This application claims priority to this Indian patent application numbers 228/CHE/2013 filed on January 17, 2013 and 635/CHE/2013 filed on February 13, 2013.
FIELD OF INVENTION
The present invention relates to an improved process for preparation of Lurasidone intermediate and its further conversion into Lurasidone or its pharmaceutically acceptable salts thereof. The present invention further provides purification of Lurasidone free base.
BACKGROUND OF THE INVENTION
Lurasidone HC1, [(3aR,4S,7R,7aS)-2-{(1 R,2R)-2-[4-( 1,2-benzisothiazol-3-yl)piperazin-
lylmethyl]cyclohexylmethyl}hexahydro-4,7-methano- 2H-isoindole-l,3-dione
hydrochloride having the structure as shown in Formula I;
Lurasidone is an azapirone derivative and an atypical antipsychotic developed by Dainippon Sumitomo Pharma. Lurasidone Hydrochloride is marketed under the brand name of LATUDA in Unites States for treatment of schizophrenia.
Lurasidone and its preparation process are primarily reported in US 5532372. US 7605260 also describes preparation of Lurasidone hydrochloride by reacting free base in acetone with aq.HCl. Trans-R,R-dimesylate having the structure shown in Formula II is one of the key intermediate for preparing Lurasidone. US 5532372 employs a racemic trans dimesylate intermediate.

Formula II
The present invention provides improved process for preparing trans-R,R-dimesylate from trans-R,R-diacid with less number of steps to give more yield. It also provides a process for the purification of Lurasidone free base and preparation of Lurasidone HC1.
OBJECT AND SUMMARY OF THE INVENTION
The principle object of the present invention is to provide an improved process for preparation of trans-R,R-dimesylate of Formula II which is a key intermediate for preparing Lurasidone Hydrochloride.
Another principle object of the present invention is to provide an improved process for preparing Lurasidone Hydrochloride.
One more object of the present invention is to provide purification of pure Lurasidone free base.
In one aspect, the present invention provides a process for preparing trans-R,R-dimesylate comprising the steps of:
a) resoluting trans-racemic acid of Formula III to give trans-R,R-diacid of Formula IV,
b) reducing the diacid of Formula IV to give trans-R,R-diol of Formula V, and

In another aspect, the present invention provides purification of Lurasidone free base comprising the steps of:
a) treating Lurasidone free base with methanol; and
b) isolating pure Lurasidone free base.
In one aspect, the present invention provides an improved process for preparing Lurasidone hydrochloride comprising the steps of:
a) providing Lurasidone free base in a mixture of water and water miscible organic solvent;
b) adding HC1 source; and
c) isolating Lurasidone hydrochloride.
DETAILED DESCRIPTION OF THE INVENTION:
The present invention is to provide an improved process for preparation of trans-R,R-dimesylate of Formula II which is a key intermediate for preparing Lurasidone Hydrochloride. The present invention also provides an improved process for preparing Lurasidone Hydrochloride and purification of Lurasidone free base.
The schematic representation of the present invention is given in scheme I.

In one aspect, the present invention provides a process for preparing trans-R,R-dimesylate comprising the steps of:
a) resoluting trans-racemic acid of Formula III to give trans-R,R-diacid of Formula IV,
b) reducing the diacid of Formula IV to give trans-R,R-diol of Formula V, and
c) converting trans-R,R-diol of Formula V into trans-R,R-dimesylate of Formula II.

In one embodiment of the present invention, trans racemic acid of Formula III is resoluted into tarns R,R-diacid of Formula IV as per the processes known in the art Analytical sciences June 1995, Vol.15 and WO2012131606.
In another embodiment of the present invention, the resoluetd trans-R,R-diacid of formula IV is reduced by treating with a suitable reducing agent and suitable solvent in presence of Lewis acid such borantrifluoride diethyl etherate (BF3.0Et2), Iodine; this reaction can also be carried out in presence of acids such as sulphuric acid. The suitable reducing agent is selected from sodium borohydride (NaBFLO, lithium borohydride (LiBFU). The suitable solvent for reduction is selected from tetrahydrofuran (THF), diethyl ether, diisopropyl ether, methyl butyl ether.
The processes known in the art for the preparation of trans-R,R diol of Formula IV from trans-R,R-diacid of Formula III is predominantly carried out via an ester intermediate, which is further reduced with reducing agent. The process exemplified in WO2012131606 for preparing trans-R,R-dimesylate proceeds via preparation ester derivative. As per the present invention, the diacid intermediate of formula IV is directly reduced with a reducing agent preferably NaBFU in suitable solvent such as THF in presence of Lewis acid, acid to give diol intermediate of formula V.
In another embodiment of the present invention, the diol intermediate of Formula V is reacted with a sulfonyl halide to give trans-R,R-dimesylate compound of formula II and converted into Lurasidone hydrochloride of formula I by the process known in the art US 5532372, WO2012131606.

