A kind of purification method of ibiprazole
A technology of ipipiprazole and a purification method, which is applied to the purification field of ipipiprazole, can solve the problems of complicated operation, high production cost and low product purity, and achieves the effects of high purity, low production cost, simple and safe operation
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Embodiment 1
[0029] Example 1: Preparation method of Ipipiprazole Intermediate II
[0030]
[0031] Add 18.5kg toluene, 3.3kg 4-bromobenzo[B]thiophene, 6.67kg piperazine, 2.24kg sodium tert-butoxide, 87g palladium acetate, and 144.7g 1,1'-binaphthalene-2 into a 100L reactor. ,2'-Bisdiphenylphosphine. The reaction kettle is heated to 105°C to 115°C, and the temperature is kept for 5 to 10 hours. Cool down to 15℃~25℃, add 11kg water, stir and stand for separation (2 times), concentrate the organic phase under reduced pressure to remove the toluene to obtain the residue, add 21kg methanol, reduce the temperature to 0~10℃, and slowly add to the reactor Drop 4L of 6N hydrogen chloride / methanol solution, stir for 2 hours, centrifuge and filter until dry. Drying at 45°C to 55°C under normal pressure for 6 to 10 hours obtains 3.1 kg of white solid Ipipiprazole Intermediate II. The yield is 80.0% and the HPLC purity is 98.52%.
Embodiment 2
[0032] Example 2: Preparation method of Ipipiprazole Intermediate III
[0033]
[0034] Add 25kg DMF, 3kg 7-hydroxy-2-quinolone, 7.7kg potassium carbonate to 7kg aqueous solution into a 100L glass reactor, slowly drop 6.39kg 1-bromo-4-chlorobutane, keep the temperature at 10℃-20℃, After stirring for 16 hours, 50 kg of water was slowly dropped into the reaction kettle liquid. Cool to 0-10°C, stir for 2 hours, centrifuge and filter to dryness, and dry at 45°C-55°C under vacuum (-0.08-0.1MPa) for 4-10 hours to obtain 3.12kg of crude product. Add 20 kg of dichloromethane and 1 kg of methanol, and slowly drop 30 kg of methyl tert-butyl ether. Cool to 0-10℃ and stir for 2 hours, centrifuge to filter to dryness, and dry at 45℃~55℃ under vacuum (-0.08~-0.1MPa) for 4~10 hours to obtain 2.85kg Ipipiprazole Intermediate III. Rate: 61.0%, HPLC purity: 97.77%.
Embodiment 3
[0035] Example 3: Preparation method of crude ipipiprazole I
[0036]
[0037] Add 42kg DMF, 3.08kg ipiprazole intermediate II, 4.71kg potassium carbonate, 2.89kg ipiprazole intermediate III, and 1.7kg sodium iodide to a 100L glass reaction vessel. The temperature is raised to 80°C to 90°C, stirred for 5 to 10 hours, and the temperature is lowered to 30°C to 45°C, and 42kg of water is added. Cool down to 0-10°C and stir for 2 hours. Centrifuge filtered to dryness, dried at 45°C to 55°C under vacuum (-0.08 to -0.1MPa) for 4 to 6 hours to obtain 5.1 kg of crude product with HPLC purity 95.68%.
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