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Synthesis method of anti-prostate cancer drug enzalutamide

A technology of enzalutamide and a synthesis method, applied in the field of synthesizing enzalutamide, can solve problems such as restricting enzalutamide amplification production, and achieve the effects of good industrialization amplification prospects, mild operating conditions and high yields

Active Publication Date: 2017-08-15
成都伊诺达博医药科技有限公司
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0021] By comparison, it can be found that the three routes inevitably use highly toxic and foul-smelling thiophosgene, and route one also uses highly toxic cyanoacetone, which restricts the scale-up production of enzalutamide, so it is necessary to find a A more environmentally friendly and more operable synthetic method

Method used

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  • Synthesis method of anti-prostate cancer drug enzalutamide
  • Synthesis method of anti-prostate cancer drug enzalutamide
  • Synthesis method of anti-prostate cancer drug enzalutamide

Examples

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Comparison scheme
Effect test

Embodiment 1

[0039] Preparation of N-(3-trifluoromethyl-4-cyano-phenyl)-N-(3-fluoro-4-carbamoylphenyl)-urea

[0040] Add 150ml of THF into a 250ml three-necked flask, and add 18.6g of 3-trifluoromethyl-4-cyano-aniline, 16.8g of 2-fluoro-4-amino-benzamide and 16.2g of CDI in sequence while stirring. Heated to reflux, reacted for 8h, and monitored the completion of the reaction by TLC. The reaction solution was concentrated to dryness under reduced pressure, and the residue was purified by column chromatography to obtain N-(3-trifluoromethyl-4-cyano-phenyl)-N-(3-fluoro-4-carbamoylphenyl) - Urea 33.4g, yield 88.1%.

Embodiment 2

[0042] Preparation of N-(3-trifluoromethyl-4-cyano-phenyl)-N-(3-fluoro-4-carbamoylphenyl)-thiourea

[0043] Add 300ml of toluene to a 500ml three-necked flask, and add 33.4g of N-(3-trifluoromethyl-4-cyano-phenyl)-N-(3-fluoro-4-carbamoylphenyl) successively under stirring )-urea and 35.5 g of Lowe's reagent, heated to reflux, stirred for 3 h, and TLC monitored the completion of the reaction. The reaction solution was concentrated to dryness under reduced pressure, and the residue was purified by column chromatography to obtain 25.2 g of N-(3-trifluoromethyl-4-cyano-phenyl)-N-(3-fluoro-4-carbamoylbenzene Base)-thiourea, yield 72.3%.

Embodiment 3

[0045] Preparation of Enzalutamide (Enzalutamide)

[0046]Add 150ml of DMF to a 250ml three-necked flask, and add 25.2g of N-(3-trifluoromethyl-4-cyano-phenyl)-N-(3-fluoro-4-carbamoylphenyl) successively under stirring )-thiourea, 8.7g methyl 2-methyl-2-chloropropionate and 6.4g triethylamine, heated to an internal temperature of 80-90°C, reacted for 5h, and monitored the completion of the reaction by TLC. Return to room temperature, add the reaction liquid to 600ml of water, and filter to obtain the crude product. After drying, column chromatography purified to obtain 19.6 g of enzalutamide with a yield of 66.4%.

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Abstract

The invention discloses a novel method for compounding a medicament of Enzalutamide for resisting the prostate cancer, belongs to the technical field of pharmacy synthetic technique, and particularly relates to novel technique for compounding Enzalutamide. Most of known methods for compounding Enzalutamide relate to use of highly toxic and mephitical thiophosgene and highly toxic oxobutyronitrile and have great difficulty in industrialization. According to the invention, a non-toxic and harmless Lawesson's agent is adopted, and a key parent nucleus of a carbonyl group is subjected to a sulfenylation reaction, so that thiophosgene and oxobutyronitrile are effectively avoided. The reaction condition of the method is mild, and the yield is relatively high, therefore, the novel method has a great industrialization prospect.

Description

technical field [0001] The invention belongs to the technical field of pharmaceutical synthesis technology, in particular to a route for synthesizing Enzalutamide. Background technique [0002] Prostate cancer (PCa) is a malignant tumor occurring in male prostate tissue, which is the result of abnormal and disordered growth of prostate acinar cells. Prostate cancer incidence varies markedly by geographic and ethnic origin. In developed countries and regions such as Europe and the United States, it is the most common malignant tumor in men, and its mortality rate ranks second among all kinds of cancers. Usually, 1 out of every 6 men suffers from PCa; in Asia, its incidence rate is low in Western countries, but has shown a rapid upward trend in recent years. The incidence of PCa in my country is also showing an upward trend. At present, the view that PCa gradually transforms into castration-resistant prostate cancer (CRPC) during treatment has been widely accepted. There ar...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D233/86
CPCC07D233/86
Inventor 付清泉岳利剑林强廖显波赵茂先秦艳
Owner 成都伊诺达博医药科技有限公司
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