WO2014064714A2

WO2014064714A2 - Process for preparation of lurasidone hydrochloride

Info

Publication number: WO2014064714A2
Application number: PCT/IN2013/000638
Authority: WO
Inventors: Sunil Kumar Singh; Sachin Srivastava; Dinesh Bansilal Deore; Shekhar Bhaskar Bhirud
Original assignee: Glenmark Pharmaceuticals Ltd
Current assignee: Glenmark Pharmaceuticals Ltd
Priority date: 2012-10-22
Filing date: 2013-10-18
Publication date: 2014-05-01
Anticipated expiration: 2015-04-22
Also published as: WO2014064714A3

Abstract

The present invention provides a process for the preparation of lurasidone hydrochloride.

Description

PROCESS FOR PREPARATION OF LURASIDONE HYDROCHLORIDE

Priority

This application claims the benefit of IN3079/MUM/2012, filed on October 22, 2012 and United States Provisional Application No. 61/734,652 the content of which is incorporated herein by reference.

Field Of Invention

The present invention relates to a process for preparation of lurasidone or a pharmaceutically acceptable salt thereof.

Background of the Invention

Lurasidone which is chemically known as (3aR, 4S, 7R,7aS)-2{(lR,2R)-2-[4-(l ,2- benzisothiazol-3-yl)piperazin-lylmethyl] cyclohexylmethyl}hexahydro-4,7-methano-2H- isoindole-l,3-dione, is represented b compound of formula I.

I

Lurasidone hydrochloride is an antipsychotic agent indicated for the treatment of patients with -schizophrenia. Commercially, it is Latuda®, Sunovion's lurasidone hydrochloride which is an oral tablet in dosage strengths of 20mg, 40mg, 80mg and 120mg.

United States Pat.No. 5532372 (US'372) discloses imide compounds, including lurasidone or its acid addition salt. US'372 patent discloses a process for preparing lurasidone which involves the resolution of racemic lurasidone using resolving agents such as tartaric acid. Disadvantageous^, the resolution of racemic lurasidone to obtain desired isomer reduces yield.

Presently, we have developed a cost effective, industrially feasible process for the preparation of lurasidone or its acid addition salt which is less time consuming.

Brief Description Of The Accompanying Figures Fig. 1 : PXRD pattern of crystalline lurasidone hydrochloride, which is substantially in accordance with example 10.

Fig. 2: DSC of crystalline lurasidone hydrochloride, which is substantially in accordance with example 10.

Fig. 3: TGA of crystalline lurasidone hydrochloride, which is substantially in accordance with example 10.

Fig 4. PXRD pattern of crystalline compound of formula II, which is substantially in accordance with example 15.

Fig 5. DSC of crystalline compound of formula II, which is substantially in accordance with example 15.

Summary of the Invention

The present invention provides a process for the preparation of lurasidone, a compound of formula I or a pharmaceutically acce table salt thereof comprising:

a) reacting reacting (3aR, 7aR)-4'-(benzo[d] isothiazol-3-yl octahydrospiroisoindole-2, - piperazin]-l '-ium methanesulfonate, a compound of formula II, with (lR,2S,6R,7S)-4- azatricylodecane-3,5-dione, a compound of formula III, to obtain lurasidone, a compound of formula I, wherein the reaction is carried out in absence of water and in absence of phase transfer catalyst; and

II III b) optionally converting lurasidone to a pharmaceutically acceptable salt thereof.

In one embodiment the present invention provides a process for the preparation of lurasidone hydrochloride comprising contacting lurasidone, compound of formula I, in C 1-C5 alcohol with aqueous hydrochloric acid at a temperature below 50°C.

In one embodiment, the present invention provides crystalline reacting (3aR, 7aR)-4'- (benzo[d] isothiazol-3-yl octahydrospiroisoindole-2, l '-piperazin]- -ium methanesulfonate, a compound of formula II characterized by X-ray diffraction (XRD) spectrum having peak reflections at about 8.0, 13.3, 15.5, 21.3, 29.6 and 33.1 ±0.2 degrees 2 theta.

Detailed Description of the Invention

The present invention provides a novel process for the preparation of lurasidone, compound of formula I, or a pharmaceutically acceptable salt thereof.

In one embodiment, the present invention provides a process for the preparation of lurasidone, a compound of formula I, or a pharmaceutically acceptable salt thereof, comprising:

I a) reacting (3aR, 7aR)-4'-(benzo[d] isothiazoI-3-yl octahydrospiroisoindole-2, l '-piperazin]- l '-ium methanesulfonate, compound of formula II, with (lR,2S,6R,7S)-4-azatricylodecane 3,5-dione, a compound of formula III, to obtain lurasidone, a compound of formula I, wherein the reaction is carried out in absence of water and in absence of phase transfer catalyst; and

II III

b) optionally converting lurasidone to a pharmaceutically acceptable salt thereof.

In one embodiment, in a) of the above process compound of formula II is reacted with compound of formula III in a suitable solvent in absence of water and in absence of phase transfer catalyst to obtain a reaction mixture. The compound of formula III, may be added to the reaction mixture at a temperature of about 20-35°C. Preferably, the compound of formula III is added at a temperature of about 25-30°C.

A suitable solvent may be selected from, but is not limited to halogenated hydrocarbons such as methylene chloride, ethylene chloride, chloroform and carbon tetrachloride; alcohols such as methanol, ethanol, n-propyl alcohol, 2-propanol, tert-butanol; esters such as ethyl acetate, isopropyl acetate and butyl acetate; hydrocarbons such as benzene, toluene, cyclohexane and toluene; or mixtures thereof. Preferably, the solvent is toluene.

In one embodiment, in a) of the above process the reaction is carried out in presence of a base.

A suitable base may_. be selected from organic or an inorganic base. The inorganic base may be selected from, but is not limited to hydroxides such as sodium hydroxide, potassium hydroxide; carbonates such as sodium carbonate, potassium carbonate; bicarbonates such as sodium bicarbonate, potassium bicarbonate, hydrides such as sodium hydride; while the organic base may be selected from, but is not limited to triethyl amine, trimethyl amine, pyridine, dimethyl amino pyridine. Preferably, the base is potassium carbonate.

