CLIAMS:We claim,

1. An improved process for preparing (3aR,4S,7R,7aS)-2-{(1R,2R)-2-[4-(1,2-benzisothiazol-3-yl)piperazin-1ylmethyl] cyclohexylmethyl}hexahydro-4,7-methano-2H-isoindole-1,3-dione hydrochloride (Formula-1a)

Formula-1a
which comprises:
(a) reacting (R,R)trans 1,2-bis(hydroxymethyl)cyclohexane with methane sulphonyl chloride in presence of organic base selected from Pyridine, N-methyl morpholine at ambient temperature to obtain (R,R) trans 1,2-Bis(methane sulphonyl methyl)cyclohexane;
(b) reacting (R,R) trans 1,2-Bis(methane sulphonyl methyl)cyclohexane with 3-(Piperazine-l-yl)benzo[d]isothiazole in presence of mixture of two or more polar aprotic solvents selected from Acetonitrile,N,N-dimethyl formamide, N,N-dimethyl acetamide and sodium hydroxide as a baseat refluxed temperature to obtain trans(R,R-3a,7a-octahydroisoindolium-2-spiro-1’-4’-(1,2-benzoisothiozole-3-yl)piperazine methane sulfonate;
(c) reacting trans(R, R-3a,7a-octahydroisoindolium-2-spiro-1’-4’-(1,2-benzoisothiozole-3-yl)piperazine methane sulfonate with (3aS,4R,7S,7aR)-hexahydro-4,7- methano-lH-isoindole-l,3-(2H)-dione in presence of dipolar aprotic solvent is N-methyl pyrrolidone and base is selected from Sodium carbonate, Potassium carbonate, Barium hydroxide at 100-120οC to obtain Lurasidone free base and
(d) converting Lurasidone free base to Lurasidone hydrochloride.

2. The process according to claim 1, wherein the ambient temperature for step (a) is 25-30οC and the reflux temperature in step (b) is 80-85οC.

3. A process for preparing (R, R) trans 1, 2-bis(methane sulphonyl methyl)cyclohexane (Formula-3)

Formula-3
which comprises:
(a) reacting(R,R)trans 1,2-bis(hydroxymethyl)cyclohexane with methane sulphonyl chloride in presence of organic solvent selected from Toluene, Xylene and triethylamine at ambient temperature for 2-3 hrs;
(b) extracting organic layer with water and
(c) isolating (R,R) trans 1,2-bis(methane sulphonyl methyl)cyclohexane.

4. The process according to any of the preceding claims, wherein purity of (3aR,4S,7R,7aS)-2-{(1R,2R)-2-[4-(1,2-benzisothiazol-3-yl)piperazin-1ylmethyl] cyclohexylmethyl}hexahydro-4,7-methano-2H-isoindole-1,3-dione hydrochloride is 99.5-99.8%.

Dated this 15th day of July, 2014

Dr. P. Aruna Sree
(Regn.No.: IN/PA 998)
Agent for the Applicant
Gopakumar Nair Associates ,TagSPECI:FORM 2
THE PATENTS ACT 1970
(39 of 1970)
AND
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule13)
1. TITLE OF THE INVENTION:
“ An improved process for preparing (3aR,4S,7R,7aS)-2-{(1R,2R)-2-[4-(1,2-
benzisothiazol-3-yl)piperazin-1ylmethyl] cyclohexylmethyl}hexahydro-4,7-
methano-2H-isoindole-1,3-dione hydrochloride.”
2. APPLICANT:
(a) NAME: HARMAN FINOCHEM LIMITED
(b) NATIONALITY: Indian Company incorporated under the
Companies Act, 1956
(c) ADDRESS: 107, Vinay Bhavya Complex, 159–A , C.S.T. Road, Kalina,
Mumbai - 400098, Maharashtra, India.
3. PREAMBLE TO THE DESCRIPTION:
The following specification particularly describes the invention and the manner in
which it is to be performed:
2
FIELD OF INVENTION:
The present invention relates to an improved, economical and advantageous process for
preparing (3aR,4S,7R,7aS)-2-{(1R,2R)-2-[4-(1,2-benzisothiazol-3-yl)piperazin-1ylmethyl]
cyclohexylmethyl}hexahydro-4,7-methano-2H-isoindole-1,3-dione hydrochloride.
