WO2013190455A2

WO2013190455A2 - Process for the preparation of lurasidone hydrochloride

Info

Publication number: WO2013190455A2
Application number: PCT/IB2013/054975
Authority: WO
Inventors: V. Vijayabaskar; S. Srimurugan; R.V. Sathish KUMAR; Munusamy Jayamani
Original assignee: Shasun Pharmaceuticals Ltd
Current assignee: Shasun Pharmaceuticals Ltd
Priority date: 2012-06-18
Filing date: 2013-06-18
Publication date: 2013-12-27
Anticipated expiration: 2014-12-18
Also published as: WO2013190455A3

Description

PROCESS FOR THE PREPARATION OF LURASIDONE HYDROCHLORIDE

TECHNICAL FIELD The present invention relates to an improved process for the preparation of Lurasidone Hydrochloride, and its intermediates in substantially pure form.

BACKGROUND OF THE INVENTION Lurasidone is an atypical antipsychotic developed by Dainippon Sumitomo Pharma for the treatment of Schizophrenia and bipolar disorders.

Lurasidone HCI is chemically known as (3aR,4S,7R,7aS)-2-[((1 R,2R)-2-{[4-(1 ,2- benzisothiazol-3-yl)-piperazin-1 -yl]methyl}cyclohexyl)methyl]hexahydro-1 H-4,7- methanisoindol-1 ,3-dione hydrochloride and is represented by the structure:

Lurasidone and the processes for its preparation are disclosed in US 5532372 and the below found schematic process postulates it:

Formula I

Na₂C0₃

Acetonitrile

Formula II

Formula III

The reaction conditions as disclosed in various disclosures for preparing Lurasidone and its intermediates may result in the generation of increased level of process related impurities. These impurities may be, for example, starting materials, by-products of the reaction and these impurities are generated by incomplete reactions, longer reaction times, and contamination of Lurasidone with a number of impurities or starting material/intermediates which makes the process difficult to isolate Lurasidone free base in its solid form. The structures of the three principal impurities formed in the '372 process are shown in Table 1 : Table 1

US20110183993 discloses the novel cycloalkane derivatives and an acid addition salt thereof which are useful as a psychotropic drug. Even though, this prior art discloses all the possible derivatives of Lurasidone, it is silent on the methods to control the impurities in the process. A further disadvantage of this prior art method is contamination by large amounts of various impurities originating from the key starting materials as well as process impurities and these impurities in turn are carried forward in subsequent reaction steps and results in Lurasidone of low purity. Those skilled in pharmaceutical arts understand that purification of an intermediate or final compound through crystallization offers best method for attaining important qualities like chemical quality, particle size, and polymorphic purity. With advent of worldwide pharmaceutical regulation, and increased emphasis on drug product quality, it is very important for pharmaceutical companies to produce drug substance having higher purity and lower impurity profile.

Therefore, there is an ongoing need for improved processes for the preparation of Lurasidone with high purity and yield, which processes are cost-effective, and well suited for an industrial scale.

SUMMARY OF THE INVENTION: The present invention relates to Lurasidone and processes for preparing Lurasidone, including process-related intermediates. The present invention also related to processes for preparing substantially pure Lurasidone and its intermediates thereof.

The present invention relates to the process to establish suitable purification methods to remove the by-product from Lurasidone intermediates at various stages, to overcome the incomplete reactions during preparation of the intermediate compounds in the process for the manufacture of Lurasidone hydrochloride.

In a further aspect, the present invention provides process for purifying the intermediate compound of formula I,

Formula I by treating the crude compound of formula I in an organic solvent.

In a further aspect, the present invention provides process for purifying the intermediate compound of formula II, by treating the compound of formula I in an organic solvent.

Formula II

In a further aspect, the present invention provides process for purifying the intermediate compound of formula III, by treating the compound of formula III in an organic solvent.

In final process step, the present invention provide the process for salification of compound as hydrochloride of Formula IV by treating with acid dissolved in suitable solvent to give the corresponding salt.

Formula IV Detailed description of the invention:

The invention will now be described in detail in connection with certain preferred and optional embodiments, so that various aspects thereof may be more fully understood and appreciated.

