Novel method for compounding medicament of Enzalutamide for resisting prostate cancer

A technology of enzalutamide and a new method, which is applied in the field of pharmaceutical synthesis technology, can solve the problems that restrict enzalutamide scale-up production, etc., and achieve the effects of good industrial scale-up prospects, mild operating conditions, and high yield

Active Publication Date: 2015-08-19
成都伊诺达博医药科技有限公司
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

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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  • Novel method for compounding medicament of Enzalutamide for resisting prostate cancer
  • Novel method for compounding medicament of Enzalutamide for resisting prostate cancer
  • Novel method for compounding medicament of Enzalutamide for resisting prostate cancer

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0038] Preparation of N-(3-trifluoromethyl-4-cyano-phenyl)-N-(3-fluoro-4-carboxamidophenyl)-urea

[0039] 150ml of THF was added to a 250ml three-necked flask, 18.6g of 3-trifluoromethyl-4-cyano-aniline, 16.8g of 2-fluoro-4-amino-benzamide and 16.2g of CDI were sequentially added with stirring. Heat to reflux, react for 8h, TLC monitors 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 N-(3-trifluoromethyl-4-cyano-phenyl)-N-(3-fluoro-4-carboxamidophenyl) -Urea 33.4g, yield 88.1%.

Embodiment 2

[0041] Preparation of N-(3-trifluoromethyl-4-cyano-phenyl)-N-(3-fluoro-4-carboxamidophenyl)-thiourea

[0042] Add 300ml of toluene into a 500ml three-necked flask, and add 33.4g of N-(3-trifluoromethyl-4-cyano-phenyl)-N-(3-fluoro-4-carboxylphenyl) in sequence while stirring )-Urea and 35.5 g of Lowe's reagent, heated to reflux, stirred for 3 hours, 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-carboxamide benzene Base)-thiourea, the yield is 72.3%.

Embodiment 3

[0044] Preparation of Enzalutamide

[0045] Add 150ml DMF into a 250ml three-necked flask, and add 25.2g N-(3-trifluoromethyl-4-cyano-phenyl)-N-(3-fluoro-4-carboxamide phenyl) with stirring. )-Thiourea, 8.7g of methyl 2-methyl-2-chloropropionate, and 6.4g of triethylamine, heated to an internal temperature of 80-90°C, reacted for 5h, and TLC monitored the completion of the reaction. Return to room temperature, add the reaction solution to 600 ml of water, and filter to obtain a crude product. After drying, column chromatography purification was performed 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, and specifically relates to a new route for the synthesis of Enzalutamide. Background technique [0002] Prostate cancer (PCa) is a malignant tumor that occurs in male prostate tissue and is the result of abnormal and disorderly growth of prostate acinar cells. The incidence of prostate cancer has obvious geographical and ethnic differences. 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 various cancers. Usually, 1 in 6 men has PCa; in Asia, its incidence is low In Western countries, it 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) in the course of treatment has been widely accepted. There ar...

Claims

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Application Information

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Patent Type & Authority Applications(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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