BACKGROUND OF INVENTION:
Lurasidone is chemically known as (3aR,4S,7R,7aS)-2-{(1R,2R)-2-[4-(1,2-benzisothiazol-3-
yl)piperazin-1ylmethyl] cyclohexylmethyl}hexahydro-4,7-methano-2H-isoindole-1,3-dione
(Formula- 1)
Formula-1
Lurasidone is marketed under the brand name Latuda which is an atypical antipsychotic
belonging to the chemical class of benzisothiazol derivatives for the treatment of Schizophrenia.
U.S. Patent 5,532,372 discloses Lurasidone and its pharmaceutically acceptable salts and its
preparation process as depicted in scheme-1.
N N S
N
N
O O
H H
OH
OH
OMs
OMs
+ N
NH
S
N
N N + S
N
-OMs
NH
O
O
N N S
N
N
O O
H H
ET3N, DCM(5X)
CH3SO2Cl
Na2CO3
Acetonitrile
Tetra-n-butylammonium
hydrogen phosphate
DM water
Toluene K2CO3
3
Scheme-1
Process for preparing Lurasidone hydrochloride is disclosed in WO 2011136383 A1 and WO
2011136384 A1.
The object of the present invention is to provide robust, economical, safe and commercially
applicable process for preparing Lurasidone hydrochloride with high purity and high yield.
SUMMARY OF THE INVENTION:
The present invention discloses cost-effective, improved and industrially feasible process for
preparing Lurasidone free base (Formula-1) and its hydrochloride salt.
Formula-1
In one aspect, the instant invention provides process for preparing (R,R) trans 1,2-Bis(methane
sulphonyl methyl)cyclohexane (Formula-3) which comprises:
Formula-3
(a) reacting Formula-2 with methane sulphonyl chloride in presence of organic base at ambient
temperature;
Formula-2
(b) extracting organic layer with water and solvent and
(c) isolating Formula-3.
N N S
N
N
O O
H H
O
O
S
O
O
CH3
S
O
O
CH3
OH
OH
4
In another aspect the present invention discloses process for preparing trans(R, R-3a,7aoctahydroisoindolium-
2-spiro-1’-4’-(1,2-benzoisothiozole-3-yl)piperazine methane sulfonate
(Fromula-5) which comprises:
Formula-5
(a) reacting Formula-3 with Formula-4 in presence of mixture of two or more polar aprotic
solvents and a base at refluxed temperature and
Formula-4
(b) isolating Formula-5.
In one other aspect the present invention provides preparation of Lurasidone free base (Formula-
1) which involves:
(a) reacting Formula-5 with Formula-6 in presence of dipolar aprotic solvent and base at
100-120οC and
Formula-6
(b) isolating Formula-1.
In further aspect the present invention discloses process for preparing hydrochloride salt of
Lurasidone comprises:
(a) dissolving Lurasidone base in an alcohol at 50-70οC;
(b) adding alcoholic hydrochloric acid and cooling at 0-5οC and
(c) isolating Lurasidone hydrochloride.
N N + S
N
N
NH
S
N
NH
O
O
5
DETAILED DESCRIPTION OF THE INVENTION:
The present invention describes an improved process for preparing (3aR,4S,7R,7aS)-2-{(1R,2R)-
2-[4-(1,2-benzisothiazol-3-yl)piperazin-1ylmethyl] cyclohexylmethyl}hexahydro-4,7-methano-
2H-isoindole-1,3-dione and its pharmaceutically acceptable salts. (Formula-1)
Formula-1
Accordingly, the process for preparing (3aR,4S,7R,7aS)-2-{(1R,2R)-2-[4-(1,2-benzisothiazol-3-
yl)piperazin-1ylmethyl] cyclohexylmethyl}hexahydro-4,7-methano-2H-isoindole-1,3-dione
hydrochloride (Formula-1a)
Formula-1a
which comprises:
(a) reacting (R,R)trans 1,2-bis(hydroxymethyl)cyclohexane with methane sulphonyl chloride in
presence of organic base at ambient temperature to obtain (R,R) trans 1,2-Bis(methane sulphonyl
methyl)cyclohexaneof formula 3;
(b) reacting (R,R) trans 1,2-Bis(methane sulphonyl methyl)cyclohexane with 3-(Piperazine-lyl)
benzo[d]isothiazole of formula 4 in presence of mixture of two or more polar aprotic solvents
and a base at refluxed temperature to obtain trans(R,R-3a,7a-octahydroisoindolium-2-spiro-1’-
4’-(1,2-benzoisothiozole-3-yl)piperazine methane sulfonate of formula 5;
(c) reacting trans(R, R-3a,7a-octahydroisoindolium-2-spiro-1’-4’-(1,2-benzoisothiozole-3-
yl)piperazine methane sulfonate with (3aS,4R,7S,7aR)-hexahydro-4,7- methano-lH-isoindolel,
3-(2H)-dioneof formula 6 in presence of dipolar aprotic solvent and base at 100-120οC to
obtain Lurasidone free base of formula 1 and
N N S
N
N
O O
H H
N N S
N
N
O O
H H
.HCl
6
(d) converting Lurasidone free base to Lurasidone hydrochloride of formula 1a.