Surprisingly and unexpectedly, it has been found that the process can be improved significantly by using molar excess of base to (3aR, 7aR)-4'-(benzo[d] isothiazol-3-yl octahydrospiroisoindole-2, r-piperazin]-l '-ium methanesulfonate, compound of formula II. In one embodiment, in step a) of the above process, the molar ratio of (3aR, 7aR)-4'- (benzo[d] isothiazol-3-yl octahydrospiroisoindole-2, Γ-piperazinJ-l '-ium methanesulfonate, compound of formula II to the base ranges from about 1 :1.8 to about 1 :3.5. Preferably, the molar ratio of compound of formula II to the base is about 1 :2.5. In one embodiment, the present invention provides a process for the preparation of compound of formula I comprising reacting a compound of formula II with a compound of formula III in the presence of potassium carbonate in toluene and in absence of water and in absence of phase transfer catalyst. The reaction is carried out at a temperature of about 25°C to about reflux temperature of toluene. Preferably the reaction transpires at about reflux temperature of toluene.

In one embodiment, the isolation of lurasidone is carried out by a process comprising removing the solvent containing lurasidone and addition of suitable alcoholic solvent selected from the group consisting of methanol, n-propanol, 2-propanol, butanol, isobutanol. Preferably, the solvent is methanol. Lurasidone thus formed is isolated by known methods in the art for example filtration, centrifugation and the like.

In one embodiment, in a) of the above process the compound of formula II reacts with compound of formula III in the absence of water and in the absence of phase transfer catalyst.

In one embodiment, in a) of the above process the compound of formula II reacts with compound of formula III in the absence of water and in the absence of phase transfer catalyst and in presence of a base.

In one embodiment, in a) of the above process the compound of formula II reacts with the compound of formula III in the absence of water and in the absence of phase transfer catalyst and in presence of a base wherein the molar ratio of the (3aR, 7aR)-4'-(benzo[d] isothiazol- 3-yl octahydrospiroisoindole-2, Γ-piperazinj-r.-iurn methanesulfonate, compound of formula II to the base ranges from about 1 : 1.8 to about 1 : 3.5. Preferably, the molar ratio of compound of formula II to the base is about 1 : 2.5.

The phrase "absence of water" is intended to mean that water is not used when compound of formula II reacts with compound of formula III.

The phrase "absence of phase transfer catalyst" is intended to mean that phase transfer catalyst is not used when compound of formula II reacts with compound of formula III.

The phase transfer catalyst may be selected from, but is not limited to dibenzo- 18-crown-6- ether, tetrabutylammoniumbromide, tetrapropylammoniumbromide, tributylbenzyl ammoniumbromide, tetraoctylammoniumbromide, tetrabutylammoniumiodide, tetra butylammoniumhydrogensulfate, benzyltrimethylammoniumchloride, benzyltriethyl ammoniumchloride, tetrabutylammoniumacetate, tetrabutylammoniumiodide, ethyltriphenyl phosphoniumbromide.

In one embodiment, the present invention provides a process for the purification of lurasidone, the process comprising treating lurasidone with a suitable solvent.

A suitable solvent may be selected from, but is not limited to esters such as ethyl acetate, propyl acetate, butyl acetate; ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone, 2-propanone; hydrocarbon such as toluene, benzene, xylene, cyclohexane; halogenated hydrocarbons such as methylene dichloride, ethylene dichloride, chloroform, carbon tetrachloride, alcohols such as methanol, ethanol, n-propanol, 2-propanol, tert- butanol, n-butanol; ethers such as diethyl ether, di-isopropyl ether; water or mixtures thereof. Preferably, the solvent is acetone.

In one embodiment, the present invention provides a process for the purification of lurasidone, the process comprising suspending lurasidone in acetone. The reaction mass is heated to a temperature of about 25°C to about reflux temperature. Preferably, the reaction mass is heated to about reflux temperature. The reaction mass is then cooled and filtered to obtain pure lurasidone, compound of formula I.

In one embodiment, in b) of the above process a compound of formula I, optionally, may be converted to a pharmaceutically acceptable salt thereof.

The pharmaceutically acceptable salt of compound of formula I may be obtained by treating a compound of formula I with a suitable acid.

Suitable acids may be selected from oxalic acid, malonic acid, succinic acid, camphorsulfonic acid, tartaric acid, p-toluene sulfonic acid, methane sulfonic acid, benzene sulfonic acid, mandelic acid, dibenzoyl tartaric acid, hydrochloric acid, sulphuric acid, nitric acid and the like. Preferably, the acid is hydrochloric acid.

In one embodiment, in step b) of the above process, lurasidone is converted to hydrochloride salt of lurasidone.

In one embodiment, the present invention provides a process for the preparation of lurasidone hydrochloride, the process comprising;

a) treating lurasidone with a suitable solvent,

b) adding hydrochloric acid to a); and

c) isolating lurasidone hydrochloride.

In one embodiment, in a) of the above process lurasidone is dissolved or suspended in a suitable solvent. The solution is heated to a temperature of about 30°C to about reflux temperature of the solvent. Preferably, the reaction mixture is heated to about reflux temperature of the solvent.

A suitable solvent may be selected from, but is not limited to alcohols such as methanol, ethanol, n-propanol, 2-propanol, n-butanol, tert-butanol; esters such as ethyl acetate, propyl acetate, n-butyl acetate; ethers such as diethyl ether, di-isopropyl ether; hydrocarbon solvents such as toluene, xylene, cyclohexane; ketones such as acetone, 2-propanone, methyl ethyl ketone, methyl isobutyl ketone; water or mixtures thereof. Preferably, the solvent is 2- propanol.

In one embodiment, in b) of the above process hydrochloric acid is added to the solution in a). The addition of hydrochloric acid may be by purging dry hydrochloride gas, addition of aqueous hydrochloric acid or by addition of hydrochloric acid dissolved in a suitable solvent. A suitable solvent may be selected from, but is not limited to an alcohol such as methanol, ethanol, n-propanol, 2-propanol; an ester such as ethyl acetate. Preferably aqueous hydrochloric acid is added to the solution in a).

