CLIAMS:We Claim:

1. A process for the preparation of Lurasidone or pharmaceutically acceptable salt, which comprises:

a) condensation of 1,2-(1R, 2R)-bis(methanesulfonyloxymethyl)cyclohexane with 1-(1,2-benzisothiazol-3-yl)piperazine or its pharmaceutically acceptable salt in presence of base and water to form spirocyclic compound; and

b) reaction of spirocyclic compound of step (a) with bicyclo[2.2.1]heptane-2-exo-3-exo-dicarboximide in presence of base and solvent to provide Lurasidone or its pharmaceutically acceptable salt.

2. The process of claim 1 wherein 0.8 to 2.0 equivalent of 1-(1,2-benzisothiazol-3-yl)piperazine used to condensed with 1.0 equivalent of 1,2-(1R, 2R)-bis(methanesulfonyloxymethyl)cyclohexane.

3. The process of claim 1, wherein said base is selected from carbonates, bicarbonates and hydroxides of alkali and alkaline earth metals.

4. The process of claim 1, wherein said the step b) is performed in presence of catalyst, for example, tetrabutyl ammonium hydrogen sulphate.

5. The process of claim 1, wherein said the solvent is aromatic hydrocarbon, for example, toluene.

6. The process of claim 1, wherein said spirocyclic compound is a compound of formula II

Formula II

having purity of greater than or equal to 99 % by HPLC.

7. A process for the preparation of Lurasidone hydrochloride comprises treatment of Lurasidone or its pharmaceutically acceptable salt with aqueous hydrogen chloride in presence of alcohol, wherein the pharmaceutically acceptable salt is other than hydrogen chloride.

8. The process of claim 7, wherein said the alcohol such as methanol, ethanol, isopropyl alcohol and n-butanol or their combination with water.

9. The process of claim 7, wherein said Lurasidone hydrochloride having residual content, for example, isopropyl alcohol below 1000 ppm.

Dated 11th March 2013 Dr. Mandar M. Kodgule
(Authorized Signatory for Wockhardt Limited)
,TagSPECI:DESCRIPTION

The present invention provides a process for the preparation of Lurasidone or pharmaceutically acceptable salt thereof. Further, it also provides a process for the preparation of intermediate of Lurasidone hydrochloride by using green chemistry.

Lurasidone hydrochloride of Formula I is chemically known as (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

Formula I

Lurasidone hydrochloride is an atypical antipsychotic belonging to the chemical class of benzisothiazol derivatives and marketed under the trade name LATUDA.

U.S. patent No. 5,532,372 discloses Lurasidone and its pharmaceutically acceptable salt. The US ‘372 also discloses a process for the preparation of Lurasidone involves reaction of trans-1,2-bis(methanesulfonyloxymethyl)cyclohexane with 1-(1,2-benzisothiazol-3-yl)piperazine in presence of sodium carbonate and acetonitrile to form trans-3a,7a-octahydroisoindolium-2-spiro-1'-[4'-(1,2-benzisothiazo1-3-y1)]piperazine methanesulfonate, which is reacted with bicyclo[2.2.1]heptane-2-exo-3-exo-dicarboximide in presence of potassium carbonate, dibenzo-18-crown-6-ether and xylene, and then treated with hydrogen chloride-2-propanol to provide Lurasidone Hydrochloride.

U.S. application No. 2011/263847A1 discloses a process for the preparation of Lurasidone, which involves reaction of 4-(1,2-benzisothiazol-3-yl)piperazine of Formula B with (lR,2R)-1,2-bis(methanesulfonyloxymethyl)cyclohexane in presence of toluene to provide 4'-(1,2-benzisothiazol-3-yl)-(3aR,7aR)-octahydro-spiro[2H-isoindole-2,1'-piperazinium]methanesulfonate, which is reacted with (3aR,4S,7R,7aS)-hexahydro-4,7-methano-2H-isoindole-1,3-dione in presence of tetra-n-butyl ammonium hydrogen sulfate, potassium carbonate, water and toluene to provide (3aR,4S,7R,7as)-2-{(lR,2R)-2-[4-(1,2-benzisothiazol-3-yl)-piperazin-1-ylmethyl]cyclohexylmethyl}-hexahydro-4,7-methano-2H-isoindole-1,3-dione.

Various other patent/applications, WO 2013/014665, US 7,605,260, WO 2012/131606 A1 and WO 2013/014665 A1, disclose processes for the preparation of Lurasidone hydrochloride.

The aforesaid processes for the preparation of Lurasidone and its intermediates use hazardous materials and further involve complicated separation techniques which make them commercially less viable. Therefore, there is a need to develop a process for obtaining Lurasidone or its pharmaceutically acceptable salt which is cost effective, uses commercially viable reagents and solvents, and is scalable with ease and industrially feasible.