In another embodiment, the present invention provides process for preparing (R,R) trans 1,2-
Bis(methane sulphonyl methyl)cyclohexane of formula-3 which comprises:
(a) reacting (R,R)trans 1,2-bis(hydroxymethyl)cyclohexane with methane sulphonyl chloride in
presence of organic base at ambient temperature for 1-2 hrs;
(b) extracting organic layer with water and solvent and
(c) isolating (R,R) trans 1,2-Bis (methane sulphonyl methyl)cyclohexane.
The term “organic base” refers to a base is selected from the group consisting of Pyridine,
Piperidine, N-methyl morpholine, diisopropyl ethyl amine, diisopropyl amine, isopropylethyl
amine, triethyl amine.
Here in above process, the organic base itself plays part of solvent in the reaction. The reaction
time decreases than reported in prior art by using the organic base and the product obtained with
higher purity.
The term “ambient temperature” refers to temperature between 25-30 οC.
The solvent is selected from the group consisting of chlorinated solvents like
dichloromethane,1,2-dichloroethane, chloroform, carbon tetra chloride, Ester solvents like ethyl
acetate, methyl acetate, n-butyl acetate, isobutyl acetate, sec butyl acetate, isopropyl acetate.
The GC purity of (R,R) trans 1,2-Bis(methane sulphonyl methyl)cyclohexane thus obtained is in
the range of 98-99.5%
In an alternate embodiment, the present invention discloses process for preparing (R,R) trans 1,2-
Bis(methane sulphonylmethy)cyclohexane which involves:
(a) reacting (R,R)trans 1,2-bis(hydroxymethyl)cyclohexane with methane sulphonyl chloride in
presence of organic solvent and base at ambient temperature for 2-3 hrs;
(b) extracting organic layer with water and
(b) isolating (R,R) trans 1,2-Bis(methane sulphonyl methyl)cyclohexane.
The organic solvent is selected from the group consisting of aromatic hydrocarbons such as
Toluene, Xylene, halobenzenes like chlorobenzene, bromobenzene, Iodobenzene,
disubstitutedhalobenzenes like dichlorobenzene, dibromobenzene and diiodobenzene.
The organic solvent contributes to increased yield with higher purity.
For the purpose of the reaction the base is an organic base is selected from the group consisting
of Triethyl amine, Pyridine, Piperidine, N-methyl morpholine, diisopropyl ethyl amine,
7
diisopropylamine, isopropylethyl amine or an inorganic base selected from Potassium carbonate,
Potassium bicarbonate, Sodium carbonate, Sodium bicarbonate, Cesium carbonate, Calcium
carbonate.
The GC purity of (R,R) trans 1,2-Bis(methane sulphonyl methyl)cyclohexane thus obtained is in
the range of 98-99.5%.
In another embodiment, the present invention discloses process for preparing trans(R, R-3a,7aoctahydroisoindolium-
2-spiro-1’-4’-(1,2-benzoisothiozole-3-yl)piperazine methane sulfonate of
formula -5 which comprises
(a) reacting (R,R) trans 1,2-Bis(methane sulphonyl methyl)cyclohexaneof formula 3 with 3-
(Piperazine-l-yl)benzo[d]isothiazoleof formula- 4 in presence of mixture of two or more polar
aprotic solvents and a base at refluxed temperature for 15-18 hrs and
(b) isolating trans(R,R-3a,7a-octahydroisoindolium-2-spiro-1’-4’-(1,2-benzoisothiozole-3-
yl)piperazine methane sulfonate of formula -5.
