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Novel method for compounding enzalutamide

A technology of enzalutamide and a new method, which is applied in the field of synthesizing enzalutamide, can solve problems such as restricting the scale-up production of enzalutamide, and achieve good industrial scale-up prospects, cheap raw materials, and mild operating conditions

Active Publication Date: 2015-08-19
成都伊诺达博医药科技有限公司
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  • Summary
  • 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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  • Novel method for compounding enzalutamide

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0044] Preparation of 5,5-dimethyl-2-thione imidazol-4-one

[0045]150ml of DMF was added to a 250ml three-neck flask, and 13.6g of 2-methyl-2-chloro-propionic acid methyl ester, 7.6g of thiourea and 10.1g of triethylamine were added in sequence under stirring. Heat to 80-90°C, react for 7h, and monitor the completion of the reaction by TLC. Cool the reaction solution to room temperature, add the reaction solution to 600ml of water, stir to precipitate solid, stir for 30min, and filter. The filter cake was stirred and washed twice with water. After the filter cake was air-dried at 50-55°C to constant weight, it was recrystallized from ethanol to obtain 13.1 g of 5,5-dimethyl-2-thioneimidazol-4-one, with a yield of 91.2%.

Embodiment 2

[0047] Preparation of 5,5-dimethyl-3-(3-trifluoromethyl-4-fluorophenyl)-2-thioneimidazol-4-one

[0048] Add 100ml of DMF into a 250ml three-neck flask, add 13.1g of 5,5-dimethyl-2-thioneimidazol-4-one in sequence under stirring, cool to 0-5°C in an ice-water bath, and add 6g of sodium hydride in batches . After the addition, the ice-water bath continued to stir for 30 min. Dissolve 22.75g of 2-trifluoromethyl-4-bromobenzocyanide in 60ml of DMF, and slowly add it dropwise to the reaction solution, controlling the internal temperature to 0-5°C. After the addition was complete, return to room temperature and continue to stir for 4 h. TLC monitored the completion of the reaction. The reaction solution was added to 500ml of water, and the crude product was obtained by filtration. After drying, it was purified by column chromatography to obtain 18.5 g of 5,5-dimethyl-3-(3-trifluoromethyl-4-fluorophenyl)-2-thioneimidazol-4-one with a yield of 65.1%.

Embodiment 3

[0050] Preparation of Enzalutamide

[0051] Add 100ml DMF into a 250ml three-necked flask, and add 5,5-dimethyl-3-(3-trifluoromethyl-4-fluorophenyl)-2-thioneimidazol-4-one 18.5 g, cooled to 0-5°C in an ice-water bath, and added 3.9 g of sodium hydride in batches. After the addition, the ice-water bath continued to stir for 30 min. Dissolve 13.68g of 2-fluoro-4-bromobenzamide in 30ml of DMF, and slowly add it dropwise to the reaction solution, controlling the internal temperature to 0-5°C. After the addition was complete, return to room temperature and continue to stir for 5 h. TLC monitored the completion of the reaction. The reaction solution was added to 500ml of water, and the crude product was obtained by filtration. After drying, column chromatography purified to obtain 23.9 g of enzalutamide, with a yield of 87.3%.

[0052]

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Abstract

The invention discloses a novel method for compounding enzalutamide, belongs to the technical field of pharmacy synthetic technology, and particularly relates to novel technology for compounding enzalutamide. Most known methods for compounding enzalutamide relate to use of highly toxic and mephitical thiophosgene and highly toxic oxobutyronitrile, and have relatively great difficulty for industrialization. According to the invention, non-toxic and harmless thiourea and an isobutyric acid derivative are used for a reaction to obtain a key parent nucleus of 5,5-dimethyl-2-thioketone imidazole-4-ketone, and therefore, thiophosgene and oxobutyronitrile are effectively avoided. The method has a mild reaction condition, is relatively high in yield, and therefore has a great industrial prospect.

Description

technical field [0001] The invention belongs to the technical field of pharmaceutical synthesis technology, and in particular relates to a new method for synthesizing Enzalutamide. Background technique [0002] Prostate cancer (PCa) is a malignant tumor that occurs in male prostate tissue and is the result of abnormal and disordered growth of prostate acinar cells. The incidence of prostate cancer has obvious geographical and racial differences. In developed countries and regions such as Europe and the United States, it is the most common malignant tumor in men, and its death rate ranks second among various cancers. Usually, every 6 cases of men have 1 case suffered from PCa; in Asia, its incidence is lower than in Western countries, but it has shown a rapid upward trend in recent years. The incidence of PCa in my country is also showing an upward trend. The vast majority of PCa patients have lost the chance of surgery when they are discovered, and they all need surgical c...

Claims

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Application Information

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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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