The addition of aqueous hydrochloric acid or a suitable solvent containing hydrochloric acid is carried out at a temperature of about 0°C to about reflux temperature of the solvent. Preferably, the addition is Carried out at 25-30°C. In c) of the above process lurasidone hydrochloride is precipitated and isolated by methods known in the art which include filtration, centrifugation and evaporation. Preferably, lurasidone hydrochloride is isolated by filtration.

In one embodiment, the present invention provides a process for the preparation of lurasidone hydrochloride, the process comprising suspending lurasidone in acetone and heating to reflux to obtain a clear solution. The reaction mass is cooled to a temperature of about 20- 30°C and hydrochloric acid in 2-propanol is added to the reaction mass. The precipitated lurasidone hydrochloride is isolated the by methods known in the art such as filtration, centrifugation and the likes .

In one embodiment the present invention provides a process for the preparation of lurasidone hydrochloride comprising contacting lurasidone, compound of formula I, in C1-C5 alcohol with aqueous hydrochloric acid at a temperature below 50°C.

In one embodiment, surprisingly and unexpectedly it was found that isopropyl chloride a known genotoxic impurity, formed by the reaction of hydrochloric acid and isopropyl alcohol, can be avoided by carrying the addition of aq hydrochloric acid to the reaction mixture of lurasidone in 2-propanol at a temperature below 50°C ,

In one embodiment the present invention provides a process for the preparation of crystalline lurasidone hydrochloride comprising contacting lurasidone, compound 6f formula I, in Cl - C5 alcohol with aqueous hydrochloric acid at a temperature below 50°C.

The C1 -C5 alcohol may be selected from, but are not limited to methanol, ethanol, n- propanol, 2-propanol, n-butanol, tert-butanol and the mixtures thereof. Preferably the C 1 -C5 alcohol is 2-propanol.

The phrase "temperature below 50°C" is intended to mean a temperature from about 0 - 50 °C. Preferably, a temperature from about 25-40°C.

In one embodiment, the present invention provides a process for the preparation of lurasidone hydrochloride comprising suspending lurasidone, compound of formula I, in 2-propanol. The reaction mass is heated to reflux temperature and stirred for a period of about 15-60 minutes. Preferably, the reaction mass is stirred at about reflux temperature for about 30 minutes and then cooled to about 25-30°C. Aqueous hydrochloric acid is added to the reaction mass containing lurasidone in 2-propanol at a temperature below 50°C. Preferably, aqueous hydrochloric acid is added at a temperature of about 20-45°C. Preferably, aqueous hydrochloric acid is added at temperature of about 25-30 °C.

The reaction mass containing lurasidone hydrochloride may be heated to about 30- 65°C.

Preferably, the reaction mass is heated to a temperature of about 45-50°C.

In one embodiment, lurasidone hydrochloride is isolated by cooling the reaction mass and isolating by known methods such as filtration, centrifugation and the like.

In one embodiment, the present invention provides a process for the purification of lurasidone hydrochloride, the process comprising treating lurasidone hydrochloride with a suitable solvent and isolating the pure lurasidone hydrochloride.

A suitable solvent may be selected from, but is not limited to alcohols such as methanol, ethanol, n-propanol, 2-propanol; esters such as ethyl acetate, butyl acetate, isopropyl acetate; hydrocarbons such as toluene, cyclohexane, xylene; ethers such as diethyl ether, di-isopropyl ether; ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone; water or mixtures thereof.

In one embodiment, the present invention provides process for the preparation of crystalline lurasidone hydrochloride, wherein the crystalline lurasidone hydrochloride is purified in an alcoholic solvent. Preferably, the solvent is 2-propanol or methanol.

In one embodiment, the present invention provides a process for the purification of lurasidone hydrochloride comprising preparing a reaction mixture by slurrying lurasidone hydrochloride in 2-propanol. The reaction mixture may be heated to a temperature of about 30°C to about reflux temperature. Preferably, the reaction mass is heated to reflux temperature of 2-propanol. The reaction may be stirred for a period of about 30 -180 minutes. Preferably, the reaction mass is stirred for about 120 minutes. Pure lurasidone hydrochloride may be isolated by known methods such as filtration, centrifugation and the like.

In one embodiment, the present invention provides a process for the purification of lurasidone hydrochloride comprising preparing a reaction mixture by slurrying lurasidone hydrochloride in methanol. The reaction mixture may be heated to a temperature of about 30°C to about reflux temperature. Preferably, the reaction mass is heated to reflux temperature of methanol. The reaction may be stirred for a period of about 30 -180 minutes. Preferably, the reaction mass is stirred for about 120 minutes. Pure lurasidone hydrochloride may be isolated by known methods such as filtration, centrifugation and the like.

As used herein the term "treating" refers to contacting, suspending or slurrying lurasidone or its acid addition salt with a suitable solvent as described above.

In one embodiment, the present invention provides lurasidone hydrochloride having less than about 0.2% of (I S, 2S) isomer of lurasidone hydrochloride, having less than about 0.15% of (I S, 2S) isomer of lurasidone hydrochloride, having less than about 0.1% of (I S, 2S) isomer of lurasidone hydrochloride as measured by HPLC. Preferably, (I S, 2S) isomer of lurasidone hydrochloride is not detected in lurasidone hydrochloride.

In one embodiment, the present invention provides lurasidone hydrochloride having chemical purity not less than about 99.5% and chiral purity of about 100% as measured by HPLC. The HPLC method is as described below.

HPLC method: High performance liquid chromatography (HPLC) was performed with the conditions described below for detecting chiral purity:

Column: chiracel OD-H, 250X4.6mm, Column Temperature: 30°C, Mobile phase: n- hexane;ethanol (94:06,v/v), Diluent: Ethano Methanol (80:20,v/v), Flow rate: l .OmL/min, Detection: UV 210nm; Injection Volume: Ι Ομί, run time: 45 min

HPLC method : High performance liquid chromatography (HPLC) was performed with the conditions described below for detecting chemical purity:

Column: Zorbax SB C8, 250X4.6mm, 5μ; Column Temperature: 30°C, Mobile phase: Mobile Phase A = Buffer; Buffer: 1ml of o-phosphoric acid in water. Mobile Phase B = Methanol.