In the above process polar aprotic solvents are selected from the group consisting of Acetonitrile,
N,N-dimethyl formamide, N,N-dimethyl acetamide and Dimethylsulfoxide. The base in said
process is selected from the group consisting of carbonate salts of alkali and alkaline earth metals
like Potassium carbonate, Potassium bicarbonate, Sodium carbonate, Sodium bicarbonate,
Cesium carbonate, Calcium carbonate.
The reflux temperature is in the range of 80-85οC.
In said process shortening of reaction time is the main advantage. The reaction may finish in 15-
18 hrs or less instead of 20-23 hrs reported in the prior the art when the mixture of two or more
polar aprotic solvents used. Moreover, the purity of obtained product is higher than the purity
reported in prior art.
The HPLC purity of trans(R, R-3a,7a-octahydroisoindolium-2-spiro-1’-4’-(1,2-benzoisothiozole-
3-yl)piperazine methane sulfonate thus obtained is in the range of 99-99.97%.
In another embodiment, the process for preparation of Lurasidone free base is disclosed which
comprises:
(a) reacting trans(R, R-3a,7a-octahydroisoindolium-2-spiro-1’-4’-(1,2-benzoisothiozole-3-
yl)piperazine methane sulfonate of formula- 5 with (3aS,4R,7S,7aR)-hexahydro-4,7- methanolH-
isoindole-l,3-(2H)-dioneof formula-6 in presence of dipolar aprotic solvent and base at 100-
120οC for 2-3 hrs and
8
(b) isolating Lurasidone free base.
The term “dipolar aprotic solvent” refers to N-methyl pyrrolidone, N,N-dimethyl formamide,
N,N-dimethyl acetamide and Dimethylsulfoxide. The base is selected from the group consisting
of Potassium carbonate, Sodium hydroxide, Barium hydroxide and Lithium hydroxide.
The HPLC purity of Lurasidone free base thus obtained is in the range of 99.5-99.97%.
In another aspect, the invention provides process for preparing hydrochloride salt of Lurasidone
which comprises:
(a) dissolving Lurasidone base in an alcohol at 50-70οC;
(b) adding alcoholic hydrochloric acid and cooling at 0-5οC; and
(c) isolating Lurasidone hydrochloride.
In the above embodiment the alcohol is isopropyl alcohol.
The HPLC purity of Lurasidone hydrochloride thus obtained is in the range of 99.5-99.8%
The process of the instant invention to obtain Lurasidone free base and its hydrochloride salt is
depicted in the reaction scheme-2.
OH
OH + H3C S
O
O
Cl
O
O
S
O
O
CH3
S
O
O
CH3
N
NH
S
N
N N + S
N
NH
O
O
N N S
N
N
O O
H H
N N S
N
N
O O
H H
.HCl
+
+
Organic base
Base
Polar aprotic solvent
Base
dipolar aprotic solvent
Alcohol Solvent
Alcoholic HCl
Formula-2
Formula-3 Formula-4
Formula-6 Formula-5
Formula-1
Formula-1a
9
The following examples, which include preferred embodiments, will serve to illustrate the
practice of this invention, it being understood that the particulars shown are by way of example
and for purpose of illustrative discussion of preferred embodiments of the invention.
Examples:
Example-1: Preparation of (R,R) trans 1,2-Bis(methane sulphonyl methyl)cyclohexane
To the 250cc Toluene25g (R,R)trans 1,2-bis(hydroxymethyl)cyclohexane and 0.571mole
Triethyl amine were added at ambient temperature and cooled to 0-5°C and followed by addition
of 0.449mole methane sulphonyl chloride. The reaction mixture was stirred at ambient
temperature about 2-3hours.De-ionized water was added. The organic layer was separated and
concentrated under reduced pressure at 45°C. Added 125cc Iso propyl alcohol to the reaction
mixture, stirredat 50-60°C for about 30 min and cooled to 0-5°C.Filtered and dried at 50°C to
obtain 80-86% (R,R)trans 1,2-bis(methane sulphonyl methyl)cyclohexane.
GC purity:98-99%
Example-2: Preparation of (R,R) trans 1,2-Bis(methane sulphonyl methyl)cyclohexane
To the 250cc Xylene 25g (R,R)trans 1,2-bis(hydroxymethyl)cyclohexane and 0.571mole Triethyl
amine were added at ambient temperature and cooled to 0-5°C and followed by addition of
0.449mole methane sulphonyl chloride. The reaction mixture was stirred at ambient temperature
about 2-3 hours.De-ionized water was added. The organic layer was separated and concentrated
under reduced pressure at 45°C. Added 125cc Iso propyl alcohol to the reaction mixture, stirred
at 50-60°C for about 30 min and cooled to 0-5°C.Filtered and dried at 50°C to obtain 80-86%
(R,R)trans 1,2-bis(methane sulphonyl methyl)cyclohexane.
