Study Of New Manufacture Process Of Iloperidone API

Iloperridone is an antipsychotic drug belonging to the chemical class ofpiperidinyl-benzisoxazole derivatives. It is combined with dopamine D2、D3and serotonin(5HT2) receptor antagonist, and used in the treatment of Schizophrenia.In this paper, one new synthetic route suitable for industrial preparation, with highyield, high purity, low toxicity and less pollution, is designed and obtained throughexperiments. One key intermediate,(Z)-4-(2,4-difluorobenzoyl)piperidineoxime(2) wasobtained from4-(2,4-difluorobenzoyl)piperidine hydrochloride as the starting materialthrough stereoselectivity reaction and the product purity is above99.9%. Another keyintermediate,1-[4-(3-bromopropoxy)-3-methoxyphenyl]ethanone (6) was obtained from1-(4-hydroxy-3-methoxyphenyl)ethanone and1,3-dibromopropane and the product purityis above99.0%. Finally, Iloperidone (1) was obtained through alkylation and cyclizationfrom the key intermediate (2) and (6) in methylisoproplyketone (MIPK, low toxicity, IVclass solvent). The total yield is65%, and the purity is over99.9%by HPLC.Six related substances, such as4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxy-α-methylbenzenemethanol (P88),4-(3-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperidin-1-yl)propoxy)-3-methoxybenzoic acid (P95),1,1’-[1,3-propanediylbis[oxy(3-methoxy-4,1-phenylene)]]bis-ethanone (A),(E)-(2,4-difluorophenyl)(piperidin-4-yl)methanone oxime (B),1-(4-(3-(4-(6-ethoxybenzo[d]isoxazol-3-yl)piperidin-1-yl)propoxy)-3-methoxyphenyl)ethanone (C),1-(3-(4-acetyl-2-methoxyphenoxy)propyl)-4-(6-fluoro-1,2-benzisoxazol-3-yl)piperi dine-N-oxide (D) were synthesized. The chemicalstructures were confirmed by IR,1H-NMR,13C-NMR and MS.13kinds of different solvents were used to recrystallize iloperidone in order to finenew crystal, and the XRD results showed the same polymorph with2θ angles of about7.1o,10.1o,11.8o,12.6o,14.2o,17.2o,17.4o,18.2o,19.0o,19.3o,19.9o,20.3o,21.5o,22.0o,23.8o,26.3o,28.9o,30.7o,31.7o,34.1o. Single crystal diffraction method was applied to prove thatthe nitrogen-bearing six-member ring in iloperidone molecule is chair form and otherrings are plane form. The molecular is no optical rotation. The molecular in crystal statekeeps the stable arrangement in space by Van der Waals’ force.