Diluent: Water; Flow Rate: 0.8mL/minute; Detection: UV 210nm; Injection Volume: 20μί. In one embodiment, the present invention provides a process for preparing crystalline lurasidone hydrochloride wherein the obtained lurasidone hydrochloride is characterized by X-ray Diffraction (XRD) spectrum having peak reflections at about 1 1.5, 13.9, 17. i, 19.6 and 22.0 ±0.2 degrees 2 theta.

In one embodiment, the present invention provides crystalline lurasidone hydrochloride, characterized by an X-ray Diffraction (XRD) spectrum having peak reflections at about 1 1.5, 13.9, 17.1, 19.6 and 22.0.±0.2 degrees 2 theta., which is substantially in accordance with Fig. 1, XRD measurement was performed on ARL X-ray diffractometer model XPERT-PRO (PANalytical) scanning parameters start position [°2Th.] 2.01 and end position [°2Th.] 49.98. In one embodiment, the present invention provides a process for preparing crystalline lurasidone hydrochloride comprising treating lurasidone, a compound of formula I, in C1 -C5 alcohol with aqueous hydrochloric acid wherein crystalline lurasidone hydrochloride is characterized by X-ray Diffraction (XRD) spectrum having peak reflections at about 1 1.5, 13.9, 17.1 , 19.6 and 22.0.±0.2 degrees 2 theta.

Instrumental settings for XRPD

The measurements were performed on Philips X-Ray Diffractometer model XPERT-PRO (PANalytical) Detector: X'celerator [1 ] using Cu lamp with type and wavelength of the X- ray radiation: K-Alphal [A] and 1.54060 under the following conditions: Generator settings: 40mA/45kV, Time per step: 50, Step size: 0.0167, Peak width 2.00 and start angle (°) 2.0 and End angle: 50.0. The XRPD instrument is calibrated using NIST SRM 6-40C silicon standard and NIST SRM 1976 Alumina.

Sample preparation: Take an adequate amount of the sample to fill the sample holder using back-loading technique. Then load the sample holder between the X-ray optics-path and scan using the above described parameters. Integrate the obtained powder X-ray diffraction profiles with the instrument's software.

In one embodiment, the present invention provides crystalline lurasidone hydrochloride, wherein the obtained lurasidone hydrochloride ischaracterized by Differential Scanning Calorimetric (DSC) thermogram having an endothermic curve at about 266.90°C with an onset at about 256.12°C and endset at about 274.02°C and a second peak at about 31 1.63 with an onset at about 298.1 1°C and endset at about 321.65°C.

In one embodiment, the present invention provides crystalline lurasidone hydrochloride characterized by Differential Scanning Calorimetric (DSC) thermogram having an endothermic curve at about 266.90°C with an onset at about 256.12°C and endset at about 274.02°C and a second peak at about 31 1.63 with an onset at about 298.1 1 °C and endset at about 321.65 °C, which is substantially in accordance with Fig. 2. The DSC thermogram is measured by a Differential Scanning Calorimeter (DSC 822, ,Mettler Toledo) at a scan rate of 10°C per minute. The DSC module was calibrated with Indium and zinc standard.

In one embodiment, the present invention provides a process for preparing crystalline lurasidone hydrochloride comprising contacting lurasidone, a compound of formula I, in Cl- C5 alcohol with aqueous hydrochloric acid at a temperature below 50°C, wherein crystalline lurasidone hydrochloride is characterized by Differential Scanning Calorimetric (DSC) thermogram having an endothermic curve at about 266.90°C with an onset at about 256.12°C and endset at about 274.02°C and a second peak at about 31 1 .63 with an onset at about 298.1 1 °C and endset at about 321.65 °C.

The present invention provides crystalline lurasidone hydrochloride further characterized by Thermogravimetric Analysis (TGA) thermogram, showing a weight loss of about 0.1924% up to 100°C determined over the temperature range of 30°C to 250°C and heating rate 10°C/min, which is substantially in accordance with Fig. 3.

In one embodiment, the present invention provides a process for the preparation of crystalline lurasidone hydrochloride comprising contacting lurasidone, a compound of formula I, in C1-C5 alcohol with aqueous hydrochloric acid at a temperature below 50°C, wherein crystalline lurasidone hydrochloride is characterized by thermogravimetric analysis (TGA) thermogram, showing a weight loss of about 0.1924% up to 100°C determined over the temperature range of 30°C to 250°C and heating rate 10°C/min, which is substantially in accordance with Fig. 3.

The specific surface area of an active pharmaceutical ingredient may be affected by various factors. It is recognized that there is an inverse relationship between surface area and particle size; where the smaller the particle size, the higher the surface area. Whereupon, the available surface area for drug dissolution correlates to the ratej3f dissolution and solubility. A greater surface area enhances both the solubility and the rate of dissolution of a drug, which in turn, may improve its bioavailability and potentially its toxicity profiles.

Thus, there is a need in the art to prepare active pharmaceutical ingredients, such as lurasidone or its hydrochloride salt, with a high surface area to obtain formulations with greater bioavailability, and to compensate for any loss of surface area before formulation. Specific surface area is defined in units of square meters per gram (m²/g).It is usually measured by nitrogen absorption analysis. In this analysis, nitrogen is absorbed on the surface of the substance. The amount of the absorbed nitrogen (as measured during the absorption or the subsequent desorption process) is related to the surface area via a formula known as the BET formula.

In one embodiment, the present invention provides crystalline lurasidone hydrochloride, wherein the obtained lurasidone hydrochloride is having a specific surface area from 0.5 m²/g to about 3 m /g, as measured by Brunauer-Emmett-Teller (BET) method. Preferably, the surface area is 0.96 m /g.

In one embodiment, the present invention provides a process for the preparation of crystalline lurasidone hydrochloride comprising contacting lurasidone, a compound of formula I, in C1 -C5 alcohol with aqueous hydrochloric acid at a temperature below 50°C, wherein crystalline lurasidone hydrochloride is having a specific surface area from 0.5 m²/g to about 3 m²/g, as measured by Brunauer-Emmett-Teller (BET) method. Preferably, the surface area is 0.96 m²/g.

In one embodiment, the present invention provides crystalline particles of lurasidone hydrochloride wherein atleast 90% of the particles have a particle size of less than about 70 microns.