GC purity:98-99%
Example-3: Preparation of (R,R) trans 1,2-Bis(methane sulphonyl methyl)cyclohexane
To the 25cc pyridine 5g of (R,R)trans 1,2-bis(hydroxymethyl)cyclohexane and 0.09mole
methane sulphonyl chloride were added at ambient temperature and cooled to 0-5°C.stirred at
ambient temperature about 1-2hours. 25cc de-ionized water and 50cc dichloromethane were
added. pH was adjusted to 3-4. Organic layer was separated and concentrated under reduced
pressure at 40°C.25cc Iso propyl alcohol was added to degass the mass and stirred at 50-60°C for
10
about 30 min and cooled to 0-5°C. Filtered the solid and dried at 50°C to obtain 80-86%
(R,R)trans 1,2-bis(methane sulphonyl methyl)cyclohexane.
GC purity: 98-99.5%
Example 4: Preparation of (R, R) trans 1, 2-Bis (methane sulphonylmethy)cyclohexane
To the 25cc N-methyl Morpholine5g (R,R)trans 1,2-bis(hydroxymethyl)cyclohexane and
0.09mole methane sulphonyl chloride were added to at ambient temperature and cooled to 0-
5°C. Stirred the reaction mixture at ambient temperature forabout 1-2 hours. De-ionized water
and ethyl acetate were added. Organic layer was separated and concentrated under pressure at
45°C.125cc Iso propyl alcohol was added and the reaction mixture was stirred at 50-60°C for
about 30 min and cooled to 0-5°C.Filtered and dried at 50°C to obtain 80-86% (R,R)trans 1,2-
bis(methane sulphonyl methyl)cyclohexane.
GC purity:96-98%
Example-5: Preparation of trans(R, R-3a,7a-octahydroisoindolium-2-spiro-1’-4’-(1,2-
benzoisothiozole-3-yl)piperazine methane sulfonate
To the 250cc mixture of Acetonitrile and DMF25g (lR,2R)-(-)-trans-cyclohexane- 1 ,2-
diylbis(methylene)dimethanesulfonateand 0.083mole 3-(Piperazine-l-yl)benzo[d]isothiazole,
0.165mole sodium carbonate were added and reaction mixture was refluxed for 15-18hours.
After completion of reaction the reaction mixture was filtered and washed solid with
acetonitrile. The filtrate was distilled under vacuum to remove acetonitrile. The residue was
treated with 250cc acetone and heated to 50-60°C for 1 hour followed by cooling. The
precipitated product was stirred for 2-3 hours at 25°C and filtered to obtain 80-85% trans(R, R-
3a,7a-octahydroisoindolium-2-spiro-1’-4’-(1,2-benzoisothiozole-3-yl)piperizine methane
sulfonate
HPLC purity:99-99.97%.
Example-6:Preparation of trans(R, R-3a,7a-octahydroisoindolium-2-spiro-1’-4’-(1,2-
benzoisothiozole-3-yl)piperazine methane sulfonate
To the 250cc mixture of Acetonitrile and DMAc25g(lR,2R)-(-)-trans-cyclohexane-1 ,2-
diylbis(methylene)dimethanesulfonate, 0.083mole 3-(piperazin-l-yl)benzo[d]isothiazole, and
0.165mole sodium carbonate were added and refluxed for 15-18 hours. After completion of
reaction the reaction mixture was filtered and washed solid with acetonitrile. The filtrate was
11
distilled under vacuum to remove Acetonitrile. The residue was treated with 250cc acetone and
heated to 50-60°C for 1 hour followed by cooling. The precipitated product was stirred for 2-3
hours at 25°C and filtered to obtain 80-85%trans(R, R-3a,7a-octahydroisoindolium-2-spiro-1’-
4’-(1,2-benzoisothiozole-3-yl)piperizine methane sulfonate.
