to the field of chemical synthesis, and specifically relates to a preparation method of enzalutamide intermediate. Background technique [0002] Enzalutamide, the chemical name is 4-[3-(4-cyano-3-trifluoromethylphenyl)-5,5-dimethyl-4-oxo-2-thioimidazolidine-1- Yl]-2-fluoro-N-methylbenzamide, its pharmaceutical preparation is called Xtandi, which is a new oral androgen receptor inhibitor originally developed by Astellas in Japan and is clinically used to treat advanced metastases Patients with castration-resistant prostate cancer who have sex or recurrence, as well as those who are treated with drugs or surgery to reduce testosterone. The drug is currently the best oral prostate cancer treatment in the world, with huge economic benefits. The agency expects its peak sales to reach US$3.5-4 billion per year. [0003] The synthetic intermediate of enzalutamide, the chemical name is 2-(3-fluoro-4-(methylcarbamoyl)phenylamino)-2-methylpropio...

Claims

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Application Information

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IPC IPC(8): C07C231/12C07C237/30
CPCC07C231/12C07C237/30
Inventor 粟骥欧阳康乐付强鲁威
Owner FERGUSON WUHAN BIOTECH
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