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New compound for synthesizing Enzalutamide

A technology of enzalutamide and compound, which is applied in the field of synthesizing a new compound for treating prostate cancer drug enzalutamide and its preparation field, can solve problems such as unfavorable industrialized production, harm to laboratory personnel and environment, high price and the like

Active Publication Date: 2016-03-02
SHANGHAI INST OF PHARMA IND CO LTD +2
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] Analyzing the synthetic route of patent CN103108549, the preparation method of synthetic compound 5 uses methyl iodide, a highly toxic and expensive reagent, which will cause relatively great harm to experimenters and the environment
In addition, the reaction of compound 5 and compound 7 in patent CN103108549 to form enzalutamide requires long-term reaction at high temperature, and the industrialization efficiency is low, which is not conducive to industrialized production (see Example 5 in patent CN103108549 for details)

Method used

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  • New compound for synthesizing Enzalutamide
  • New compound for synthesizing Enzalutamide
  • New compound for synthesizing Enzalutamide

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0024] The synthesis of embodiment 1.2-(3-fluoro-4-(methylcarbamoyl) phenylamino) allyl 2-methylpropionate Z-M-1

[0025]

[0026] 2-(3-fluoro-4-(methylcarbamoyl)phenylamino)2-methylpropionic acid (10.0 g, 39.4 mmol), potassium carbonate (10.9 g, 78.8 mmol), allyl bromide ( 4.77g, 39.4mmol), DMF (100ml) was added into the reaction flask, under nitrogen protection, heated to 30°C, and stirred for 3 hours. Slowly add 800ml of ice water under stirring to precipitate a crystalline solid, continue to stir at room temperature for 2 hours, filter, rinse with 100ml of water, take out the filter cake and dry it in vacuum at 50°C to obtain 9.8g of white crystalline solid Z-M-1, HPLC purity 98.7%. The rate is 84.5%. ESI-MS(m / z): 295.14[M+H] + , 317.12[M+Na] + , 1 HNMR(DMSO-d6)δ: 1.480(s, 6H, 2CH 3 ), 2.728-2.740 (d, J=4.8, 3H, NCH 3 ), 4.555-4.575 (m, 2H, CH 2 ), 5.143-5.245 (m, 2H, CH 2 ), 5.769-5.866 (m, 1H, CH), 6.121-6.163 (dd, J 1 =2.0,J 2 =12.4, 1H, Ar-H), 6.293-6.320...

Embodiment 2

[0027] Example 2.2-(3-fluoro-4-(methylcarbamoyl) phenylamino) 2-methacrylic acid allyl ester Z-M-1 synthesis

[0028] 2-(3-Fluoro-4-(methylcarbamoyl)phenylamino)2-methylpropanoic acid (1.0 g, 3.94 mmol), potassium carbonate (1.09 g, 7.88 mmol), allyl bromide ( 0.95g, 7.88mmol), DMF (10ml) was added to the reaction flask, under nitrogen protection, heated to 30°C, and stirred for 3 hours. Slowly add 80ml of ice water under stirring to precipitate a crystalline solid, continue to stir at room temperature for 2 hours, filter, rinse with 10ml of water, take out the filter cake and dry it in vacuum at 50°C to obtain 0.96g of white crystalline solid Z-M-1, yield 83.0%.

Embodiment 3

[0029] Example 3.2-(3-fluoro-4-(methylcarbamoyl) phenylamino) 2-methacrylic acid allyl ester Z-M-1 synthesis

[0030]2-(3-Fluoro-4-(methylcarbamoyl)phenylamino)2-methylpropanoic acid (1.0 g, 3.94 mmol), potassium carbonate (1.09 g, 7.88 mmol), allyl bromide ( 1.43g, 11.82mmol), DMF (10ml) was added to the reaction flask, under nitrogen protection, heated to 30°C, and stirred for 3 hours. Slowly add 80ml of ice water under stirring to precipitate a crystalline solid, continue to stir at room temperature for 2 hours, filter, rinse with 10ml of water, take out the filter cake and dry it in vacuum at 50°C to obtain 0.91g of light yellow crystalline solid Z-M-1, yield 78.1% .

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Abstract

The present invention provides a compound Z-M for synthesizing enzalutamide, and a preparation method thereof, wherein R is selected from allyl, propargyl, benzyl, glycidyl or other groups containing alpha and beta unsaturated groups. According to the present invention, with the new series of the compound Z-M, the use of the toxic reagent iodomethane can be avoided during the key intermediate 2-(3-fluoro-4-(methylcarbamoyl)phenylamino)2-methyl methyl propionate preparation, and the conditions of the enzalutamide synthesis Edman degradation reaction of the new intermediate Z-M and an isothiocyanate compound 7 are superior to the reaction conditions of the methyl ester intermediate in the original literature report. The structure of the compound Z-M is defined in the specification.

Description

technical field [0001] The invention belongs to the field of chemical synthesis, and in particular relates to a new compound used for synthesizing enzalutamide, a drug for treating prostate cancer, and a preparation method thereof. Background technique [0002] Enzalutamide, jointly developed by Medicare Prostate Medical Co., Ltd. and Astellas Pharmaceuticals, was approved by the US FDA in August 2012 for the treatment of metastatic castration ineffective after docetaxel treatment Resistant Prostate Cancer (mCRPC). The English name of enzalutamide is Enzalutamide, and its chemical name is 4-[3-[4-cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo- 2-thioimidazolidin-1-yl]-2-fluoro-N-methyl-benzamide. [0003] [0004] Regarding the synthesis of enzalutamide, it is disclosed in the patent CN103108549 and the journal document J.Med.Chem.2010, 53, 2779-2796. In these documents, 2-(3-fluoro-4-(methylaminomethyl Acyl) phenylamino) 2-methyl propionate and other compounds as...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C237/30C07C231/12C07D233/86
Inventor 张颢胡志袁哲东朱雪焱胡宏亮
Owner SHANGHAI INST OF PHARMA IND CO LTD
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