Aspects of the present invention provides process for purifying the intermediate compound of formula I,

Formula I by treating the crude compound of formula I in an organic solvent.

The aforesaid process involves providing a solution of the crude compound of formula I in an organic solvent. The organic solvents which may be used for providing a solution of the compound of formula I include, but are not limited to: Alcohols such as for example methanol, ethanol, isopropyl alcohol and the like; ethers such as for example diethyl ether, di-isopropyl ether, methyl tert-butyl ether, and the like; and any combinations thereof.

More preferably, the organic solvent may comprise Isopropyl alcohol, di-isopropyl ether, and methyl tert-butyl ether.

It is preferably carried out at temperature ranging from 0°C to reflux conditions. More preferably, the temperatures can be ranging from about 25-85°C or the solution may need to be heated to elevated temperatures depending on the quantity and nature of solvent used. The isolated solid may be further dried by using conventional techniques. The drying may be carried out at temperatures of about 35-45°C, optionally under reduced pressure. The drying may be carried out for any time periods necessary for obtaining a desired purity, such as about 1 to about 10 hours, or longer.

Aspects of the present invention provide process for purifying the intermediate compound of formula II, by providing a solution of the crude compound of formula II in an organic solvent.

The aforesaid process involves providing a solution of the compound of formula II in an organic solvent. The organic solvents which may be used for providing a solution of the compound of formula II include, but are not limited to: a nitrile solvent, such as acetonitrile, propionitrile, and the like; esters such as for example ethyl acetate, butyl acetate, isopropyl acetate and the like; and any mixtures thereof.

More preferably, the organic solvent may comprise acetonitrile, ethyl acetate and the mixtures thereof.

It is preferably carried out at temperature ranging from 0°C to reflux conditions. More preferably, the temperatures can be ranging from about 25-85°C or the solution may need to be heated to elevated temperatures depending on the quantity and nature of solvent used.

The isolated solid may be further dried by using conventional techniques. The drying may be carried out at temperatures of about 35-50°C, optionally under reduced pressure. The drying may be carried out for any time periods necessary for obtaining a desired purity, such as about 1 to about 10 hours, or longer.

After purification, the compound of formula II typically has purity greater than or equal to about 99.75%, and contains less than about 0.2% of the impurities as determined using high performance liquid chromatography (HPLC).

Aspects of the present invention provide process for purifying the intermediate compound of formula III, by providing a solution of the crude compound in an organic solvent.

Formula III

The aforesaid process involves providing a solution of the compound of formula III in an organic solvent. The organic solvents which may be used for providing a solution of the crude compound of formula III include, but are not limited to: a nitrile solvent, such as acetonitrile, propionitrile, and the like; esters such as for example ethyl acetate, butyl acetate, isopropyl acetate and the like; ethers such as for example diethyl ether, di- isopropyl ether, methyl tert-butyl ether, and the like; Alcohols such as for example methanol, isopropyl alcohol and the like; The ketone solvents that may be used in the process of step (a) include, but are not limited to, acetone, methyl isobutyl ketone, ethyl methyl ketone, and the like; and any combination with water thereof.

More preferably, the organic solvent may comprise acetonitrile, ethyl acetate, methyl tert-butyl ether, isopropyl alcohol, acetone, methanol and the mixtures thereof. Water may be optionally employed with the aforesaid solvent or solvent mixtures thereof. It is preferably carried out at temperature ranging from 0°C to reflux conditions. More preferably, the temperatures can be ranging from about 25-85°C or the solution may need to be heated to elevated temperatures depending on the quantity and nature of solvent used. The isolated solid may be further dried by using conventional techniques. The drying may be carried out at temperatures of about 35-50°C, optionally under reduced pressure. The drying may be carried out for any time periods necessary for obtaining a desired purity, such as about 1 to about 10 hours, or longer. After purification, the compound of formula III typically has purity greater than or equal to about 99.8%, and contains less than about 0.2% of the impurities as determined using high performance liquid chromatography (HPLC).

Aspects of the present invention provide the process for salification of compound as hydrochloride of Formula IV by treating with hydrochloric acid dissolved in suitable solvent at temperature of about 35-40°C.