In an aspect, the present invention is to provide a process for the preparation of Lurasidone or pharmaceutically acceptable salt, which include steps of:
a) condensation of 1,2-(1R, 2R)-bis(methanesulfonyloxymethyl)cyclohexane with 1-(1,2-benzisothiazol-3-yl)piperazine or its pharmaceutically acceptable salt in presence of base and water to form spirocyclic compound; and
b) reaction of spirocyclic compound of step (a) with bicyclo[2.2.1]heptane-2-exo-3-exo-dicarboximide in presence of base and solvent to provide Lurasidone or its pharmaceutically acceptable salt.

The step a) involves condensation of 1.0 equivalent of 2-(1R, 2R)-bis(methanesulfonyloxymethyl)cyclohexane with 0.8 to 2.0 equivalent of 1-(1,2-benzisothiazol-3-yl)piperazine or its pharmaceutically acceptable salt in presence of base and water to form spirocyclic compound.

The reaction of step a) performed green chemistry in presence of a green solvent such as water to provide pure condensed spirocyclic compound of Formula II


Formula II

The reaction is conducted at a temperature of about 50 °C to about 100 °C or in between 80 to about 85 °C for a certain period of time, for example, 2 hours or more.

The base used for the step a) includes but are not limited to carbonates, bicarbonates and hydroxides of alkali and alkaline earth metals such as sodium carbonate, potassium carbonate, sodium bicarbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide and the like.

The quantity of base used for conducting the reaction is about 0.5 to about 4 molar equivalents per molar equivalent of 2-(1R, 2R)-bis(methanesulfonyloxymethyl)cyclohexane or its pharmaceutically acceptable salt. In an embodiment, the quantity of base is 0.5 to 1 equivalent when potassium carbonate used as base. In another embodiment, the quantity of base is 1 to about 4 equivalents when sodium carbonate used as base.

The compound of formula II may or may not be isolated from the reaction mixture.

After completion of the reaction, the reaction mixture may be utilized for further reaction to provide Lurasidone or its pharmaceutically acceptable salt or it may be concentrated completely to remove water and then extracted into organic layer, which can be utilized for further reaction.

The step b) involves reaction of spirocyclic compound of step (a) with bicyclo[2.2.1]heptane-2-exo-3-exo-dicarboximide in presence of base and solvent to provide Lurasidone or its pharmaceutically acceptable salt.

The reaction of step b) may be carried out in presence of catalyst such as tetrabutylammonium hydrogensulphate, tetrabutylammonium bromide, tetrabutylammoium iodide, benzyltriethylammonium chloride and the like.

The reaction may be conducted at a reflux temperature for a period of about 4 hours or more to affect the conversion of starting material completely.

The base used for the step b) includes but are not limited to carbonates, bicarbonates and hydroxides of alkali and alkaline earth metals such as sodium carbonate, potassium carbonate, sodium bicarbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide and the like.

The solvent used for the preparation of Lurasidone or its salt of step b) includes but are not limited to water, aromatic hydrocarbon such as toluene, nitrile such as acetonitrile and the like or combination thereof.

The inventors of the present invention found that the use of single base, for example, potassium carbonate, for the preparation of Lurasidone or its pharmaceutically acceptable salt from 3-(1-Piperazinyl)-1,2-Benzisothiazole or its pharmaceutically acceptable salt provides higher yield.

After completion of the reaction, the reaction mixture may be quenched with quenching agent such as water or acid like hydrochloric acid, methane sulfonic acid and the like and then subjected for isolation of solid of Lurasidone or its salt by using alcohol, for example, isopropyl alcohol.

The pharmaceutically acceptable salt includes hydrogen chloride, hydrogen bromide, mesylate, tosylate, tartarate, fumarate, and the like.

In another aspect, the present invention provides a process for the preparation of Lurasidone hydrochloride comprises treatment of Lurasidone or its pharmaceutically acceptable salt with aqueous hydrogen chloride in presence of alcohol, wherein the pharmaceutically acceptable salt is other than hydrogen chloride.

In an embodiment, Lurasidone hydrochloride obtained from the present invention having high quality in view of purity and content of residual solvent. The invention of the present application provides Lurasidone hydrochloride to meet the requirement of ICH guidelines.

The alcohol used for preparation of Lurasidone hydrochloride is selected from methanol, ethanol, isopropyl alcohol, n-butanol, and the like or combination of alcohol with water. The preparation of hydrochloride salt of Lurasidone of the present invention optionally involves use of alcohol in combination with water.

In another aspect, the present invention also provides Lurasidone hydrochloride having residual content of isopropyl alcohol below 1000 ppm, which comprises treatment of Lurasidone with aqueous hydrochloric acid in presence of isopropyl alcohol and water.