The particle size distribution of lurasidone hydrochloride was determined by laser diffraction on Malvern Mastersizer 2000.

In another embodiment, the present invention provides the preparation of a compound of formula II, the process comprising reacting 3-(piperazin- l -yl)-l ,2-benzothiazole, a compound of formula IV with trans (1R, 2R)-cyclohexane-l ,2-diyl dimethanediyl dimethanesulfonate, a compound of formula V, in the presence of a suitable base in a suitable solvent.

A suitable base may be selected from organic or inorganic base. The inorganic base may be selected from the group consisting of hydroxides such as sodium hydroxide, potassium hydroxide, calcium hydroxide; alkoxides such as sodium methoxide, potassium methoxide, sodium tert-butoxide, potassium tert-butoxide; carbonates such as sodium carbonate, potassium carbonate; bicarbonates such as sodium bicarbonate, potassium bicarbonate and the like. The organic base may be selected from triethyl amine, trimethyl amine, diisopropyl ethylamine, dimethyl amino pyridine, picoline, dimethyl amino pyridine and pyridine. Preferably the reaction is carried out in the presence of sodium carbonate.

A suitable solvent may be selected from, but is not limited to alcohols such as methanol, ethanol, tert-butanol, n-propanol, 2-propanol; nitriles such as acetonitrile; esters such as ethyl acetate, isopropyl acetate; ketones such as methyl ethyl ketone, acetone; ethers such as, methyl tert-butyl ether, diethyl ether, diisopropyl ether; halogenated solvents such as ethylene dichloride, methylene dichloride, chloroform, carbon tetrachloride; hydrocarbon solvents such as, cyclohexane. toluene, benzene, hexane; water or mixtures thereof. Preferably the reaction is carried out in acetonitrile.

The reaction transpires at a temperature of about 0°C to about reflux temperature of the solvent. Preferably the reaction transpires at about reflux temperature of the solvent.

In one embodiment, the present invention provides a preparation for the preparation of compound of formula II, the process comprising reacting a compound of formula IV with a compound of formula V in the presence of sodium carbonate in acetonitrile and heating the reaction mixture to about reflux temperature and stirring for a period of about 30 minutes to 12 hrs. Preferably, the reaction mass is heated to about reflux temperature for a period of about 7 - 8 hrs.

In one embodiment, compound of formula II is purified by treating with a suitable solvent. A suitable solvent may be selected from water, alcohols such as methanol, ethanol, propanol, -2-propanol, tert-butanol, n-butanol; esters such as ethyl acetate, propyl acetate, butyl acetate, isopropyl acetate; chlorinated hydrocarbon solvents such as methylene dichloride, ethylene dichloride, chloroform, carbon tetrachloride; hydrocarbon solvent such as cyclohexane, toluene, xylene; ethers such as diethyl ether, di-isopropyl ether; ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone or mixtures thereof. In one embodiment, the present invention provides crystalline (3aR, 7aR)-4'-(benzo[d] isothiazol-3-yl octahydrospiro isoindole-2, 1 '-piperazinj-l '-ium methanesulfonate, a compound of formula II , obtained by purifying in a solvent selected from ketones such as acetone , methyl ethyl ketone. Preferably, compound of formula II is purified in acetone. In one embodiment, compound of formula II is suspended in acetone and the reaction mass is heated to a temperature of about 55-60°C. The compound of formula II is isolated by known methods in the art such as filtration, centrifugati^'on and the like.

In one embodiment, the present invention provides crystalline (3aR, 7aR)-4'-(benzo[d] isothiazol-3-yl octahydrospiro isoindole-2, -piperazinJ-l '-ium methanesulfonate, a compound of formula II characterized by X-ray diffraction (XRD) spectrum having peak reflections at about 8.0, 13.3, 15.5, 21.3, 29.6and 33.1 ±0,2 degrees 2 theta.

In one embodiment, the present invention provides crystalline (3aR, 7aR)-4'-(benzo[d] isothiazol-3-yl octahydrospiro . isoindole-2, r-piperazinj-l '-ium methanesulfonate, a compound of formula II characterized by differential scanning calorimetric (DSC thermogram) having three endothermic peaks at 105°C, 126°C and 225°C and one exothermic peak at about 326°C.

In one embodiment, the present invention provides, crystalline (3aR, 7aR)-4'-(benzo[d] isothiazol-3-yl octahydrospiro isoindole-2, l '-piperazin]-l '-ium methanesulfonate, a compound of formula II characterized by X-ray diffraction (XRD) spectrum, which is substantially in accordance with fig 4.

In one embodiment, the present invention provides crystalline (3aR, 7aR)-4'-(benzo[d] isothiazol-3-yl octahydrospiro isoindole-2, l '-piperazinj- -ium methanesulfonate, a compound of formula II characterized by differential scanning calorimetric (DSC thermogram) which is substantially in accordance with fig 5.

In one embodiment, the present invention provides use of crystalline (3aR, 7aR)-4'- (benzo[d] isothiazol-3-yl octahydrospiro isoindole-2, l '-piperazin]-l '-ium methanesulfonate, a compound of formula II characterized by X-ray diffraction (XRD) spectrum having peak reflections at about 8.0, 13.3, 15.5, 21.3, 29.6and 33.1 ±0.2 degrees 2 theta in the preparation of lurasidone hydrochloride. W

In one other embodiment, the present invention provides a process for the preparation of the compound of formula V using 1 ,2-cyclohexane dicarboxylate anhydride by a process as depicted schematically:

In still another embodiment, the present invention provides a process for the preparation of the compound of formula V using 2,5-dihydrothiophene by a process as depicted schematically:

{IR2R} t¾rs (Sslcoho!

In one embodiment, the present invention provides a process for the preparation of the compound of formula V comprising reducing the (1R, 2R) trans diacid directly to (1 R, 2R) trans dialcohol by using a suitable reducing agents.

In one embodiment, the present invention provides a process for the preparation of the compound of formula V the process comprising epimerization of a mixture of cis and trans diacid to obtain trans diacid.

In one embodiment, the present invention provides a process for the preparation of the compound of formula V, the process comprising using of (1 R, 2R) trans diacid obtained by racemisation of the (I S, 2 S) trans diacid followed by resolution to obtain (1R, 2 R) trans diacid.