Formula IV

The suitable solvent, as described above, comprises of lower alcohol. More preferably, lower alcohol is isopropyl alcohol. After purification, the compound of formula IV typically have purity greater than or equal to about 99.85%, and contains less than 0.05% of each of the impurities as described below in Table II using high performance liquid chromatography (HPLC).

Table II

The Lurasidone hydrochloride prepared as per the prior art process having purity around 97-98% and containing impurities such as Impurity A, Impurity B, Impurity C, impurity D and Impurity in the range of 0.2 -0.8% respectively by HPLC. By following the purification process of the present invention, the said impurities are not in detectable level by HPLC. Lurasidone hydrochloride prepared as per the present invention is having purity greater than 99.50% by HPLC; preferably 99.75%; more preferably

99.95% by HPLC.

Lurasidone hydrochloride prepared as per the present invention containing less than 0.05% of impurity-D and Impurity- E; preferably less than 0.01 % by HPLC.

Lurasidone hydrochloride prepared as per the present invention containing less than 0.15% of impurity-A, Impurity-B, Impurity-C by HPLC; preferably less than 0.05% by HPLC; more preferably less than 0.01 % by HPLC. The related substances of Lurasidone free base and its hydrochloride salt measured using HPLC with the following chromatographic conditions: Column: YMC-PACK PRO C18 (250 X 4.6) mm, 5μ

Other parameters of the method are as shown in the following table.

Flow : 1.0 mL/minute

Elution : Gradient Wavelength : 230 nm Injection volume 15 ml_ Oven temperature: 30c Mobile phase:

Mobile phase A: 2.72 g of potassium dihydrogen phosphate in water preparation having pH adjusted to 2.5 with ortho phosphoric acid

Mobile phase B: Methanol + Acetonitrile in the volume ratio of 70:30

Diluent Mobile phase A: Mobile phase B in the volume ratio of (70:30)

This drastic yield and purity improvement caused by the above-described variations thus lead to an efficient and commercially acceptable synthetic process for the preparation of Lurasidone. The invention is explained in more detail in the following working examples. The examples, which illustrate improvement in the method according to the invention, have a purely illustrative character and do not limit the extent of the invention in any respect. Example-1 :

Preparation of compound I using isopropyl alcohol (IPA):

To a solution of 1 ,2-bis(hydroxymethyl)cyclohexane, 70g (0.4854 moles) in 700 ml of dichloromethane and triethylamine, 223ml (1.602 moles, 3.3 mol eq) added methanesulfonyl chloride, 97.7ml (1.262 moles, 2.6 mol eq) drop wise at 0-5°C. The reaction mass stirred for about 2 h. After the completion of the reaction (followed by GC), the reaction mass washed twice with 280ml of process water. The dichloromethane layer collected and concentrated under vacuum at 40°C.

Purification using Isopropyl alcohol:

The residue obtained by the above method was dissolved in 350 ml of isopropyl alcohol at 70-75°C, cooled to 30-35°C and further chilled down to 5-10°C. The solid formed filtered and washed with 70ml of chilled isopropyl alcohol. The solid dried under vacuum at 40°C to get methane sulfonic acid 2-methanesulfonyloxymethyl-cyclohexylmethyl ester (bis-mesylate) as off-white to pale brown solid (125g, 1.78 w/w; 85.8%; GC purity: 99.86%). Example-2:

Isolation using di-isopropyl ether:

To a solution of 1 ,2-bis(hydroxymethyl)cyclohexane, 5g in 45ml of dichloromethane, 14.5ml of triethylamine and methanesulfonyl chloride, 6.36 ml are added at 0-5°C. The reaction mass stirred for about 4 h. After the completion of the reaction (followed by TLC), the reaction mass washed twice with 40ml of process water. The dichloromethane layer collected and concentrated under vacuum at 40°C. To the obtained residue added 50ml of di-isopropyl ether and stirred at 25-30°C for about 1 h. The solid formed filtered and washed with 10ml of di-isopropyl ether. The solid dried under vacuum at 40°C to get methane sulfonic acid 2-methanesulfonyloxymethyl- cyclohexylmethyl ester (bis-mesylate) as pale brown solid (8.0g, 1 .6 w/w;).