The schematic representation of the preparation of Lurasidone Hydrochloride is given in scheme II.
In another aspect, the present invention provides purification of Lurasidone free base comprising the steps of:
a) treating Lurasidone free base with methanol; and
b) isolating pure Lurasidone free base.
In one embodiment of the present invention, methanol is added to Lurasidone free base and filtered to isolate pure Lurasidone free base.

In another embodiment of the present invention, methanol is added to Lurasidone free base and heated to reflux. The reaction mixture is cooled and filtered to isolate pure Lurasidone free base.
Yet another embodiment of the present invention, the pure Lurasidone free base can be converted into Lurasidone HC1 by treating with the source of HC1.
In one aspect, the present invention provides a process for preparing Lurasidone Hydrochloride comprising the steps of:
a) providing Lurasidone free base in a mixture of water and water miscible organic solvent;
b) adding HCI source; and
c) isolating Lurasidone hydrochloride.
In one embodiment of the present invention, the Lurasidone free base is provided in mixture of water and water miscible organic solvent by treating Lurasidone free with mixture of water and water miscible organic solvent. The water miscible organic solvent is selected from polar solvents such as methanol (MeOH), ethanol (EtOH), isopropanol (IPA), n-propanol, dimethylsulfoxide (DMSO), diemthylformammide (DMF), acetonitrile (ACN), tetrahydrofuran (THF), acetone or mixtures thereof; preferably methanol, ethanol, isopropanol and acetone.
In another embodiment of the present invention, HCI source is added to the provided Lurasidone free base to isolate Lurasidone hydrochloride. The HCI source is selected from HCI gas; aqueous HCI; alcoholic HCI such as methanolic HCI, IPA HCI; Ether-HC1; preferably IPA HCI.
The following non-limiting example illustrates specific embodiments of the present invention. The example is not intended to be limiting the scope of the present invention in any way

Examples:
Example 1: Preparation of (lR,2R)-l,2-Cyclohexanedimethanol.
4.4 g of sodium borohydride was added to RBF and to this was added 10 ml of tetrahydrofuran at 25-30 °C. The reaction mixture was cooled to -5 to 10 °C and was added a solution of (lR,2R)-l,2-cylcohexanedicarboxillic acid (5 g of (1R,2R)-1,2-cylcohexanedicarboxillic acid in 20 ml of tetrahydrofuran) and 47-49% boran trifluoride diethyl etherate; and stirred for ~ 1 hr. The reaction mixture temperature was raised to 25-30 °C and maintained the same for 6 hrs with stirring. After completion of the reaction, the reaction mixture was cooled to 0-5 °C and was slowly added 15 ml of methanol and stirred. The reaction mixture is heated to 25-30 °C and stirred for 1 hour. The solvent was distilled off completely from the reaction mixture and water was added to the crude and extracted with ethyl acetate. The organic layers were combined and washed with sodium chloride solution; dried over sodium sulfate and the solvent was distilled off completely. To the residue was added 50 ml of hexane and filtered. The obtained solid was washed with n-hexane and dried to give ~3.6 g of (lR,2R)-l,2-Cyclohexanedimethanol.
Example 2: Preparation of trans (R, R)-3a, 7a-Octahydroisoindolium-2-Spiro-l'-[4'-(l,2-Benzoisothiazole-3-yl)] piperazine Methane Sulfonate
35.3g of Sodium carbonate was added to a suspension of 100 g of trans (R, R)-l, 2-bis (methanesulfonylmethyl) cyclohexane and 72.7 g of 3-(l-Piperazinyl-l, 2-benzisothiazole) in 1000 mL of acetonitrile at ambient temperature. The reaction mixture was re fluxed for about 24 hours, filtered at hot condition and washed with 50 mL of acetonitrile. The combined filtrate was concentrated under reduced pressure at about 45-50°C and the resulting residue was co-distilled with 50 mL of hexane. The crude material was charged with 200 mL of acetone and 300 mL of hexane and stirred the reaction mass for about one hour at ambient temperature. The reaction mass was filtered and the product was dried under reduced pressure to obtain 120g of trans (R, R)-3a,7a-octahydroisoindolium-2-Spiro-r-[4'-(l,2-benzoisothiazole-3-yl)]piperazine methanesulfonate. HPLC Purity: -99.5%.

