Preparation method of antipsychotic drug iloperidone

Abstract

The invention provides a preparation method of a novel antipsychotic drug iloperidone, which comprises the following steps that: 6-fluoro-3-(4-piperidinyl)-1,2-benzo isoxazole hydrochloride is reacted with 1-[4-(3- chlorophenoxy)-3-methoxyphenyl]ethanone in an aqueous solution of a non-ionic surfactant by using an inorganic base as an acid binding agent and potassium iodide as a catalyst to obtain the iloperidone. The process has the advantages of high yield, high purity, good product appearance, simpleness and convenience in operation, and low cost, has no adverse impact on the environment, and is very suitable for industrial mass production.

Description

Technical field: [0001] The present invention relates to an anti-schizophrenia drug iloperidone, i.e. 1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidine A preparation method of base] propoxyl]-3-methylphenyl]ethanone belongs to the field of medicine and chemical industry. Background technique: [0002] Iloperidone has a structural formula such as formula (I), and its chemical name is 1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidine base] propoxy] -3-methoxyphenyl] ethanone. [0003] [0004] Iloperidon (Iloperidon) is a mixed dopamine D 2 / 5-hydroxytryptamine 5HT2A receptor blocker, for 5-hydroxytryptamine 5HT2A and dopamine D 2 、D 3 High affinity receptor for dopamine D 4 and serotonin 5HT6, 5HT7 and norepinephrine NEα 1 Moderate affinity for receptors, for 5HT1A, dopamine D 1 and histamine H 1 Receptor low affinity, no detectable affinity for cholinergic muscarinic receptors. iloperidone via dopamine D 2 、D 3 , 5-hydroxytryptamine 5HT1A and nor...

AI Technical Summary

Problems solved by technology

Can cause fetal damage, irritating and carcinogenic] dimethylformamide is used as a solvent, dimethylformamide is basically insoluble to potassium carbonate, and the reaction system is completely in a heterogeneous state, which is not conducive to 6-fluoro-3-(4 -piperidinyl)-1,2-benzisoxazole hydrochloride is rapidly dissociated and reacted, and the waste liquid generated after the reaction will cause environmental problems and needs special treatment; post-reaction treatment requires ethyl acetate extraction, and then Washing, the process is cumbersome; the reaction time is 16 hours, the cycle is long, and the yield of the refined product iloperidone is 58%, the yield is low, and the cost is high

[0009] Chinese patent CN 101768154 has improved above-mentioned patent, and its key technology is to replace DMF as reaction solvent with water, although improved the yield of iloperidone crude product (yield is 91%~92.20%), refining needs to use Recrystallization of toluene and decolorization of activated carbon, the purity of the refined product is 99.50%; the operation is troublesome, and the treatment of activated carbon waste residue is increased

Although the reaction system is in liquid phase, the intermediates participating in the reaction and the reaction medium are two phases of oil and water, and the reaction product is insoluble in water. The iloperidone crystals generated during the reaction continue to separate out and easily form agglomerates. During the process, a large number of agglomerates stick to the stirring rod and the stirring blade, and the color of the part exposed to the liquid surface turns yellow and brown, resulting in crystallization and wrapping of unreacted intermediates or impurities, which brings inconvenience to post-processing, filtration and washing, and the quality of crude products Fluctuation increases the difficulty of recrystallization and refining, and the industrialized large-scale production operation is very troublesome

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