Example-3: Isolation using methyl tert-butyl ether:

To a solution of 1 ,2-bis(hydroxymethyl)cyclohexane, 25g in 125ml of dichloromethane 72.5ml of triethylamine and 31 ml of methane sulfonyl chloride are added at 0-5°C. The reaction mass stirred for about 3 h. After the completion of the reaction (followed by TLC), the reaction mass washed twice with 100ml of process water. The dichloromethane layer collected and concentrated under vacuum at 40°C. To the obtained residue added 75ml of methyl tert-butyl ether and stirred at 25-30°C for about 1 h. The solid formed filtered and washed with 50ml of d methyl tert-butyl ether. The solid dried under vacuum at 40°C to get methane sulfonic acid 2- methanesulfonyloxymethyl-cyclohexylmethyl ester (bis-mesylate) as pale brown solid (43g, 1 .72 w/w; 80.7%).

Example-4: Preparation of compound II by using ethyl acetate:

To a solution of methane sulfonic acid 2-methanesulfonyloxymethyl-cyclohexylmethyl ester, 38g in 380ml of acetonitrile added 3-(1 -piperazinyl)-1 ,2-benzisothiazole, 27.7g and sodium carbonate, 13.45g and heated to reflux (80-85°C) for about 24 h. After the completion of the reaction (followed by TLC), filtered the solid under hot condition and washed with 40ml of pre heated acetonitrile. The filtrate concentrated completely under vacuum at 40-45°C.To the obtained residue, added 190ml of ethyl acetate and stirred for about 1 h at 30-35°C. The solid formed filtered and washed with 80 ml of ethyl acetate. The solid dried under vacuum at 60-65°C for 10-12 h to get trans -3a, 7a- octahydroisoindolium-2-spiro-1 '-[4-(1 ,2-benzisothiazol-3-yl)]piperazine methane sulfonate as a yellow solid (48g, 1 .26 w/w; 89.5%)

Example-5:

Isolation using acetonitrile:

To a solution of methane sulfonic acid 2-methanesulfonyloxymethyl-cyclohexylmethyl ester, 1 1 Og (0.3662 moles) in 825ml of acetonitrile added 3-(1 -piperazinyl)-1 ,2- benzisothiazole,80.31 g (0.3662 moles, 1 .0 mol eq) and sodium carbonate, 38.80g (0.3662 moles, 1 .0 mol eq) and heated to reflux (80-85°C) for about 28 h. After the completion of the reaction (followed by HPLC), the reaction mass cooled to 50-55°C, filtered the solid under hot condition and washed with 440ml of pre heated acetonitrile. The filtrate concentrated under vacuum at 40-45°C to obtain the residue.

Example-6:

Purification using ethyl acetate/acetonitrile mixture:

Crude trans -3a,7a-octahydroisoindolium-2-spiro-1 '-[4-(1 ,2-benzisothiazol-3- yl)]piperazine methane sulfonate, 1 g heated to reflux(75-80°C) in 2ml of ethylacetate. Added 10ml of acetonitrile and stirred for about 30 minutes. The obtained clear solution cooled to 30-35°C and further cooled to 5-10°C. The solid formed filtered and washed with 2 ml of pre chilled acetonitrile. The solid dried under vacuum at 60-65°C for 10-12 h to get trans -3a,7a-octahydroisoindolium-2-spiro-1 '-[4-(1 ,2-benzisothiazol-3- yl)]piperazine methane sulfonate as a yellow solid (0.58g, HPLC purity:100%) Example-7:

Preparation of compound III: To a stirred slurry of trans-3a,7a-octahydroisoindolium-2-spiro-1 '-[4-(1 ,2-benzisothiazol- 3-yl)]piperazine methane sulfonate, 105g(0.2478 moles) in 525ml of toluene, added (3aR, 4S,7R,7aS)-rel-hexahydro-4,7-methano-1 -H-isoindole-1 ,3(2H)-dione, 53.2g (0.3221 moles, 1.3 mol eq), potassium carbonate,41.1 g(0.2973, 1.2 mol eq), tetra-n-butyl ammonium hydrogen sulfate, 3.36 g (0.0099 moles, 0.04 mole eq) and 2.1 ml of process water and heated to reflux (105-1 10°C) for about 20 h. After the completion of the reaction (followed by HPLC), cooled the reaction mass to 30-35°C and washed with 525ml of process water. The layers separated and the aqueous layer back extracted with 315ml of toluene. The toluene layers combined and washed with 315ml of process water. Separated the organic layer and treated with activated carbon, 3.15g under stirring for about 30 minutes. Filtered the mass through hyflow bed, washed the bed with toluene, 120ml. The filtrate distilled out completely under vacuum at 45-50°C. Acetonitrile, 1050ml added to the residue obtained and heated to 80-85°C for about 1.0 h to get a homogeneous solution. Cooled the mass to 30-35°C and further cooled down to 5-10°C. The solid formed filtered and washed with 105ml of pre-chilled acetonitrile. The solid dried under vacuum at 50-55°C for 10-12 h to get (3aR,4S,7R,7aS)-2- {(1 R,2R)-2-[4-(1 ,2-benzisothiazol-3-yl)piperazin-1 -ylmethylcyclohexylmethyl}hexahydro- 4,7-methano-2H-isoindole-1 ,3-dione (Lurasidone) as a white solid (107g, 1.019 w/w; 87.8%, HPLC purity: 99.8% Chiral purity: 99.9%). Example-8:

Purification by ethyl acetate:

To a stirred slurry of trans-3a,7a-octahydroisoindolium-2-spiro-1 '-[4-(1 ,2-benzisothiazol- 3-yl)]piperazine methane sulfonate, 20g in 300ml of toluene added (3aR, 4S,7R,7aS)- rel-hexahydro-4,7-methano-1 -H-isoindole-1 ,3(2H)-dione, 10.14g potassium Carbonate, 7.96, tetra-n-butyl ammonium hydrogen sulfate, 0.64 g and 1 ml of process water and heated to reflux (105-1 10°C) for about 1 1 h. After the completion of the reaction (followed by TLC), cooled the reaction mass to 30-35°C and washed with 100ml of process water. Separated the toluene layer and treated with activated carbon, 0.5g under stirring for about 30 minutes. Filtered the mass through hyflo bed, washed the bed with toluene, 25 ml. and distilled out completely under vacuum at 45-50°C. Ethyl acetate, 40 ml added to the residue obtained and heated to 45°C for about 30 minutes to get a homogeneous solution. Cooled the mass to 30-35°C and further cooled down to 5-10°C. The solid formed filtered and washed with 105ml of pre-chilled ethylacetate. The solid dried under vacuum at 50-55°C for 10 h to get (3aR,4S,7R,7aS)-2-{(1 R,2R)-2- [4-(1 ,2-benzisothiazol-3-yl)piperazin-1 -ylmethyl]cyclohexylmethyl}hexahydro-4,7- methano-2H-isoindole-1 ,3-dione (Lurasidone) as a off-white solid (15.8g, 0.79 w/w; 68%) Example-9:

Purification using methyl tert-butyl ether:

To a stirred slurry of trans-3a,7a-octahydroisoindolium-2-spiro-1 '-[4-(1 ,2-benzisothiazol- 3-yl)]piperazine methane sulfonate, 15g in 150ml of toluene added (3aR, 4S,7R,7aS)- rel-hexahydro-4,7-methano-1 -H-isoindole-1 ,3(2H)-dione, 7.6g potassium carbonate, 5.97, tetra-n-butyl ammonium hydrogen sulfate, 0.5 g and 1 .5ml of process water and heated to reflux (105-1 10°C) for about 1 1 h. After the completion of the reaction (followed by TLC), Cooled the reaction mass to 30-35°C and washed with 75ml of process water. The layers separated and the toluene layers treated with activated carbon, 0.5g under stirring for about 30 minutes. Filtered the mass through hyflow bed, washed the bed with toluene, 25 ml and distilled out completely under vacuum at 45- 50°C. Methyl tert-butyl ether, 15 ml added to the obtained residue and heated to 45- 50°C for about 30 minutes to get a homogeneous solution. Cooled the mass to 30-35°C. The solid formed filtered and washed with15ml of methyl tert-butyl ether. The solid dried under vacuum at 50-55°C to get (3aR,4S,7R,7aS)-2-{(1 R,2R)-2-[4-(1 ,2- benzisothiazol-3-yl)piperazin-1 -ylmethyl] cyclohexylmethyl}hexahydro-4,7-methano-2H- isoindole-1 ,3-dione (Lurasidone) as a off- white solid (1 1 .8g, 0.79 w/w; 68%, HPLC purity: 99.58%). Example-10:

