Method for preparing lurasidone

Abstract

The invention relates to a method for preparing lurasidone and preparation of atypical antipsychotic compound lurasidone, and in particular relates to a method for preparing single salt silicate. The method comprises the following steps of: halogenating hydroxy by using a compound I as an initial raw material to prepare an intermediate compound II; reacting the intermediate compound II with a compound V under an alkalinity condition to generate an intermediate compound VI; and reacting the intermediate compound VI with a compound III under the alkalinity condition to prepare a target product of lurasidone. The method is short in process routine, easy to control and convenient to operate; and the generation of impurities is avoided, the reaction yield is obviously improved, the raw materials are cheap and easy to acquire, and the large-scale production is facilitated.

Description

technical field

[0001] The invention relates to a preparation method of an atypical antipsychotic compound lurasidone (Lurasidone, Latuda). Background technique

[0002] The chemical name of lurasidone is (3aR,4S,7R,7aS)-2-{(1R,2R)-2-[4-(1,2-benzisothiazol-3-yl)piperazinyl] Methyl]cyclohexylmethyl}hexahydro-4,7-methylene-2H-isoindole-1,3-dione hydrochloride, the English chemical name is (3aR, 4S, 7R, 7aS)-2 -{(1R,2R)-2-[4-(1,2-benzisothiazol-3-yl)piperazinyl]methyl]cyclohexylmethyl}hexahydro-4,7-methano-2H-isoindole-1,3-dionehydrochloride, also The literature is called: N-[4-[4-(1,2-benzisothiazol-3-yl)-1-piperazinyl]-(2R,3R)-2,3-tetramethylene-butyl Base]-(1'R,2'S,3'R,4'S)-2,3-bicyclo[2,2,1]heptane diimide hydrochloride, the molecular formula is C 28 h 36 N 4 o 2 S HCl, the molecular weight is 529.14; its chemical structural formula is:

[0003]

[0004] There are two kinds of synthetic routes of I reported in the literature, specifically as follows:

[0005] Sy...

Examples

Embodiment 1

[0083] Embodiment 1: the preparation of the iodide of formula II intermediate

[0084]

[0085] In dichloromethane (DCM), add 1 equivalent of the compound of formula I at one time, triphenylphosphine (PPh 3 ) 1.2 equivalents, stirring in the greenhouse, adding elemental iodine (I 2 ) 1.2 equivalents, TLC chromogenic method monitors reaction, and chromogenic agent is phosphomolybdic acid chromogenic agent, to raw material formula I compound reaction completes, and column chromatography separates, and obtains the formula II intermediate compound containing iodine functional group, and this intermediate compound is White powder. The yield is about 95%.

Embodiment 2

[0086] Embodiment 2: the preparation of the iodide of formula II intermediate

[0087]

[0088] Add 1 equivalent of the compound of formula I and 2.2 equivalents of triethylamine (TEA) to dichloromethane (DCM) at one time, control the temperature below 0°C, add 2.2 equivalents of methanesulfonyl chloride (MsCl), and monitor the reaction by TLC chromogenic method. The chromogenic agent is phosphomolybdic acid chromogenic agent, until the reaction of the raw material compound I is completed, water is added, dichloromethane (DCM) is extracted, a solid is obtained after concentration, and 2.5 equivalents of sodium iodide (NaI) is added to the solid, an appropriate amount of Acetone (Acetone) was dissolved, reacted in the dark for 10 hours, added water to remove the solid, filtered to obtain the intermediate compound of formula II containing iodine functional group, the intermediate compound was a white powder, and the yield was about 87%.

