A kind of preparation method of apalutamide and its intermediate
A compound and selected technology, applied in the field of medicinal chemistry, can solve the problems of many steps, long routes, unsuitable for industrial scale-up production, etc.
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Embodiment 1
[0076] The preparation of embodiment 1 formula Ⅱ-1 compound
[0077]
[0078] Add formula IV-1 compound (131.9mmol), formula III-1 compound (86.2mmol) in 1000ml reaction bottle, K 2 CO 3 (303.9mmol), 500ml DMF and 20ml water, the air in the reaction flask was replaced with nitrogen, then heated to an internal temperature of 100°C, reacted for 18h, and the reaction was completed, the reaction liquid was evaporated under reduced pressure to remove DMF, added 400ml ethyl acetate, 400ml water, washed 10 minutes, liquid separation, the aqueous phase was adjusted to pH 4 with a saturated citric acid solution, and a solid was precipitated, stirred at room temperature for 2 hours, cooled to 10°C and stirred for 1 hour, filtered, rinsed with 100ml of pure water, filtered, and vacuum-dried at 50°C. 19.5 g of white solid were obtained.
[0079] MS: m / z=267[M+1] + ;
[0080] 1 HNMRδ(DMSO): 1.94-2.19 (4H, m, CH 2 ), 2.58-2.64 (2H, m, CH 2 ), 2.73-2.74 (3H, d, CH 3 ), 6.00-6.25 (...
Embodiment 2
[0081] The preparation of embodiment 2 formula Ⅱ-1 compound
[0082]
[0083] Add formula IV-1 compound (13.2mmol), formula III-1 compound (8.6mmol), TEA (34.6mmol), 50ml DMF, 2ml water in 100ml reaction bottle, nitrogen replaces the air in the reaction bottle, then heat to internal temperature 80°C, react for 36 hours, the reaction is over, the reaction liquid is evaporated under reduced pressure to remove DMF, add 40ml of ethyl acetate, 40ml of water, wash and separate, adjust the pH value of the water phase to 4 with a saturated citric acid solution, precipitate a solid, and stir at room temperature for 2 hours , cooled to 10°C and stirred for 1 h, filtered, rinsed the solid with 10 ml of pure water, and dried in vacuum at 50°C to obtain 1.37 g of white solid. MS: m / z=267[M+1] + .
Embodiment 3
[0084] The preparation of embodiment 3 formula Ⅱ-1 compound
[0085]
[0086] Add formula IV-1 compound (13.2mmol), formula III-1 compound (8.6mmol) in 100ml reaction bottle, K 2 CO 3 (30.2mmol), 50ml DMSO, 2ml water, replace the air in the reaction flask with nitrogen, then heat to an internal temperature of 120°C, react for 10h, and the reaction is completed. The reaction liquid is evaporated under reduced pressure to remove DMSO, add 40ml ethyl acetate, 40ml water, and wash Separation, the water phase was adjusted to pH 4 with a saturated citric acid solution, solids precipitated, stirred at room temperature for 2 hours, cooled to 10°C and stirred for 1 hour, filtered, rinsed with 10ml of pure water, and dried in vacuum at 50°C to obtain a white solid 0.96 g. MS: m / z=267[M+1] + ;
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