Purification using IPA:

Lurasidone, 1 .0g (HPLC purity :99.2%) dissolved in 1 1 .5 ml of isopropyl alcohol under reflux (80-85°C) for about 30 minutes, cooled the mass to 30-35°C. Further cooled to 5- 10°C and the solid formed filtered and washed with 2.0ml of pre-chilled isopropyl alcohol. The wet solid dried under vacuum at 50-55°C to get Lurasidone as off- white solid (0.935g). Example-11 :

Purification using acetone:

Lurasidone, 1 .0g (HPLC purity :99.2%) dissolved in 13.0 ml of acetone under reflux (55- 60°C) for about 30 minutes, cooled the mass to 30-35°C. Further cooled to 5-10°C and the solid formed filtered and washed with 2.0ml of pre-chilled acetone. The wet solid dried under vacuum at 50-55°C to get Lurasidone as white solid (0.685g, HPLC purity: 100%). Example-12:

Purification using methanol:

Lurasidone, 30g (HPLC purity: 99.6%) stirred with 450 ml of methanol under reflux(62- 66°C) for about 30 minutes, cooled the mass to 30-35°C. The solid filtered and washed with 10 ml of methanol. The wet solid dried under vacuum at 50-55°C to get lurasidone as white solid (28.5g, HPLC purity: 99.83%).

Example-13:

Purification using methanol-acetonitrile mixture:

Lurasidone, 1 .0g (HPLC purity :99.7%) dissolved in 20 ml of 1 :1 methanol-acetonitrile mixture under reflux for about 30 minutes, cooled the mass to 30-35°C. The solid formed filtered and washed with 2.0 ml of 1 :1 methol-acetonitrile mixture. The wet solid dried under vacuum at 50-55°C to get lurasidone as white solid (0.78g, HPLC purity: 99.98%).

Example-14:

Purification using methanol-acetonitrile-water mixture:

Lurasidone, 1 .0g (HPLC purity: 99.7%) dissolved in a mixture of 25ml of acetonitrile, methanol and water (acetonitrile: 14ml, methanol:9ml and water:2 ml) under reflux for about 30 minutes, cooled the mass to 30-35°C. The solid formed filtered and washed with 6.0ml of 6:4 acetonitrile-methanol mixture. The wet solid dried under vacuum at 50- 55°C to get Lurasidone as white solid (0.85g, HPLC purity: 99.92%)

Example-15:

Purification using acetonitrile-water mixture:

Lurasidone, 1 .0g (HPLC purity: 99.7%) dissolved in a mixture of 20ml of acetonitrile, and water (acetonitrile: 27ml, water:5 ml) under reflux for about 30 minutes, cooled the mass to 30-35°C. The solid formed filtered and washed with 2.0 ml of 15% aqueous acetonitrile. The wet solid dried under vacuum at 50-55°C to get lurasidone as white solid (0.9g, HPLC purity: 99.93%)

Example-16:

Purification using acetone-water mixture:

Lurasidone, 1 .0g (HPLC purity :99.7%) dissolved in a mixture of 20ml of acetone and water mixture(acetone: 23ml, water:2 ml) under reflux for about 30 minutes, cooled the mass to 30-35°C, further cooled ot 0-5°C. The solid formed filtered and washed with 2.0 ml of 8.0% aqueous acetone. The wet solid dried under vacuum at 50-55°C to get Lurasidone as white solid (0.9g, HPLC purity: 99.89%)