Example 3: Preparation of Lurasidone free base
39.2 g of Bicyclo[2.2.1]heptane-2-exo-dicarboximide, 38.8 g of potassium carbonate, 3.2 g of tetrabutyl ammonium hydrogen sulfate and water (1.5 g) were added to a suspension of 100 g of trans (R,R)-3a,7a-Octahydroisoindolium-2-spiro-l'-[4'-(l,2-benzoisothiazole-3-yl)]piperazine methanesulfonate in 1000 mL toluene. The reaction mixture was refluxed for about 8-12 hours, cooled, filtered and washed with 50 mL of toluene. The combined filtrate was washed with water (2 x 200mL) and 5% aqueous sodium chloride solution. The toluene layer was then concentrated under reduced pressure at about 45°C to obtain 115g of crude Lurasidone free base. The obtained crude Lurasidone free base was stirred with 700 mL of methanol at reflux for 3-6 hours, and cooled to ambient temperature, filtered, washed with methanol and dried under reduced pressure at about 45°C to obtain 100 g of Lurasidone free base. HPLC Purity: -99.5%.
Example 4: Preparation of Lurasidone Hydrochloride
To a suspension of 100 g of Lurasidone free base in 1000 mL of isopropyl alcohol, 100 mL of water was added and heated reflux. 55 mL of IPA.HC1 was added to the reaction mixture at the same temperature and stirred for about 30 minutes. The contents was slowly cooled to ambient temperature and stirred for about 3 hours, filtered, washed with 50 mL of isopropyl alcohol and dried under reduced pressure at about 45°C for about 6 hours to obtain 96 g of Lurasidone hydrochloride as white crystalline powder. HPLC Purity: -99.6%.
Example 5: Preparation of Lurasidone Hydrochloride
To a suspension of 100 g of Lurasidone free base in 1000 mL of methanol, 100 mL of water was added and heated to reflux. 55 mL of IPA.HC1 was added to the reaction mixture at the same temperature and stirred for about 30 minutes. The contents was slowly cooled to ambient temperature and stirred for about 3 hours, filtered, washed with 50 mL of methanol and dried under reduced pressure at about 45 °C for about 6 hours to obtain 95 g of Lurasidone hydrochloride as white crystalline powder. HPLC Purity: -99.6%.