In one embodiment, the present invention provides the preparation of a compound of formula IV, the process comprising a schematic diagram depicted as below:

In one embodiment, the present invention provides the preparation of a compound of formula III, the process comprising a schematic diagram as depicted below, the process comprising using maleic anhydride to arrive at a compound of formula III:

In one embodiment, the present invention provides the preparation of a compound of formula III, the process comprising a schematic diagram as depicted below, the process comprising using maleimide to arrive at a compound of formula III:

The following examples are provided to enable one skilled in the art to practice the invention and are merely illustrative of the invention. The examples should not be read as limiting the scope of the invention.

Examples:

Example-1:

Preparation of (3aR, TaRM'-fbenzofdl isothiazol-3-yl octahvdrospiroisoindole-2, 1 piperazinl-1 '-ium methanesulfonate

In a clean round bottom flask, lOgms of 3-(piperazinyl-l -yl)-l ,2-benzisothiazole,14gm of (lR,2R)-cyclohexane-l ,2-diylmethanediyl dimethanesulphonate,7.3gm of sodium carbonate and 50ml of acetonitrile were charged. The reaction mass was reflux ed for about 8-15hrs. The solvent distilled out under vacuum and acetone (80ml) was added. The reaction mass was heated and stirred at about reflux. The reaction mass was cooled to about 25-30°C. The reaction mass was filtered and washed with acetone to yield 17.0gms of titled product. HPLC purity:99.67%

Example-2:

Preparation of (3aR,4S,7R,7aS -2-K(lR,2R)-2-(r4-(l,2-benzisothiazol-3-yl)-piperazin-l- vnmethyl)cvclohexyl)methvnhexahvdro-lH-4,7-methanisoindoI-l,3-dione.

In a clean round bottom flask, lOgms of (3aR, 7aR)-4'-(benzo[d] isothiazol-3-yl octahydrospiroisoindole-2, l '-piperazinj-l '-ium methanesulfonate, 4.1 gm 1 R*2S*6R*7S*4- Azatricylodecane-3,5-dione,6.3gm potassium carbonate and 50ml of toluene were charged and refluxed for 8-12hrs. The reaction mass was cooled to about 25-30°C, then added 30ml water and separated the layers. The solvent was distilled out under vacuum and added 80ml methanol. The reaction mass was heated to about reflux and stirred at reflux for about 2hrs and then cooled to about 25-30°C. The reaction -mass was stirred at about 25-30°C for 2hrs and filtered, washed with methanol. Dry wt: 9.0gms. I S, 2S isomer: 0.27%. . HPLC purity: 99.58%, Chiral purity:99.73%

Example-3:

Purification of Lurasidone :

In a clean round bottom flask, l Ogms of crude Lurasidone base and 50ml of acetone were charged. The reaction mass was heated to reflux and maintained for 2hrs. The reaction mass was cooled to 0-5°C and maintained for l hr. This reaction mass was then filtered and the solid and washed with acetone. Dry wt: 9.0gms. HPLC purity: 99.79%, Chiral isomer (I S, 2S): 0.06% , HPLC purity: 99.74%, Chiral Purity: 99.94%

Example 4: Preparation of Lurasidone hydrochloride in IPA and IPA.HCl

In a clean round bottom flask, 5 gms of (3ai?,45,7i?,7aS)-2-[((l ?,2 ?)-2-{[4-(l ,2- benzisothiazol-3 -yl)-piperazin- 1 -yl] methyl } cyclohexyl)methyl] hexahydro-1 H-4,7- methanisoindol-l,3-dione and 25ml of IPA were charged. 2.5ml of IPA.HCl (about 30%) was added at about 25-30°C to a pH between about 2.0 to 4.0. The reaction mass was maintained at about 25-30°C for 2 hrs. The reaction mass was filtered and washed with 5ml IPA. Dry wt: 4.9gms.

Example-5:

Preparation of Lurasidone hydrochloride in Acetone and IPA. HC1

In a clean round bottom flask, 40gms of (3ai?,45,77?,7aS)-2-[((l^,2i?)-2-{[4-(l ,2- benzisothiazol-3-yl)-piperazin-l-yl]methyl}cyclohexyl)methyl]hexahydro-lH-4,7- methanisoindol-l,3-dione and 800ml of Acetone were charged. The reaction mass was heated to about reflux till clear solution; then cooled to about 45-50°C and added 10ml IPA.HCl (about 30%) dropwise at 45-50°C. The reaction mass was maintained at 45-50°G for lhr and at room temperature for l hr. The reaction mass was filtered and washed with 40ml Acetone. Dry wt: 41 gms.

Example-6:

Preparation of Lurasidone hydrochloride in methanol and Aq. HC1

In a clean round bottom flask, 2gms of (Sa/^A^/i a^^-^l^^/ ^-l^l ^- benzisothiazol-3-yl)-piperazin-l -yl]methyl}cyclohexyl)methyl]hexahydro-l /-4,7- methanisoindol-l ,3-dione and 30ml of methanol were charged. Added 0.6ml Conc.HCl at about 25-30°C. The reaction mass was heated to about 60-65°C and maintained for about lhr;then cooled to about 25-30°C and maintained for an hour.The reaction mass was filtered and washed with 2ml methanol. Dry wt: l .Ogm.

Example~7:

Preparation of Lurasidone hydrochloride in water and Aq. HCl

In a clean round bottom flask, /2gms of (3a7?,4S,7/?,7aS)-2-[((l/?,27?)-2-{[4-(l ,2- benzisothiazol-3-yl)-piperazin-l-yl]methyl}cyclohexyl)methyl]hexahydro-lH-4,7- methanisoindol-l ,3-dione and 20ml of water were charged. Added 0.5ml Conc.HCl dropwise at room temperature. The reaction mass was heated to about 60-65°C and maintained for about 3hrs. The reaction mass was cooled to room temp and maintained for an hr.The reaction mass was filtered and washed with water. Dry wt: 2.0gms.

