Enzalutamide preparation method

A technology of enzalutamide and triethylamine, which is applied in the field of pharmaceutical chemical synthesis, can solve the problems of non-production process, high cost, and low reaction yield, and achieve the effects of reducing production cost, reducing the generation of impurities, and improving purity

Inactive Publication Date: 2016-04-06
JIANGSU HANSOH PHARMA CO LTD
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Problems solved by technology

Disadvantages of this method: ①The reaction uses microwave radiation, which is not suitable for amplification; ②The post-treatment uses column chromatography, which is not suitable for industrial production; ③The reaction yield is low, the yield is only 25%, and the cost is high
[0008] 2. Medicare Prostate Medical Co., Ltd. reported (CN103108549A) that 4-bromo-2-fluorobenzoic acid was used as the starting material, and condensed with 2-aminoisobutyric acid to obtain 2-((3-fluoro -4-(methylcarbamoyl)phenyl)amino)-2-methylpropionic acid, then esterified with methyl iodide to obtain 2-((3-fluoro-4-(methylcarbamoyl)phenyl )amino)-2-methylpropionic acid, and finally react with 4-isothiocyano-2-(trifluoromethyl)benzonitrile in DMSO and isopropyl acetate to prepare enzalutamide, but the The purity of the product obtained by the method is not good, and it is not the best production process
The method intermediate 4-((1-((4-cyano-3-(trifluoromethyl)phenyl)amino)-2-methyl-1-oxopropan-2-yl)amino)-2 -Fluoro-N-methylbenzamide has a low reaction yield with thiophosgene, and requires column chromatography for separation and purification, which is not suitable for industrial production

Method used

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Examples

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Embodiment 1

[0031] Example 1: 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioimidazolidin-1-yl )-2-fluoro-N-methylbenzamide preparation

[0032] 2-((3-fluoro-4-(methylcarbamoyl)phenyl)amino)-2-methylpropionic acid (5.08g, 0.02mol, 1eq), triethylamine (2.42g, 0.024mol, 1.2eq), 4-isothiocyanoyl-2-(trifluoromethyl)benzonitrile (5.47g, 0.024mol, 1.2eq) and chloroform (100mL) were added in a 250mL reaction flask, and the temperature was raised to 50 The reaction was carried out under reflux at ℃ for 2 hours, and the progress of the reaction was monitored by TLC (n-hexane:ethyl acetate=1:1). After the reaction was completed, cool to room temperature, wash the chloroform layer successively with 1mol / L sodium hydroxide solution (once), and saturated brine (twice), dry over anhydrous sodium sulfate, filter, and concentrate to obtain a yellow-white solid. Add 50ml of isopropanol to the distillate, raise the temperature to reflux and stir to dissolve, cool to room temperature to...

Embodiment 2

[0035] Example 2: 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioimidazolidin-1-yl )-2-fluoro-N-methylbenzamide preparation

[0036] 2-((3-fluoro-4-(methylcarbamoyl)phenyl)amino)-2-methylpropionic acid (2.54g, 0.01mol, 1eq), triethylamine (1.21g, 0.012mol, 1.2eq), 4-isothiocyanato-2-(trifluoromethyl)benzonitrile (2.73g, 0.012mol, 1.2eq) and dichloromethane (50mL) were added in a 100mL reaction flask, and the temperature was raised to 40 The reaction was carried out under reflux at ℃ for 5 hours, and the progress of the reaction was monitored by TLC (n-hexane:ethyl acetate=1:1). After the reaction was completed, cool to room temperature, wash the dichloromethane layer successively with 1mol / L sodium hydroxide solution (once), and saturated brine (twice), dry over anhydrous sodium sulfate, filter, and concentrate to obtain a yellow-white solid, which was sent to Add 25ml of isopropanol to the fraction, raise the temperature to reflux and stir to dissolve, co...

Embodiment 3

[0037] Example 3: 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioimidazolidin-1-yl )-2-fluoro-N-methylbenzamide preparation

[0038] 2-((3-fluoro-4-(methylcarbamoyl)phenyl)amino)-2-methylpropionic acid (2.5g, 0.01mol, 1eq), triethylamine (1.2g, 0.012mol, 1.2eq), 4-isothiocyanato-2-(trifluoromethyl)benzonitrile (2.7g, 0.012mol, 1.2eq) and tetrahydrofuran (50mL) were added to a 100mL reaction flask, heated to 60°C and refluxed The reaction was carried out for 3 hours, and the progress of the reaction was monitored by TLC (n-hexane:ethyl acetate=1:1). After completion of the reaction, concentrate under reduced pressure to dryness, cool to room temperature, add 100 ml of dichloromethane to the fraction, wash the dichloromethane layer with 1mol / L sodium hydroxide solution (once) and saturated brine (twice) successively, Dry over anhydrous sodium sulfate, filter, and concentrate to obtain a reddish-yellow oil. Add 25ml of isopropanol to the fraction, heat up to ...

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Abstract

The present invention provides an enzalutamide preparation method, wherein 2-((3-fluoro-4-(methylcarbamoyl)phenyl)amino)-2-methyl propionic acid is adopted as a starting raw material, and reacts with 4-isothiocyanato-2-(trifluoromethyl)benzonitrile in a non-protonic organic solvent environment in the presence of an inorganic or organic base to obtain the target product. The method of the present invention has characteristics of simple operation, high yield and high product purity, and is suitable for industrial production.

Description

technical field [0001] The invention relates to the field of chemical synthesis of medicines, in particular to a preparation method of enzalutamide. Background technique [0002] Enzalutamide, chemical name: 4-(3-fluoro-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thio Imidazolidin-1-yl)-2-fluoro-N-methylbenzamide, CAS: 915087-33-1, structure: [0003] [0004] Enzalutamide is an androgen receptor (AR) antagonist jointly developed and marketed by Medivation and AstellasPharma under the license of the University of California. For the treatment of metastatic castration-resistant prostate cancer previously treated with docetaxel. [0005] At present, the preparation methods of enzalutamide disclosed in the literature include the following: [0006] 1. Charles L. Sawyers and others (CN101222922B) reported the preparation method of enzalutamide: using 4-nitro-2-fluorobenzoic acid as the starting material, through formamidation and reduction to obtain N-methyl ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D233/86
Inventor 李赛戚郜飞武华周杜祖银余雷
Owner JIANGSU HANSOH PHARMA CO LTD
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