Example 6: Preparation of Lurasidone Hydrochloride
To a suspension of 100 g of Lurasidone free base in 1000 mL of ethanol, 100 mL of water was added and heated to reflux. 55 mL of IPA.HC1 was added to the reaction mixture at the same temperature and stirred for about 30 minutes. The contents was slowly cooled to ambient temperature and stirred for about 3 hours, filtered, washed with 50 mL of ethanol and dried under reduced pressure at about 45 °C for about 6 hours to obtain 93 g of Lurasidone hydrochloride as white crystalline powder. HPLC Purity: -99.6%.
Example 7: Preparation of Lurasidone Hydrochloride
To a 100 g of suspension of Lurasidone free base in 1000 mL of acetone, 100 mL of water was added and heated to reflux. 55 mL of IPA.HC1 was added to the reaction mixture at the same temperature and stirred for about 30 minutes. The contents was slowly cooled to ambient temperature and stirred for about 3 hours, filtered, washed with 50 mL of acetone and dried under reduced pressure at about 45 °C for about 6 hours to obtain 93 g of Lurasidone hydrochloride as white crystalline powder. HPLC Purity: -99.6%.
Example 8: Preparation of Lurasidone Hydrochloride
39.2 g of Bicyclo[2.2.1]heptane-2-exo-dicarboximide, 38.8 g of potassium carbonate, 3.2 g of tetrabutyl ammonium hydrogen sulfate, and water (1.5 g) were added to a suspension of 100 g of trans (R, R)-3a,7a-Octahydroisoindolium-2-Spiro-l'-[4'-(l,2-Benzoisothiazole-3-yl)]Piperazine methanesulfonate in 1000 mL toluene. The reaction mixture was refluxed for about 8-12 hours, cooled, filtered and washed with 50 mL of toluene. The combined filtrate was washed with water (2 x 200mL) and 5% aqueous sodium chloride solution. The toluene layer was then concentrated under reduced pressure at about 45°C to obtain 115 g of crude Lurasidone free base. To a suspension of Lurasidone free base in 1000 mL of methanol, 100 mL of water was added and heated to reflux. 55 mL of IPA.HC1 was added to the reaction mixture at the same temperature and stirred for about 30 minutes. The contents was slowly cooled to ambient temperature and stirred for about 3 hours, filtered, washed with 50 mL of methanol and dried under

reduced pressure at about 45°C for about 6 hours to obtain 100 g of Lurasidone hydrochloride as white crystalline powder. HPLC Purity: -99.5%.
Example 9: Preparation of Lurasidone Hydrochloride
39.2 g of Bicyclo[2.2.1]heptane-2-exo-dicarboximide, 38.8 g of potassium carbonate, 3.2 g of tetrabutyl ammonium hydrogen sulfate, and water (1.5 g) were added to a suspension of 100 g of trans (R, R)-3a,7a-Octahydroisoindolium-2-Spiro-l'-[4'-(l,2-Benzoisothiazole-3-yl)]piperazine methanesulfonate in 1000 mL toluene. The reaction mixture was refluxed for about 8-12 hours, cooled, filtered and washed with 50 mL of toluene. The combined filtrate was washed with water (2 x 200mL) and 5% aqueous sodium chloride solution. The toluene layer was then concentrated under reduced pressure at about 45°C to obtain 115 g of crude Lurasidone free base. To a suspension of Lurasidone free base in 1000 mL of acetone, 100 mL of water was added and heated to reflux. 55 mL of IPA.HC1 was added to the reaction mixture at the same temperature and stirred for about 30 minutes. The contents was slowly cooled to ambient temperature and stirred for about 3 hours, filtered, washed with 50 mL of acetone and dried under reduced pressure at about 45°C for about 6 hours to obtain 100 g of Lurasidone hydrochloride as white crystalline powder.
Example 10: Preparation of Lurasidone Hydrochloride
To a suspension of 100 g of Lurasidone free base in 600 mL of isopropyl alcohol, 60 mL of water and 100ml of methanol was added and heated to about 75°C. 90 mL of hydrogen chloride solution in methanol (methanolic HC1; -12% w/w) was added to the reaction mixture at the same temperature and stirred for about 30 minutes. The contents were slowly cooled to ambient temperature and stirred for about 3 hours, filtered, washed with 50 mL of isopropyl alcohol and dried under reduced pressure at about 45 °C for about 6 hours to obtain 97 g of Lurasidone hydrochloride as white crystalline powder. HPLC Purity: -99.6%.

