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Method for preparing lurasidone and salt thereof

A technology of lurasidone hydrochloride and intermediate, which is applied in the field of medicine and can solve problems such as difficulty in controlling impurities in the intermediate

Active Publication Date: 2020-01-31
HUNAN DONGTING PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0014] Based on synthetic route 2, the prior art discloses some methods for preparing lurasidone free base from (R,R')-1,2-bis(methylsulfonyl-2oxymethyl)cyclohexane in one pot, However, these methods are difficult for the control of intermediate impurities

Method used

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  • Method for preparing lurasidone and salt thereof
  • Method for preparing lurasidone and salt thereof
  • Method for preparing lurasidone and salt thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0115] Embodiment 1: Preparation of lurasidone hydrochloride

[0116] Step 1, preparation of intermediate I

[0117] (R,R)-1,2-bis(methylsulfonyloxymethyl)cyclohexane (which can be referred to as raw material 1 in the present invention) 300.4g (1mol), 3-(1-piperazinyl )-1,2-benzisothiazole hydrochloride (it can be referred to as raw material 2 in the present invention) 1mol, anhydrous potassium carbonate 2mol, acetonitrile (its amount is 15 times of raw material 1 weight) add in the reactor , Stir the reaction at 70°C until TLC detection (acetone / ethyl acetate=1:9) until the spot of the starting material (raw material 1) disappears; cool to room temperature, filter, and concentrate the filtrate to 1 / 3 volume by distillation under reduced pressure, then add Ethanol (its amount is 5 times of raw material 1 weight), stirred for 1.5 hours, and the solvent was evaporated; Added toluene (its amount was 6 times of raw material 1 weight), stirred at 70 ° C for 1.5 hours, evaporated...

Embodiment 2

[0122] Embodiment 2: Preparation of lurasidone hydrochloride

[0123] Step 1, preparation of intermediate I

[0124] (R,R)-1,2-bis(methylsulfonyloxymethyl)cyclohexane 300.4g (1mol), 3-(1-piperazinyl)-1,2-benzisothiazole hydrochloride Add 1.1 mol of salt, 1.8 mol of anhydrous potassium carbonate, and acetonitrile (the amount is 12 times the weight of raw material 1) into the reaction kettle, stir and react at 80°C until TLC detection (acetone / ethyl acetate=1:9) The spots of the starting material (raw material 1) disappeared; cooled to room temperature, filtered, and the filtrate was concentrated to 1 / 3 volume by distillation under reduced pressure, then added ethanol (its amount was 4 times the weight of raw material 1), stirred for 2 hours, and evaporated the solvent; Toluene (the amount is 5 times the weight of raw material 1), stirred at 80°C for 1 hour, evaporated to remove the solvent to concentrate the material to 2 / 3 volume, cooled to 2-8°C, filtered, and the filter c...

Embodiment 3

[0129] Embodiment 3: Preparation of lurasidone hydrochloride

[0130] Step 1, preparation of intermediate I

[0131] (R,R)-1,2-bis(methylsulfonyloxymethyl)cyclohexane 300.4g (1mol), 3-(1-piperazinyl)-1,2-benzisothiazole hydrochloride Add 0.9 mol of salt, 2.2 mol of anhydrous potassium carbonate, and acetonitrile (the amount is 18 times the weight of raw material 1) into the reaction kettle, stir and react at 60°C until TLC detection (acetone / ethyl acetate=1:9) The spots on the starting material (raw material 1) disappeared; cooled to room temperature, filtered, and the filtrate was concentrated to 1 / 3 volume by distillation under reduced pressure, then added ethanol (its amount was 6 times the weight of raw material 1), stirred for 1 hour, and evaporated the solvent; Toluene (the amount is 7 times the weight of the raw material 1), stirred at 60°C for 2 hours, evaporated to remove the solvent to concentrate the material to 2 / 3 volume, cooled to 2-8°C, filtered, and the filt...

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Abstract

The invention relates to a method for preparing lurasidone and a salt thereof. The method comprises the following steps: reacting (R,R)-1,2-bis(methanesulfonyloxymethyl)cyclohexane and 3-(1-piperazinyl)-1,2-benzoisothiazole hydrochloride in acetonitrile in the presence of potassium carbonate to obtain an intermediate I; reacting the intermediate I with (3aR,4S,7R,7aS)-4,7-methylene-1H-isoindole-1,3(2H)-dione in DMF in the presence of potassium carbonate to prepare lurasidone free alkali; and reacting the lurasidone free alkali with hydrochloric acid in isopropanol to obtain lurasidone hydrochloride. The invention also relates to lurasidone and the salt thereof prepared by using the method, and application of lurasidone and the salt thereof in medicines for resisting psychosis, especially schizophrenia. The method disclosed by the invention has one or more advantages in a group consisting of simple process, high product yield, few impurities and the like.

Description

technical field [0001] The invention belongs to the technical field of medicine, and relates to a preparation method of lurasidone, a drug used for atypical antipsychotics, and a salt thereof. It also relates to lurasidone and its salt prepared by the method, and the use of the lurasidone in antipsychotic drugs, especially schizophrenia. Background technique [0002] Lurasidone (Lurasidone, commercially available under the trade name of Latuda) is often clinically used in the form of its hydrochloride. The chemical name of lurasidone hydrochloride 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, molecular formula for C 28 h 36 N 4 o 2 S HCl, the molecular weight is 529.14; its chem...

Claims

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Application Information

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IPC IPC(8): C07D417/12
CPCC07D417/12
Inventor 王波侯奇伟宋宜志
Owner HUNAN DONGTING PHARMA
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