Example-17: Salification of Lurasidone using IPA-IPA-HCI:

To a stirred solution of (3aR,4S,7R,7aS)-2-{(1 R,2R)-2-[4-(1 ,2-benzisothiazol-3- yl)piperazin-1 -ylmethyl] cyclohexylmethyl}hexahydro-4,7-methano-2H-isoindole-1 ,3- dione, 90g(0.1827moles) in 1350ml of isopropyl alcohol at 50-55°C added drop wise 56.8ml of 12.9%(w/v) isopropyl alcohol-HCI over a period of 1 h. The reaction mass stirred for a period of 30 min at 50-55°C, and then cooled to 30-35°C over a period of 1 .5-2.0 h and further chilled down to 5-10°C. The solid formed filtered and washed with 90ml of pre-chilled isopropyl alcohol. The solid dried under vacuum at 40-45°C for 10- 12 h to get (3aR,4S,7R,7aS)-2-{(1 R,2R)-2-[4-(1 ,2-benzisothiazol-3-yl)piperazin-1 - ylmethyl]cyclohexylmethyl}hexahydro-4,7-methano-2H-isoindole-1 ,3-dione

hydrochloride (Lurasidone hydrochloride) as white solid (92.5g, 1 .027 w/w; 95.9%, HPLC purity:99.84, Chiral purity: 99.96% ).

Example-18:

Salification of Lurasidone using Ethyl acetate-Ethyl acetate-HCI: To a stirred solution of (3aR,4S,7R,7aS)-2-{(1 R,2R)-2-[4-(1 ,2-benzisothiazol-3- yl)piperazin-1 -ylmethyl] cyclohexylmethyl}hexahydro-4,7-methano-2H-isoindole-1 ,3- dione(lurasidone), 1 .0g in 10ml of ethyl acetate at 50-55°C added drop wise 0.7ml of 13% (w/v) ethyl acetate-HCI. The reaction mass cooled to 30-35°C and further chilled down to 10-15°C. The solid formed filtered and washed with 3ml of pre chilled ethyl acetate The solid dried under vacuum at 40-45°C to get (3aR,4S,7R,7aS)-2-{(1 R,2R)- 2-[4-(1 ,2-benzisothiazol-3-yl)piperazin-1 -ylmethyl]cyclohexylmethyl}hexahydro-4,7- methano-2H-isoindole-1 ,3-dione hydrochloride (Lurasidone hydrochloride) as white solid (1 .0g).

Example-18:

Salification of Lurasidone using Ethyl acetate-aq.HCI:

To a stirred solution of (3aR,4S,7R,7aS)-2-{(1 R,2R)-2-[4-(1 ,2-benzisothiazol-3- yl)piperazin-1 -ylmethyl] cyclohexylmethyl}hexahydro-4,7-methano-2H-isoindole-1 ,3- dione(lurasidone), 1 .0g in 10ml of ethyl acetate at 50-55°C added drop wise 0.55ml of aq. hydrochloric acid [(Con.HCI-water (1 : 1 )]. The reaction mass cooled to 30-35°C and further chilled down to 10-15°C. The solid formed filtered and washed with 3ml of pre chilled ethyl acetate The solid dried under vacuum at 40-45°C to get (3aR,4S,7R,7aS)- 2-{(1 R,2R)-2-[4-(1 ,2-benzisothiazol-3-yl)piperazin-1 -ylmethyl]

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

hydrochloride(Lurasidone hydrochloride) as white solid (1 .02g, HPLC purity: 99.90%)

Example-19:

Salification of Lurasidone using Ethyl acetate- IPA.HCI: To a stirred solution of (3aR,4S,7R,7aS)-2-{(1 R,2R)-2-[4-(1 ,2-benzisothiazol-3- yl)piperazin-1 -ylmethyl] cyclohexylmethyl}hexahydro-4,7-methano-2H-isoindole-1 ,3- dione(lurasidone), 1 g in 10ml of ethyl acetate at 50-55°C was added drop wise 0.55ml of 16% (w/v) isopropyl alcohol -HCI. The reaction mass was cooled to 30-35°C and further chilled down to 10-15°C. The solid formed was filtered and washed with 2ml of pre chilled ethyl acetate The solid was dried under vacuum at 40-45°C to get (3aR,4S,7R,7aS)-2-{(1 R,2R)-2-[4-(1 ,2-benzisothiazol-3-yl)piperazin-1 - ylmethyl]cyclohexylmethyl}hexahydro-4,7-methano-2H-isoindole-1 ,3-dione

hydrochloride (Lurasidone hydrochloride) as white solid (1 .0g, HPLC purity: 99.81 %)