Example 11: Preparation of Lurasidone Hydrochloride
To a suspension of 100 g of Lurasidone free base in 500 mL of methanol, 60 mL of water was added and heated to about 65°C. 90 mL of methanolic HC1 (methanolic HC1; -12% w/w) was added to the reaction mixture at the same temperature and stirred for about 30 minutes. The contents were slowly cooled to ambient temperature and stirred for about 3 hours, filtered, washed with 50 mL of methanol and dried under reduced pressure at about 45 °C for about 6 hours to obtain 75 g of Lurasidone hydrochloride as white crystalline powder. HPLC Purity: -99.6%.
Example 12: Preparation of Lurasidone Hydrochloride
To a suspension of 100 g of Lurasidone free base in 600 mL of ethanol, 60 mL of water was added and heated to about 70°C. 90 mL of methanolic HC1 (methanolic HC1; -12% w/w) was added to the reaction mixture at the same temperature and stirred for about 30 minutes. The contents were slowly cooled to ambient temperature and stirred for about 3 hours, filtered, washed with 50 mL of ethanol and dried under reduced pressure at about 45°C for about 6 hours to obtain 83 g of Lurasidone hydrochloride as white crystalline powder. HPLC Purity: -99.6%.
Example 13: Preparation of Lurasidone Hydrochloride
To a 100 g of suspension of Lurasidone free base in 600 mL of acetone, 60 mL of water was added and heated to 60 °C. 90 mL of methanolic HC1 (methanolic HC1; -12% w/w) was added to the reaction mixture at the same temperature and stirred for about 30 minutes. The contents were slowly cooled to ambient temperature and stirred for about 3 hours, filtered, washed with 50 mL of acetone and dried under reduced pressure at about 45°C for about 6 hours to obtain 83 g of Lurasidone hydrochloride as white crystalline powder. HPLC Purity: -99.6%.

Example 14: Preparation of Lurasidone Hydrochloride
39.2 g of Bicyclo[2.2.1]heptane-2-exo-dicarboximide, 38.8 g of potassium carbonate, 3.2 g of tetrabutyl ammonium hydrogen sulfate, and water (1.5 g) were added to a suspension of 100 g of trans (R, R)-3a,7a-Octahydroisoindolium-2-Spiro-l'-[4'-(l,2-Benzoisothiazole-3-yl)]Piperazine methanesulfonate in 1000 mL toluene. The reaction mixture was refluxed for about 8-12 hours, cooled, filtered and washed with 50 mL of toluene. The combined filtrate was washed with water (2 x 200mL) and 5% aqueous sodium chloride solution. The toluene layer was concentrated under reduced pressure at about 45°C to obtain 115 g of crude Lurasidone free base. To a suspension of Lurasidone free base in 600 mL of isoporpyl alcohol, 60 mL of water and 100ml of methanol was added and heated to about 70°C. 90 mL of methanolic HC1 (methanolic HC1; -12% w/w) was added to the reaction mixture at same temperature and stirred for about 30 minutes. The contents were slowly cooled to ambient temperature and stirred for about 3 hours, filtered, washed with 50 mL of isopropyl alcohol and dried under reduced pressure at about 45°C for about 6 hours to obtain 100 g of Lurasidone hydrochloride as white crystalline powder. HPLC Purity: -99.5%.

We Claim:
1. A process for the preparation of Lurasidone hydrochloride comprising the steps
of:
a) providing Lurasidone free base in a mixture of water and water miscible organic solvent;
b) adding HC1 source; and
c) isolating Lurasidone hydrochloride.

2. The process according to the claim 1, wherein the water miscible organic solvent is selected from methanol, ethanol, isopropanol, n-propanol, dimethylsulfoxide, diemthylformammide, acetonitrile, tetrahydrofuran, acetone or mixtures thereof.
3. The process according to the claim 1, wherein HC1 source is selected from HC1 gas; aqueous HC1; alcoholic HC1 such as methanolic HC1, IPA HC1 and Ether-HC1.
4. A process for the preparation of trans-R,R-dimesylate comprising the steps of: a) reducing the diacid of Formula IV to give trans-R,R-diol of Formula V, and
b) converting trans-R,R-diol of Formula V into trans-R,R-dimesylate of Formula II.
5. The process according to the claim 4, wherein the reducing agent is selected from sodium borohydride (NaBFLi), lithium borohydride (LiBFLt).

6. The process according to the claim 4, wherein the reduction is carried out in presence of a Lewis acid selected from borantrifluoride diethyl etherate (BF3.OEt2) and Iodine.
7. The process according to the claim 4, wherein the compound of formula II is further converted into Lurasidone and the pharmaceutically acceptable salts.
8. A process for the purification of Lurasidone free base comprising the steps of:

a) treating Lurasidone free base with methanol; and
b) isolating pure Lurasidone free base.
9. The process according to the claim 8, wherein the purified Lurasidone base is
further converted into Lurasidone and the pharmaceutically acceptable salts.