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A kind of preparation method of enzalutamide intermediate

A technology of enzalutamide and intermediates, applied in the preparation of carboxylic acid amides, organic compounds, carboxylic acid nitriles, etc., can solve the problems of low synthesis yield and high production cost, and achieve simple process, easy operation, The effect of mild reaction conditions

Active Publication Date: 2020-12-29
YANCHENG TEACHERS UNIV +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0010] 4-((2-cyanopropan-2-yl)amino)-2-fluoro-N-methylbenzamide (compound 6) is an important intermediate for the preparation of enzalutamide, and the invention provides a kind of intermediate The preparation method of the intermediate overcomes the problems of low synthesis yield, high production cost and environmental pollution in the preparation process of the intermediate in the prior art, and develops a production route with clean process and easy operation

Method used

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

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Embodiment 1

[0034] Embodiment 1: the preparation of compound 15

[0035] Ammonium chloride (9.6g, 0.18mol), propan-2-one (10.2g, 0.17mol), and ammonia (30% aqueous solution, 10mL) were added to 20mL of pure water, and cyanide was added under stirring at 0°C. Sodium chloride (8.6 g, 0.17 mol). The mixed solution was stirred at room temperature for 60 h to stop the reaction, extracted with dichloromethane (2*10 mL), and the combined organic layer was washed with saturated sodium chloride (5 mL) solution, then dried with anhydrous sodium sulfate, filtered, and the filtrate was After concentrating under reduced pressure, a white oil was obtained with a yield of 85-90%.

Embodiment 2

[0036] The preparation of embodiment 2 compound 10

[0037] Compound 9 (2.2g, 10mmol) was added to anhydrous ethylene glycol dimethyl ether (20mL), the solution was cooled to 0°C, and thionyl chloride (1.5g, 13mmol) was slowly added under stirring. The reaction was mild Exothermic, during the addition of thionyl chloride, the solution temperature does not exceed 5°C, after the addition is complete, react at 0°C for 1 hour, and then react the solution at 50°C for no less than 6 hours or TLC monitoring shows that the reaction is complete, and the solution temperature Cool down to 25°C, slowly add a solution of methylamine (0.9g, 30mmol) dissolved in ethylene glycol dimethyl ether (5mL) dropwise, and react the mixed solution at 35°C for 0.5h or stop the reaction after TLC monitoring shows that the reaction is complete , add saturated brine (15mL), extract with ethyl acetate (2*15mL), separate the layers, combine the organic layers, dry over anhydrous sodium sulfate, filter, conce...

Embodiment 3

[0038] The preparation of embodiment 3 compound 10

[0039] To a stirred solution of compound 9 (1.5 g, 6.84 mmol) in DCM (15 mL) was added dropwise oxalyl chloride (3.45 g, 27.39 mmol) at 0°C. After the addition was complete, 2-3 drops of DMF were added at 0 °C and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in anhydrous THF (20 mL). To this solution was added methylamine (50 mL) at 0°C. The reaction mixture was warmed to room temperature and stirred at room temperature for 30 minutes. The solvent was removed under reduced pressure and the residue was azeotroped with toluene to give the product in 80-85% yield.

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Abstract

The invention discloses a preparation method of an enzalutamide intermediate and belongs to the field of pharmaceutical and chemical industry. According to the preparation method of the enzalutamide intermediate, the reaction of every process is high up to higher than 80%, certain reaches up to 93%. Meanwhile, the preparation method of the enzalutamide intermediate is simple in aftertreatment process, easy to operate and applicable to industrializing, mild in reaction conditions and free from severe reaction conditions of high temperature, high pressure and ultralow temperature.

Description

technical field [0001] The invention relates to a preparation method of an enzalutamide intermediate, which belongs to the field of medicine and chemical industry. Background technique [0002] Prostate cancer (PCa) is a common malignant tumor in men. In recent years, it has rapidly risen to a global tumor disease. In many European and American countries, the incidence of prostate cancer accounts for the first among male malignant tumors, and the mortality rate Take second place. About 220,800 men were diagnosed with prostate cancer in the United States in 2015, and about 20,710 of them died. It ranks first and second among all male tumors. In recent years, with the improvement of the early diagnosis level of prostate cancer, the incidence of prostate cancer in my country has been increasing year by year, and it will become a common malignant tumor affecting the health of men in my country. [0003] Enzalutamide is a new androgen inhibitor drug, a prostate cancer drug joi...

Claims

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Application Information

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IPC IPC(8): C07C255/24C07C253/00C07C253/30C07C231/02C07C233/65A61P35/00
CPCC07C231/02C07C253/00C07C253/30C07C255/24C07C233/65
Inventor 杨康顾惠雯孙雅泉
Owner YANCHENG TEACHERS UNIV
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