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A kind of preparation method of enzalutamide

A technology based on enzalutamide and phenylamine, which is applied in the field of preparation of enzalutamide, can solve the problems of harsh reaction conditions, harm to the environment, and low yield of large-scale production, so as to increase yield and reduce environmental pollution , Overcome the effect of harsh reaction conditions

Active Publication Date: 2016-05-25
HANGZHOU XINBOSI BIOMEDICAL CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0019] It can be seen that the preparation process of enzalutamide reported at present is widespread: technical defects such as environmental hazards, low large-scale production yield, harsh reaction conditions, etc., cannot meet the requirements of current industrial production

Method used

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  • A kind of preparation method of enzalutamide
  • A kind of preparation method of enzalutamide
  • A kind of preparation method of enzalutamide

Examples

Experimental program
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Embodiment 1

[0038] Embodiment 1: the preparation of enzalutamide:

[0039] Add 20g (0.119mol) of 4-amino-2-fluoro-N-methylbenzamide (I) and 86.2g (0.476mol) of methyl 2-bromoisobutyrate (II) into a 250ml reaction flask, then Add 50.5g (0.476mol) sodium carbonate to the bottle, heat to 130°C, stir and react for 16 hours, monitor the reaction progress by HPLC, add 150ml water to the reaction solution after the reaction, then add 150ml ethyl acetate to extract, use the same amount The ethyl acetate was extracted three times, the ethyl acetate layers were combined, washed once with 100ml of saturated brine, the ethyl acetate was dried with anhydrous sodium sulfate, filtered, and the ethyl acetate was spin-dried to obtain a yellow solid, and 100ml of methanol was added to the yellow solid Slurry for 5 hours, filter, and dry to obtain 27.2 g of white solid 2-(3-fluoro-4-(methylaminocarboxamide) phenylamino)-2-methylpropanoic acid methyl ester (III), HPLC purity 99.5% , Yield 85% (based on comp...

Embodiment 2

[0041] Embodiment 2: the preparation of enzalutamide:

[0042] Add 200g (1.19mol) of 4-amino-2-fluoro-N-methylbenzamide and 862g (4.76mol) of methyl 2-bromoisobutyrate into a 5L reaction flask, and then add 614g (4.76 mol) diisopropylethylamine, heated to 130°C and stirred for 16 hours. The reaction process was monitored by HPLC. After the reaction, 1500ml of water was added to the reaction liquid, and then 1500ml of ethyl acetate was added for extraction. Extract three times, combine the ethyl acetate layers, wash once with 100ml saturated brine, dry the ethyl acetate with anhydrous sodium sulfate, filter, spin dry the ethyl acetate to obtain a yellow solid, add 1000ml methanol to the yellow solid for 5 hours, filter Dry to obtain white solid 2-(3-fluoro-4-(methylaminocarboxamide) phenylamino)-2-methylpropanoic acid methyl ester (III), 258g, HPLC purity 99.3%, yield 81% ( Calculated as compound I).

[0043] Add 100g (0.373mol) 2-(3-fluoro-4-(methylaminocarboxamide) phenylam...

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Abstract

The invention relates to a method for preparing enzalutamide shown in a formula (V). The method comprises the following steps: (a) carrying out substitution reaction on 4-ammonia-2-fluorine-N-methyl formamide shown in a formula (I) and 2-bromo acid methyl ester shown in a formula (II) under the action of an acid-binding agent, so as to obtain 2-(3-fluorine-4-(methyl amino formamide) phenyl amine)-2-isobutyric acid-methyl ester shown in a formula (III); and (b) carrying out cyclization on the 2-(3-fluorine-4-(methyl amino formamide) phenyl amine)-2-isobutyric acid-methyl ester and 4-isothiocyano-2-(trifluoromethyl) benzonitrile shown in a formula (IV) in a mixed solvent of methylbenzene and dimethylsulfoxide (DMSO), so as to obtain the enzalutamide. The invention provides a preparation process of the enzalutamide, which is different from that in the prior art, safe and environment-friendly, simple and convenient to operate, and high in yield, and has great practical production value.

Description

technical field [0001] The invention relates to the technical field of preparation methods of enzalutamide. Background technique [0002] Enzalutamide, chemical name 4-[3-(4-cyano-3-trifluoromethylphenyl)-5,5-dimethyl-4-oxo-2-thioimidazolidine-1 -Base]-2-fluoro-N-methylbenzamide is a new oral androgen receptor inhibitor developed by Medivation and Astellas. It is currently on the market in the United States, Europe, and Canada under the product name Xtandi. It is clinically used to treat patients with advanced metastatic or recurrent castration-resistant prostate cancer, and patients who have undergone drug or surgical treatment to reduce testosterone. [0003] Enzalutamide was superior to castration therapy in men with hormone-naïve prostate cancer and significantly prolonged chemotherapy in patients with metastatic castration-resistant prostate cancer after failure of docetaxel It has the characteristics of good curative effect, safety and few side effects, and has been...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D233/86
CPCC07D233/86
Inventor 杜焕达罗瑾叶鑫杰刘艳华
Owner HANGZHOU XINBOSI BIOMEDICAL CO LTD
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