Example-8:

Preparation of Lurasidone hydrochloride in Acetone and IPA. HC1

In a clean round bottom flask, 5gms of (3ai?,45,7 ?,7aS)-2-[((l/?,2i?)-2-{ [4-(l ,2- benzisothiazol-3-yl)-piperazin-l-yl]methyl)cyclohexyl)methyl]hexahydro-lH-4,7- methanisoindol-l ,3-dione and 100ml of acetone were charged. The reaction mass was heated to about reflux to obtain a clear solution. The reaction mass was cooled to about 25-30°C and added 2.0ml IPA.HC1 (about 30%) dropwise at about 25-30°C (pH between about 2 and 4). The reaction mass was maintained at about 25-30°C for about 2hrs. The reaction mass filtered and washed with acetone. Dry wt: 5.15gms.

Examp^'le-9:

Preparation of Lurasidone hydrochloride in IPA and Aq. HC1

In a clean round bottom flask, 5gms of (3aR,4S,7R,7aS)-2-[((\R,2R)-2-{[4-(\ ,2- benzisothiazol-3-yl)-piperazin- 1 -yl]methyl } cyclohexyl)methyl]hexahydro- 1 H-4,7- methanisoindol-l ,3-dione and 25ml of IPA were charged. Added 2.0ml Conc.HCl dropwise at about 25-30°C (pH between about 2 and 4). The reaction mass heated to about 60-65°C and maintained for an hour; then cooled to about 25-30°C and maintained for about an hour. The reaction mass filtered and washed with IPA. Dry wt: 5.30gms. 1 S, 2S isomer: 0.06% · HPLC Purity: 99.89%, (1 S, 2S) isomer: 0.09%

Example-10:

Purification of Lurasidone hydrochloride in IPA

In a clean round bottom flask, 5gms of crude Lurasidone hydrochloride and 25ml of IPA were charged. The reaction mass was heated to about reflux and maintained for about 2hrs. The reaction mass was cooled to about 0-5 °C and maintained for an hour. The reaction mass was filtered to obtain lurasidone hydrochloride. Dry wt: 4.70gms. I S, 2S isomer: Not detected, chiral purity: 100%, chemical purity: 99.99%, D₉₀: 48.84 um, D₅₀: 23.0045, D,₀: 6.544; bulk density: 0.6g/ml,

XRD of lurasidone hydrochloride:

xample- :

Preparation of Lurasidone hydrochloride in MEK and Aq. HC1

In a clean round bottom flask, 3gms of (3ai?,4S,7i?,7aS')-2-[((l/?,2^)-2-{[4-(l ,2- benzisothiazol-3-yl)-piperazin-l-yl]methyl}cyclohexyl)methyl]hexahydro-lH-4,7- methanisoindol-l,3-dione and 18ml of MEK were charged. The reaction mass was heated to^* about reflux until a clear solution was obtained. Then it was cooled to about 45-50°C and added 1.0ml Cone. HC1 dropwise at about 45-50°C to a pH between about 2 and 4.Heated the reaction mass to reflux and maintained reflux for about 30min. The reaction mass maintained at about 45-50°C for abut 30min and at about 25-30°C for about an hour.The reaction mass was filtered and washed with MEK. Dry wt: 2.90gms.

Example-12:

Preparation of Lurasidone hydrochloride in Methanol and IP A. HO

In a clean round bottom flask, 2gms of (3a ?,45',7 ?,7aS)-2-[((l^,2i?)-2-{[4-(l ,2- benzisothiazol-3 -yl)-piperazin- 1 -yl]methyl } cyclohexyl)methyl]hexahydro- 1 H-4,7 - methanisoindol-l ,3-dione and 10ml of methanol were charged. The reaction mass was heated to about 50-55°C and 0.6ml IPA. HCl (about 30%) was added dropwise at about 50-55°C and maintained at about 55-60°C for about an hour. Then it was cooled to about 25-30°C and maintained at about 25-30°C for about an hour. The reaction mass was filtered and washed with MEK. Dry wt: 1.66gms.

Example-13:

Preparation of Lurasidone hydrochloride in MDC and IPA. HCl

In a clean round bottom flask, 5gms of (3aR,4S R,7aS)-2-[((lR,2R)-2-{[4-(\ ,2- benzisothiazol-3 -yl)-piperazin- 1 -yl]methy 1 } cyclohexyl)m^'ethy ljhexahydro- 1 H-4 ,7- methanisoindol-l ,3-dione and 25ml of MDC were charged. Then 2.0ml IPA. HCl (about 30%) was added dropwise at about 25-30°C (pH between about 2 and 4). The reaction mass heated to about reflux and maintained reflux for about 30min. Then it was cooled to about 25-30°C and maintained for an hour. The reaction mass filtered and washed with 5ml MDC. Dry wt: 2.10gms.

Example-14:

Preparation of Lurasidone hydrochloride in IPA and Aq.Hcl

In a clean round bottom flask, 7gms of (3aR,4S,7R,7aS)-2-[((lR,2R)-2-{[4-( l ,2- benzisothiazol-3 -yl)-piperazin- 1 -yljmethyl } cyclohexyl)methyl]hexahydro- 1 H-4,7- mefhanisoindol-l ,3-dione and 35ml of IPA were charged. The reaction mass was^' heated to reflux and maintained for about 30min. The reaction mass was cooled to about 25-30°C and to this 3.0ml 1 : 1 Aq. HCl dropwise was added at about 25-30°C (pH between about 2 and 4). The reaction mass was then heated to about 40-45°C and maintained for about 30min. The reaction mass was then cooled to about 25-30°C and maintained for about 2hrs. The reaction mass was filtered and washed with IPA.

