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Process for the preparation of highly pure Lurasidone hydrochloride and its crystalline intermediates thereof.

IP.com Disclosure Number: IPCOM000236208D
Publication Date: 2014-Apr-11

Publishing Venue

The IP.com Prior Art Database

Abstract

This article provides process for the preparation of highly pure Lurasidone hydrochloride and its intermediates thereof. The said article also provides crystalline forms of Lurasidone hydrochloride and its intermediates.

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Process for the preparation of (3aR,4S,7R,7aS)-2-{(1R,2R)-2-[4-(1,2-benzisothiazol-3-yl)

piperazin-1ylmethyl]cyclohexylmethyl}hexahydro-4,7-methano-2H-isoindole-1,3-dione

hydrochloride, its intermediates and crystalline forms thereof

    (3aR,4S,7R,7aS)-2-{(1R,2R)-2-[4-(1,2-benzisothiazol-3-yl)piperazin-1ylmethyl]cyclohexyl methyl}hexahydro-4,7-methano-2H-isoindole-1,3-dione hydrochloride which is represented by the structural formula-1a is commonly known as Lurasidone hydrochloride.

Formula-1a

    Lurasdione hydrochloride is a new atypical antisphychotic drug developed by Dainippon Sumitomo Pharma and marketed by Sunovion in the USA. It is approved in USA on Octomber 28, 2010 and in Europe on March 21, 2014. It is a potent antagonist of dopamine D2, serotonin 7 receptors with a high affinity for serotonin 1A receptor.

Described herein after, a process for the preparation of Lurasidone hydrochloride.

    The use of an inorganic base such as sodium carbonate and potassium carbonate which has been described in the prior art for the condensation of (1R,2R)-cyclohexane-1,2-diylbis(methylene) dimethanesulfonate and 3-(piperazin-1-yl)benzo[d]isothiazole involves longer reaction times of the order of 24 to 48 hours. Whereas, the long maintenance hours result in formation of by products and thereby reducing the yield and purity of the product.

    Therefore, selection of a suitable base for the above said condensation reaction will improve the yield and purity of the resultant compound i.e., (3aR,7aR)-4'-(benzo[d]isothiazol-3- yl)octahydrospiro [isoindole-2,1'-piperazin]-1'-ium mesylate which in-turn increases the yield and purity of final compound i.e., Lurasidone hydrochloride. The suitable base used in the present process is organic base, preferably triethylamine.

    Accordingly, the present process for the preparation of Lurasidone hydrochloride compound of formula-1a provides the final compound with increased yield and purity.

Further, the process comprises the following steps of:

a) Reacting (1R,2R)-cyclohexane-1,2-diyldimethanol compound of formula-2 with methane sulfonyl chloride in presence of triethylamine in dichloromethane, followed by purifying the obtained compound using n-heptane to provide (1R,2R)-cyclohexane-1,2-diylbis(methylene)

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dimethanesulfonate compound of formula-3,

b) reacting the compound of formula-3 with 3-(piperazin-1-yl)benzo[d]isothiazole compound of formula-4 in presence of triethylamine in acetonitrile, followed by purifying the obtained compound using acetone provides (3aR,7aR)-4'-(benzo[d]isothiazol-3-yl)octahydrospiro [isoindole-2,1'-piperazin]-1'-ium mesylate compound of formula-5,

c) reacting the compound of formula-5 with (3aR,4S,7R,7aS)-hexahydro-4,7-methano-2H- isoindole-1,3-dione compound of formula-6 in presence of potassium carbonate in toluene to provide (3aR,4S,7R,7aS)-2-{(1R,2R)-2-[4-(1,2-benzisothiazol-3-yl)piperazin-1ylmethyl] cyclohexylmethyl}hexahydro-4,7-methano-2H-isoindole-1,3-dione comp...