HPLC purity: 99-99.97%
Example 7: Preparation of Lurasidone free base
To the 350cc N-methyl pyrrolidone charged 0.173mole potassium carbonate; 50g trans(R, R-
3a,7a-octahydroisoindolium-2-spiro-1’-4’-(1,2-benzoisothiozole-3-yl)piperazine methane
sulfonate and 0.153mole (3aS,4R,7S,7aR)-hexahydro-4,7- methano-lH-isoindole-l,3-(2H)-dione
and heated the mixture up to 100-120°C for 2-3hours.After completion of the reaction added
750ccwater and 500cc ethyl acetate. The organic layer was separated and treated with activated
carbon and concentrated under reduced pressure at 45°C. Added 500cc Iso propyl alcohol and
the reaction mixture was stirred at 50-60°C for about 15-30 min and cooled to 0-5°C.Filtered
solid and cake washedwith isopropyl alcohol to give 87% Lurasidone free base.
HPLC purity: 99.5-99.97%
Example 8: Preparation of Lurasidone free base
To the 50cc N-methyl pyrrolidone charged 0.023mole Sodium hydroxide; 5g(R, R-3a,7aoctahydroisoindolium-
2-spiro-1’-4’-(1,2-benzoisothiozole-3-yl)piperazine methane sulfonate and
0.153mole (3aS,4R,7S,7aR)-hexahydro-4,7- methano-lH-isoindole-l,3-(2H)-dione and heated the
mixture upto 100-120°C for 2-3hours. After completion of the reaction added 75ccwater and
50cc ethylacetate. The organic layer was separated and treated with activated carbon and
concentrated under reduced pressure at 45°C.50cc Isopropylalcohol was added and reaction
mixture was stirred at 50-60°C for about 15-30 min and cooled to 0-5°C. Filtered solid and cake
washed with isopropyl alcohol to give 84-87% Lurasidone free base.
HPLC purity: 99.5-99.97%
Example 9:Preparation of Lurasidone free base
To the 50cc N-methyl pyrrolidone charged 0.03mole Barium hydroxide,5g(R, R-3a,7aoctahydroisoindolium-
2-spiro-1’-4’-(1,2-benzoisothiozole-3-yl)piperazine methane sulfonate and
12
0.015mole (3aS,4R,7S,7aR)-hexahydro-4,7- methano-lH-isoindole-l,3-(2H)-dione and heated the
contents up to 100-120°C for 2-3hours. After completion of the reaction added 75ccwater and
50cc ethylacetate. The organic layer was separated and treated with activated carbon and
concentrated under reduced pressure at 45°C.50cc Iso propyl alcohol was added and the reaction
mixture was stirred at 50-60°C for about 15-30 min and cooled to 0-5°C. Filtered solid and cake
washed with isopropyl alcohol to obtain 84-87% Lurasidone free base.
HPLC purity: 99.5-99.97%
Example 10:Preparation of Lurasidone hydrochloride salt
To the 100cc isopropyl alcohol10g Lurasidone was added, dissolved and stirred for 10-15min at
room temperature and heated the solution upto 50-70°C. Solution of 14% of 4ml hydrogen
chloride in Iso propyl alcohol was added to the reaction mass. Clear solution observed then
cooled the mass slowly up to 0-5°C for 1-2 hours. Filtered solid and cake washed with isopropyl
alcohol. The solid obtained was dried at 40-50°C under vacuum for 4-5 hours to obtain
Lurasidone hydrochloride.
HPLC purity: 99.5-99.8%
Example 11: Preparation of Lurasidone free base (Insitu)
To the 150cc Toluene charged 10g (R,R)trans 1,2-bis(hydroxymethyl)cyclohexane, 0.227mole
triethylamine, 0.178mole methane sulphonyl chloride and stirred for 4-5 hours. After completion
of reaction water was added and separated organic layer. To the Organic layer 0.166mole
potassium carbonate, 0.066mole 3-(Piperazine-l-yl)benzo[d]isothiazole were added and refluxed
for 24 hours. Charged 0.061mole (3aS,4R,7S,7aR)-hexahydro-4,7- methano-lH-isoindole-l,3-
(2H)-dione to this reaction mixture and refluxed for another 24 hours. After completion of
reaction charged water and separated organic layer and distilled under reduced pressure to obtain
residue. The residue was treated with 100cc Iso propyl alcohol .The reaction mixture was stirred
at 50-60°C for about 15-30 min and cool to 0-5°C. Filtered solid and cake washed with isopropyl
alcohol to give a 84-87% Lurasidone free base.
HPLC purity: 95-98%