Preparation method of lurasidone

A technology of lurasidone and diketone, applied in the field of preparation of pharmaceutical compounds, can solve the problems of unstable acid anhydride, low process yield and the like, and achieve the effects of simple operation, simple purification and convenient recovery

Inactive Publication Date: 2013-01-09
SHANDONG BESTCOMM PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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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,...

Method used

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  • Preparation method of lurasidone
  • Preparation method of lurasidone
  • Preparation method of lurasidone

Examples

Experimental program
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Effect test

Embodiment 1

[0025]

[0026] Put 3.8g (17.4mmol) 3-(1-piperazinyl)-1,2-benzisothiazole into 150ml toluene, stir to dissolve, add 5.7g (19.0mmol) (1R,2R)-1,2- Bis(methanesulfonate oxymethyl)cyclohexane, and 7.2g (52mmol) potassium carbonate, heat up, reflux at 110-130°C for 30h, until TLC detects the intermediate 3-(1-piperazinyl)-1,2 - Benzisothiazole basically disappears (main peak LC-MS: M + =328.2), add 3.1g (18.7mmol) (3αR,4S,7R,7αS) 4,7-methylene-1H-isoindole-1,3(2H)-dione, stir and heat up, 110-130 Reflux at ℃ for 8 hours, cool, recover toluene under reduced pressure, add 200ml of ethyl acetate to the residue, stir to dissolve, wash with 5% hydrochloric acid solution three times, separate the organic layer, add anhydrous magnesium sulfate to dry for 2 hours, and filter out the desiccant to obtain ethyl acetate solution. The above ethyl acetate solution was evaporated and concentrated to about 80ml, concentrated hydrochloric acid was added dropwise, a large amount of white solid ...

Embodiment 2

[0028] Put 3.8g (17.3mmol) 3-(1-piperazinyl)-1,2-benzisothiazole into 150ml toluene, stir to dissolve, add 7.84g (26.10mmol) (1R,2R)-1,2- Bis(methanesulfonate oxymethyl)cyclohexane, and 7.2g (52mmol) potassium carbonate, heat up, reflux at 110-130°C for 24h, until TLC detects the intermediate 3-(1-piperazinyl)-1,2 - Benzisothiazole basically disappears, add 4.3g (26.1mmol) (3αR,4S,7R,7αS) 4,7-methylene-1H-isoindole-1,3(2H)-dione, stir and heat up , reflux at 110-130°C for 4 hours, cool, recover toluene under reduced pressure, add 200ml of ethyl acetate to the residue, stir to dissolve, wash with 5% hydrochloric acid solution three times, separate the organic layer, add anhydrous magnesium sulfate to dry for 2 hours, filter off Desiccant, in ethyl acetate solution. The above ethyl acetate solution was evaporated and concentrated to about 80ml, concentrated hydrochloric acid was added dropwise, a large amount of white solid was precipitated, and filtered by suction to obtain 6....

Embodiment 3

[0030]Put 3.8g (17.3mmol) 3-(1-piperazinyl)-1,2-benzisothiazole into 120ml toluene, stir to dissolve, add 4.2g (13.8mmol) (1R,2R)-1,2- Bis(methanesulfonate oxymethyl)cyclohexane, and 7.2g (52mmol) potassium carbonate, heat up, reflux at 110-130°C for 30h, until TLC detects the intermediate 3-(1-piperazinyl)-1,2 - Benzisothiazole basically disappears, add 2.8g (13.9mmol) (3αR,4S,7R,7αS) 4,7-methylene-1H-isoindole-1,3(2H)-dione, stir and heat up , reflux at 110-130°C for 8 hours, cool, recover toluene under reduced pressure, add 150ml of ethyl acetate to the residue, stir to dissolve, wash with 5% hydrochloric acid solution three times, separate the organic layer, add anhydrous magnesium sulfate to dry for 2 hours, filter off Desiccant, in ethyl acetate solution. The above ethyl acetate solution was evaporated and concentrated to about 60ml, concentrated hydrochloric acid was added dropwise, a large amount of white solid was precipitated, and filtered by suction to obtain 5.24g...

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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...

Claims

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Application Information

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IPC IPC(8): C07D417/12C07D209/56
Inventor 宫风华张志强王观磊
Owner SHANDONG BESTCOMM PHARMA CO LTD
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