The suitable temperature for above reaction is about 20 to about 45 °C. The reaction may be stirred for period of 20 hours to 24 hours for complete solidification of Lurasidone hydrochloride without affecting the quality of the product.

In another aspect, the present invention relates to pharmaceutical composition comprising residual free of Lurasidone hydrochloride and pharmaceutically acceptable carriers and/or diluents thereof, and if desired, other active ingredients, which may be administered orally, intravascularly, subcutaneously, intramuscularly or topically for the treatment of schizophrenia in need thereof.

In another aspect, the present invention provides a process for the preparation of intermediate of Lurasidone, trans (R,R)-3a,7a-octahydroisoindolium-2-spiro-1'-[4'-(1,2-benzisothiazo1-3-y1)]piperazinemethanesulfonate of Formula II:

Formula II
which includes the reaction of 2-(1R,2R)-bis(methanesulfonyloxymethyl)cyclohexane with 1-(1,2-benzisothiazol-3-yl)piperazine or pharmaceutically acceptable salt thereof in presence of base and water.

The reaction performed green chemistry in presence of water to provide pure condensed spirocyclic compound of Formula II.

In another aspect, the present invention provides a process for the preparation of compound of Formula II includes the condensation of 2-(1R, 2R)-bis(methanesulfonyloxymethyl)cyclohexane with 1-(1,2-benzisothiazol-3-yl)piperazine hydrochloride in presence of base such as sodium carbonate or potassium carbonate and water.

The reaction is conducted at a temperature of about 50 to about 100 °C or in between 80 °C to about 85 °C for a certain period of time, for example, 2 hours or more.

The base used for the step a) includes but are not limited to carbonates, bicarbonates and hydroxides of alkali and alkaline earth metals such as sodium carbonate, potassium carbonate, sodium bicarbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide and the like.

The compound of formula II obtained from the present invention has a purity more than or equal to 99% determined by HPLC.

The present invention is further illustrated by the following example, which does not limit the scope of the invention. Certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present application.

EXAMPLES

Example -1: Process for trans (R,R)-3a,7a-octahydroisoindolium-2-spiro-1'-[4'-(1,2-benzisothiazo1-3-y1)]piperazinemethanesulfonate of Formula II

3-(1-Piperazinyl)-1,2-Benzisothiazole Hydrochloride (10 gm, 0.03909 mole), water (120 ml) and potassium carbonate (0.5 equivalents) were charged into round bottom flask and stirred for one hour at room temperature. Finally, (R, R)-1,2-bis(methanesulfonyloxymethyl)cyclohexane (11.8 gm, 0.0395 mole) was charged and then reaction mixture was heated at 80-85°C for 5-8 hours. After completion of reaction, water was distilled out and obtained residue was extracted in acetonitrile at 60-70°C and then concentrated to get the pure condensed product.

Purity-99.29% by HPLC

Example-2: Process for Lurasidone:

To obtained condensed product residue of example-1 was charged toluene (200 ml), 50 ml toluene was distilled under vacuum, reaction mixture was cooled to room temperature and charged (3aR, 4S, 7R, 7aS) 4,7-Methano-1H-isoindole-1, 3(2H)-dione OR Bicyclo[2,2,1]Heptane-2-exo-3-exo-dicarboximide, potassium carbonate and catalytic amount of tetrabutyl ammonium hydrogen sulphate. The reaction mixture was heated at reflux temperature for 5-7 hours. After completion of reaction, the reaction mixture was cooled to room temperature and quenched using water, layer separated, washed with water and then concentrated over rotavapour at 65°C to get oily mass. The solid was isolated from oily mass using isopropyl alcohol (40 ml) with stirring at room temperature for 4-6 hours. The precipitated solid was filtered and wet cake washed with isopropyl alcohol (10-20 ml). The resultant wet material was further crystallized in isopropyl alcohol and then dried under vacuum at 60°C to get pure Lurasidone base.

Yield: 12.8 gm
Purity: 98.72%

Example-3: Process for Lurasidone hydrochloride

Isopropyl alcohol (10 ml), water (4 ml) and Lurasidone base (2 gm) were combined and stirred. Aqueous hydrochloric acid (1.8 ml, about 35% w/w) mixture was charged to the reaction mass and heated to 40 °C. The reaction mass was stirred at room temperature for 24 hours to get Lurasidone hydrochloride.

Yield: 1.9 gm
Purity: 99.94%

Example-4: Process for Lurasidone Hydrochloride

Lurasidone base (1 gm) and methanol (10 ml) charged into round bottom flask, stirred and charged aqueous hydrochloric acid (0.9 ml, about 35% w/w) mixture. The reaction was heated at 40°C and stirred for 24 hours at room temperature to get Lurasidone hydrochloride.
Yield : 0.8 gm
Purity-98.85 %