Method for preparation of iloperidone and crystallization method thereof

摘要

A method for preparation of iloperidone is provided which comprises reacting 6-fluoro-3-(4-piperidinyl)-1,2-benzoisoxazole hydrochloride with 1-[4-(3-chloropropoxyl)-3-methoxyphenyl]ethyl ketone in an inorganic alkaline aqueous solution. A crystallization method of iloperidone is also provided which comprises adding seed crystal to the iloperidone solution in ethyl acetate, and then iloperidone crystal is obtained with high purity by controlling the temperature and the stirring speed.

主权项

1. A crystallization method for preparing a crystal form of iloperidone, comprising the following steps:
a) crude iloperidone is dissolved under stirring at 70° C.˜80° C. in an appropriate amount of ethyl acetate as a crystallization solvent and then filtered while hot to remove insoluble impurities in the solution to obtain a clear iloperidone solution; b) the resulting iloperidone solution is slowly cooled to 40° C.˜60° C.; c) 1% to 5% of iloperidone crystal seed relative to the weight of the crude iloperidone is slowly added thereto; d) stirring speed is controlled at 60 r/min-120 r/min, and stirring is performed for 1 hour to 3 hours at a constant temperature; e) the resulting solution is slowly cooled to room temperature under stirring, and then continuously stirred for 3 hours to 7 hours; f) the resulting crystalline slurry is filtered, and the resulting crystals are washed with ethyl acetate and dried to obtain iloperidone crystals, wherein the crystal form of iloperidone has the following X-ray diffraction pattern measured by copper cathode X-ray diffractometer and expressed as the interplanar spacing d, Bragg angle 2θ, intensity and relative intensity, wherein the relative intensity is expressed as a percentage relative to the strongest ray:2θ (°)D (À)intensity (%)foundfoundfound7.14612.36033.010.1298.72621.011.9057.42771.112.6666.98341.814.3326.17486.214.8525.95990.816.7765.280610.7 17.1545.1649100.0 17.5485.04994.818.2644.85351.819.4094.56971.519.9674.44318.320.3574.359017.6 20.7164.284218.6 21.5654.117410.2 22.1514.009813.1 23.2663.82012.823.6063.76598.123.9593.711213.7 25.1593.53681.126.3333.38173.528.9633.08041.730.5082.92781.430.7522.90511.931.8152.8105 8.5.