Embodiment 3

[0089] Embodiment 3: the preparation of the bromide of formula II intermediate

[0090]

[0091] Using acetic acid (AcOH) as a solvent, add 1 equivalent of the compound of formula I, 5-10 equivalents of 40% hydrobromic acid (HBr), 0.1 equivalent of sulfuric acid, react at 60-80 °C, monitor the reaction by TLC color development, and the color developer is phosphorus Molybdic acid chromogenic agent, until the reaction of the raw material formula I compound is completed, add water, dichloromethane (DCM) extraction, after concentration, obtain the formula II intermediate compound containing bromine functional group, this compound is an oil, and the yield is about 92- 98%.

technical field

[0001] The invention relates to a preparation method of an atypical antipsychotic compound lurasidone (Lurasidone, Latuda). Background technique

[0002] The chemical name of lurasidone is (3aR,4S,7R,7aS)-2-{(1R,2R)-2-[4-(1,2-benzisothiazol-3-yl)piperazinyl] Methyl]cyclohexylmethyl}hexahydro-4,7-methylene-2H-isoindole-1,3-dione hydrochloride, the English chemical name is (3aR, 4S, 7R, 7aS)-2 -{(1R,2R)-2-[4-(1,2-benzisothiazol-3-yl)piperazinyl]methyl]cyclohexylmethyl}hexahydro-4,7-methano-2H-isoindole-1,3-dionehydrochloride, also The literature is called: N-[4-[4-(1,2-benzisothiazol-3-yl)-1-piperazinyl]-(2R,3R)-2,3-tetramethylene-butyl Base]-(1'R,2'S,3'R,4'S)-2,3-bicyclo[2,2,1]heptane diimide hydrochloride, the molecular formula is C 28 h 36 N 4 o 2 S HCl, the molecular weight is 529.14; its chemical structural formula is:

[0003]

[0004] There are two kinds of synthetic routes of I reported in the literature, specifically as follows:

[0005] Sy...

Examples

Embodiment 1

[0083] Embodiment 1: the preparation of the iodide of formula II intermediate

[0084]

[0085] In dichloromethane (DCM), add 1 equivalent of the compound of formula I at one time, triphenylphosphine (PPh 3 ) 1.2 equivalents, stirring in the greenhouse, adding elemental iodine (I 2 ) 1.2 equivalents, TLC chromogenic method monitors reaction, and chromogenic agent is phosphomolybdic acid chromogenic agent, to raw material formula I compound reaction completes, and column chromatography separates, and obtains the formula II intermediate compound containing iodine functional group, and this intermediate compound is White powder. The yield is about 95%.

Embodiment 2

[0086] Embodiment 2: the preparation of the iodide of formula II intermediate

[0087]

[0088] Add 1 equivalent of the compound of formula I and 2.2 equivalents of triethylamine (TEA) to dichloromethane (DCM) at one time, control the temperature below 0°C, add 2.2 equivalents of methanesulfonyl chloride (MsCl), and monitor the reaction by TLC chromogenic method. The chromogenic agent is phosphomolybdic acid chromogenic agent, until the reaction of the raw material compound I is completed, water is added, dichloromethane (DCM) is extracted, a solid is obtained after concentration, and 2.5 equivalents of sodium iodide (NaI) is added to the solid, an appropriate amount of Acetone (Acetone) was dissolved, reacted in the dark for 10 hours, added water to remove the solid, filtered to obtain the intermediate compound of formula II containing iodine functional group, the intermediate compound was a white powder, and the yield was about 87%.

Embodiment 3

[0089] Embodiment 3: the preparation of the bromide of formula II intermediate

[0090]

[0091] Using acetic acid (AcOH) as a solvent, add 1 equivalent of the compound of formula I, 5-10 equivalents of 40% hydrobromic acid (HBr), 0.1 equivalent of sulfuric acid, react at 60-80 °C, monitor the reaction by TLC color development, and the color developer is phosphorus Molybdic acid chromogenic agent, until the reaction of the raw material formula I compound is completed, add water, dichloromethane (DCM) extraction, after concentration, obtain the formula II intermediate compound containing bromine functional group, this compound is an oil, and the yield is about 92- 98%.

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