Preparation method of lurasidone

Abstract

The invention provides a preparation method of lurasidone. On the basis of the existing preparation method of lurasidone, a one-pot method is adopted to replace the method including multiple steps and obtain a target product once. The preparation method comprises the following steps: adding 3-(1-piperazinyl)-1,2-benzisothiazole in toluene, stirring to dissolve; adding (1R,2R)-1,2-bis(methanesulfonyloxymethyl)cyclohexane and an inorganic alkali, heating and carrying out reflux reaction for 12-36 hours; adding (3alpha R,4S,7R,7alpha S)4,7-methano-1H-isoindole-1,3(2H)-dione; heating and refluxing; recycling toluene at reduced pressure; adding ethyl acetate in the residue, stirring to dissolve, washing for 2-3 times with 5% hydrochloric acid, separating out the organic layers, drying for 20-120 minutes, filtering to remove the drying agent, concentrating the obtained ethyl acetate solution, dropwise adding concentrated hydrochloric acid, precipitating the solid, and performing suction filtration to obtain crude lurasidone; and refining crude lurasidone to obtain pure lurasidone. By adopting the preparation method of lurasidone, the solvent can be recycled conveniently and the method is simple in operation.

Description

technical field [0001] The invention relates to a preparation method of a pharmaceutical compound, in particular to a preparation method of lurasidone. Background technique [0002] Lurasidone is a new type of atypical antipsychotic. On October 28, 2010, the U.S. Food and Drug Administration (FDA) approved it for marketing. Its trade name is Latuda, and it is used for the treatment of schizophrenia. [0003] Japanese patent JP2800953 first reported a synthetic route using salt as an intermediate: [0004] [0005] The route starts with (1R,2R)-1,2-bis(methanesulfonate oxymethyl)cyclohexane (A) and 3-(piperazin-1-yl)benzo[d]isothiazole (B) Use acetonitrile as solvent to reflux, then add water to obtain intermediate salt D, and finally use DMF as solvent to react with (3αR,4S,7R,7αS) 4,7-methylene-1H-isoindole-1,3(2H) - Reaction of diketone (C) to give lurasidone. This route requires the separation of intermediates, including the final extraction of three solvents, aceto...

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Problems solved by technology

[0011] For example: Journal of Organic Chemistry, 1982, 47 (20): P3953-3959 and WO2012016569, etc., all use palladium-carbon catalytic hydrogenation to reduce double bonds to obtain saturation The acid anhydride of the latter was refluxed with ammonia water at 130°C for 2 hours to obtain (3αR,4S,7R,7αS) 4,7-methylene-1H-isoindole-1,3(2H)-dione with a yield of 75.54 %; literature Chemical & Pharmaceutical Bulletin, 1991, 39 (9) P2288-2300 gave only 80.5% yield, and the results of LC-MS showed that the anhydride is unstable, very easy to open the ring, and produce by-products under hydrogenation conditions product, which is the reason for the low yield of the process

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