Example-20:

Salification of Lurasidone using Acetone-IPA.HCI:

To a stirred solution of (3aR,4S,7R,7aS)-2-{(1 R,2R)-2-[4-(1 ,2-benzisothiazol-3- yl)piperazin-1 -ylmethyl] cyclohexylmethyl}hexahydro-4,7-methano-2H-isoindole-1 ,3- dione(lurasidone), 1 .0g in 15ml of acetone at 50-55°C added drop-wise 0.55ml of 16% (w/v) isopropyl alcohol-HCI. The reaction mass cooled to 30-35°C and further chilled down to 10-15°C. The solid formed filtered and washed with 3ml of pre-chilled acetone. The solid dried under vacuum at 40-45°C to get (3aR,4S,7R,7aS)-2-{(1 R,2R)-2-[4-(1 ,2- benzisothiazol-3-yl)piperazin-1 -ylmethyl]cyclohexylmethyl}hexahydro-4,7-methano-2H- isoindole-1 ,3-dione hydrochloride (Lurasidone hydrochloride) as white solid (1 .03g, HPLC purity: 99.77%)

Claims

We Claim:

1. A process for preparation of compound of Formula IV (Lurasidone Hydrochloride) of pharmaceutically acceptable quality by salification of compound of Formula III (Lurasidone base) having greater than 99.5% purity

2. The process as claimed in claim 1 where said compound of Formula III is

prepared by a process comprising of:

a. converting a compound of Formula II to crude compound of formula III b. treating said crude compound of formula III with an organic solvent, c. heating the reaction mixture to reflux,

d. Isolating said compound of formula III

3. The process as claimed in claim 2, wherein said organic solvent comprises of nitriles, esters, ethers, alcohols, ketone, water or mixtures thereof.

4. The process as claimed in claim 3, wherein said organic solvent is selected from acetonitrile, ethyl acetate, methanol, isopropyl alcohol, acetone, water or mixtures thereof.

5. The process as claimed in claim 2 where said compound of Formula II is

prepared by a process comprising of

a) Treating the compound of formula I with an organic solvent at an ambient temperature;

b) Optionally heating the reaction mixture for sufficient time;

c) Isolating the compound of formula I in pure form.

6. The process as claimed in claim 4, wherein said organic solvent comprises of alcohols or ethers.

7. The process as claimed in claim 5, wherein said organic solvent is Isopropyl alcohol, di-isopropyl ether or methyl tert-butyl ether.

8. The process as claimed in claim 1 wherein said compound of Formula II is purified prior to said conversion to compound of Formula III by a process comprising of: a) treating the crude compound of formula II with an organic solvent;

b) optionally heating the reaction mixture for sufficient time;

c) isolating the compound of formula II in pure form.

9. The process as claimed in claim 7, wherein said organic solvent comprises of nitriles, esters or mixtures thereof.

10. The process as claimed in claim 8, wherein said organic solvent is acetonitrile, ethyl acetate or mixtures thereof.

1 1. The process as claimed in claim 1 , wherein said salification involves reaction of Lurasidone base with hydrochloric acid dissolved in isopropyl alcohol at temperature range of about 35-45°C.

12. The process as claimed in claim 1 , wherein said impurity profile comprises of impurity A, Impurity B, Impurity C is less than about 0.15 percent.

13. A composition of matter comprising compound of Formula IV (Lurasidone

Hydrochloride) of more than 99.95% purity or less than 0.05% impurity.

14. A composition of matter as claimed in claim 13 wherein said impurity is less than about 0.05 percent by weight of each impurity D & impurity E.