Dry wt: 6.70gms.HPLC Purity: 99.94%, (I S, 2S) isomer: 0.22%

Example 15 Preparation of (3aR, 7aR)-4'-(benzo[dl isothiazol-3-yl octahydrospiroisoindole-2, 1 '-piperazinl-l Mum methanesulfonate

In a clean round bottom flask, 4.4gms of 3-(piperazinyl-l -yl)-l ,2-benzisothiazole, 6.16gm of (lR,2R)-cyclohexane-l ,2-diylmethanediyl dimethanesulphonate^^ l gm of Sodium carbonate and 22ml of acetonitrile were charged. The reaction mass was refluxed for about 8- 15hrs. The solvent distilled out under vacuum and methanol (10ml) was added. The reaction mass was heated and stirred for 15-20 min. The reaction mass was cooled, filtered and distilled the filtrate. Acetone (9ml) was added to the residue and the slurry obtained was maintained for about 90-120 min at about 55-60 °C. The reaction mass was cooled to about 25-30°C and filtered to yield7.48 gms of titled product. HPLC purity: 99.74%s

XRD of (3aR, 7aR)-4'-(benzo[d] isothiazol-3-yl octahydrospiroisoindole-2, l '-piperazin]-l '- ium methanesulfonate:

Example 16 Preparation of (3aR,4S RJaSV2-IYaR,2R)-2-(i4-a,2-te^

piperazin-l-yllmethv cvclohexyI)methyl]h^

In a clean round bottom flask, 6.9gms of (3aR, 7aR)-4'-(benzo[d] isothiazol-3-yl octahydrospiroisoindole-2, l '-piperazin]-l '-ium methanesulfonate, 2.83gm lR*2S*6R*7S*4-Azatricylodecane-3,5-dione, 4.49gm potassium carbonate and 70ml of toluene were charged and refluxed for 10-20hrs. The reaction mass was cooled to about 25- 30°C, then added 28ml water and separated the layers. Toluene was distilled out under vacuum. To the residue 13.8ml methanol was added and stirred and distilled the solvent. To the residue 55,2ml methanol was added. The reaction mass was heated to about 60-65 °C for about 1-5 hours. The reaction mass was cooled and filtered.

Crude lurasidone (lgm) in acetone (5ml) was heated to about 55-60°C for about 1-4 hours, cooled to about 25-30°C and filtered. Dry wt: 0.90 gms. 1 S, 2S isomer: 0.2%

Example 17 Preparation of (3aR,4S,7R,7aS)-2-f((lR,2R)-2-{f4-(l,2-benzisothiazol-3-yl)- piperazin-l-yllmethyl|cvclohexyl)methyllhexahvdro-lH-4,7-methanisoindol-l,3-dione. In a clean round bottom flask methylene chloride (25ml) was charged and lurasidone (5ml) was dissolved. This solution was filtered through hyflo and filtrate was distilled. To the residue isopropyl alcohol (10ml) was added and the temperature was raised to50 °C. The solvent was distilled off and isopropyl alcohol (25ml) was added. The reaction mass was heated to 78-82°C for a period of about 30 min. The reaction mass was cooled to about 25- 30°C and aq hydrochloric acid (17.5 %) was added to the reaction mass. The reaction mass was heated to 45-50°C and stirred for 30 min. The reaction mass was stirred for about 1 -5 hours at about 25-30°C and precipitated solid was filtered. The wet cake was slurried in isopropyl alcohol. The temperature of reaction mass was raised to 78-82°C for a period of aboutl-2hr. The reaction mass was cooled to 0-5°C and stirred for about 30 min to about 3 hours. The product was filtered and dried.

Methanol (15ml) was added to lurasidone hydrochloride 6.0 gm and stirred for about 1-3 hr at about 25-30 °C. The reaction mass was cooled to about 0-5 °C and stirred for an hour. The product was filtered and dried to obtain 4.75 gm of lurasidone hydrochloride. HPLC purity: 99.95% chiral purity:99.99% D₉₀: 48.84 μπι, D₅₀: 23.0045, D,₀: 6,544; bulk density: 0.6g/ml.

Claims

Claims:

1] A process for the preparation of lurasidone, a compound of formula I, or a pharmaceutically acceptable salt

I

a) reacting (3aR, 7aR)-4'-(benzo[d] isothiazol-3-yl octahydrospiroisoindole-2, 1 '-piperazin]- -ium methanesulfonate, a compound of formula II, with (l R,2S,6R,7S)-4-azatricylodecane- 3,5-dione, a compound of formula III, to obtain lurasidone, a compound of formula I, wherein the reaction is carried out in absence of water and in absence of a phase transfer catalyst; and

II III

2] The process as claimed in step a), wherein the reaction is carried out in presence of a base.

3] The process as claimed in step a), wherein the molar ratio of (3aR, 7aR)-4'-(benzo[d] isothiazol-3-yl octahydrospiro isoindole-2, r-piperazin]-l '-ium methanesulfonate, compound of formula II to the base ranges from about 1 : 1.8 to about 1 :3.5.

4] The process as claimed in step b) of claim 1 , wherein lurasidone is converted to hydrochloride salt of lurasidone. 5] The process as claimed in claim 1 , wherein the process for preparation of lurasidone hydrochloride comprises contacting lurasidone in C1-C5 alcohol with aqueous hydrochloric acid at a temperature below 50°C.

6] A process for the preparation of crystalline lurasidone hydrochloride comprising contacting lurasidone, compound of formula I, in C1-C5 alcohol with aqueous hydrochloric acid at a temperature below 50°C.

7] The process as claimed in claim 6, wherein the crystalline lurasidone hydrochloride is purified in an alcoholic solvent.

8] The process as claimed in claim 7, wherein crystalline lurasidone hydrochloride obtained is characterized by X-ray powder diffraction having peak reflections at about 1 1.5, 13.9, 17.1 , 19.6 and 22.0.±0.2 degrees 2 theta.

9] The process as claimed in claim 7, wherein the crystalline lurasidone hydrochloride is characterized by DSC having endothermic peak at about 266.90 °C and a second peak at about 31 1.63 °C.

10] The process as claimed in claim 7, wherein the crystalline lurasidone hydrochloride has specific surface area from about 0.5 m²/g to about 3m²/g, as measured by Brunauer-Emmett- Teller (BET) method.

1 1] Crystalline (3aR, 7aR)-4'-(benzo[d] isothiazol-3-yl octahydiOspiroisoindole-2, - piperazin]-l '-ium methanesulfonate, a compound of formula II characterized by X-ray diffraction (XRD) spectrum having peak reflections at about 8.0, 13.3, 1 .5, 21.3, 29.6 and 33.1 ±0.2 degrees 2 theta.

12] The compound of formula II, as claimed in claim 1 1 obtained by purifying in a solvent selected from ketones such as acetone, methyl ethyl ketone.

13] Use of compound of formula II as claimed in cl 1 1 in the preparation of lurasidone hydrochloride.