FORM 2
THE PATENTS ACT, 1970
(Act 39 of 1970)
&
THE PATENT RULES, 2003
COMPLETE SPECIFICATION
(See Section 10 & rule 13)
"AN IMPROVED PROCESS FOR THE PREPARATION OF LURASIDONE BASE AND ITS SALT"
ZCL CHEMICALS LIMITED
215 ATRIUM, "C" WING, 8™ FLOOR
819-821, ANDHERI-KURLA ROAD, CHAKALA,
ANDHERI (EAST), MUMBAI-400 093,
MAHARASHTRA, INDIA.
(An Indian Organization)
The following specification particularly describes the invention and the manner in which it is to be performed.

"AN IMPROVED PROCESS FOR THE PREPARATION OF LURASIDONE
BASE AND ITS SALT"
FIELD OF THE INVENTION
The present invention relates to an industrially feasible process for preparation of substantially pure Lurasidone base of formula la and its conversion to pharmaceutically acceptable salts such as hydrochloride salt and the like in significantly high yields.

BACKGROUND OF THE INVENTION
Lurasidone is an atypical antipsychotic agent belonging to the chemical class of
benzisothiazole derivatives developed by Dainippon Sumitomo Pharma for the
treatment of Schizophrenia and bipolar disorders in human subjects.
Lurasidone hydrochloride is chemically known as (3aR,4S,7R,7aS)-2-{(lR,2R)-2-[4-
(1,2-benzisothiazol-3 -yl)piperazin-1 ylmethyl] cyclohexylmethyl} hexahydro-4,7-
methano-2H-isoindole-l,3-dione hydrochloride, and is commercially launched in USA, Japan and other countries under brand name LATUDA® (trademark of Sunovion Inc, USA) and represented by the chemical structure:

Lurasidone and a process for its preparation are described in U.S. Pat. No. 5,532,372, wherein below cited compounds bearing formula (II) and formula (III)

are mixed and refluxed in xylene in the presence of dibenzo-18-crown-6-ether and an inorganic base like potassium carbonate. The crude Lurasidone base thus generated is then converted in situ to corresponding Lurasidone hydrochloride. This process has few drawbacks; for example, dibenzo-18-crown-6 is a potential carcinogenic, toxic and expensive substance and hence its use is a concern for drug manufacturing or for industrial production. Besides this, the use of such crown ethers with alkali metal carbonates such as potassium carbonate can result in the formation of by-products having further toxicological concerns. Moreover, the chemical
4
synthesis conditions involve heterogeneous processing which lead to lesser purity of Lurasidone base, which, consequently lowers purity and potency of salts derived from such impure lurasidone base and calls for one or more additional purifications. This additional processing while essential to meet quality demand expected for formulating any human medicine, causes great stress to the manufacturing design. It is widely known that extended process operations and purifications cause economic distress by increasing process time, equipment engagement, energy consumption, solvent recovery procedures, storage space, more quality checks and interventional means, excess effluent volumes and overwhelmingly adds burden to other resources deployed for mass production of Lurasidone hydrochloride. Thus, the cited prior art process appears cumbersome, may require tedious reprocessing to achieve the purity desired for a CNS active agent like lurasidone and suffer from use of toxic reagents and difficult to maintain stable reaction times on an industrial scale.

Further, PCT application 2013/121440 described process for the preparation of Lurasidone hydrochloride by reacting below cited compounds bearing formula (II) and formula (III)

in presence of a base and phase-transfer agent in xylene at 130-140°C followed by the
reaction mixture distilled under vacuum. The obtained residue is then treated with
isopropanol to get crystalline Lurasidone base. The obtained Lurasidone base is added
in methanol and 14% isopropanolic hydrochloric acid at 60-65°C. After completion of
reaction the methanol is removed by vacuum distillation and product is isolated from
the residue by adding fresh methanol, cooling the mass and filtration.
No mention of the product purity and isolated yield for lurasidone base as well as
lurasidone hydrochloride is made.
Another reported preparation of lurasidone hydrochloride is as per Indian patent
2013MU00217, which describes a process for the preparation of lurasidone
hydrochloride by reacting below cited compounds bearing formula (II) and (III)

in xylene in the presence of base and phase transfer agent at 125-130°C. After completion of the reaction, xylene is distilled under vacuum followed by addition of water and dichloromethane. The mass is settled and layers are separated and dichloromethane layer is subjected for distillation under vacuum to get semi solid

mass of crude lurasidone base with reported HPLC purity as about 91%. This crude lurasidone base is subjected to acetone purification to get around 77% yield. In alternate process, lurasidone base obtained by treating formula II and formula III in toluene and water in the presence of base and phase transfer agent at 100-110°C. After completion of reaction, reaction mass is cooled and water is added and after settling the mass, layers are separated. The separated toluene layer is distilled under vacuum to obtain semi-solid mass of crude lurasidone base as about 94% pure. This crude product mass may be purified by treating with toluene and methanol to give about 54% yield.
Above obtained Lurasidone base is then converted to Lurasidone hydrochloride by treating with hydrochloric acid of varying concentrations as 33.12%, 4.0%, 32.41%o, 16.19% weight by weight dissolved in isopropanol or various solvents like methanol/water, tetrahydrofuran, isopropanol, acetone, ethyl acetate and water. The purity or similar quality attributes of Lurasidone hydrochloride formed by such processing are not disclosed.
Yet another process for manufacturing lurasidone hydrochloride is reported in PCT application 2013/190455. It describes a process for the preparation of Lurasidone hydrochloride by reacting below cited compounds

in the presence of base and phase transfer agent in toluene/water at 105-110°C for about 20 hours. After completion of the reaction, the mass is settled and layers are separated and toluene layer is distilled out completely followed by addition of acetonitrile in the obtained residue. The reaction mixture is heated at 80-85°C and cooled to give 87% lurasidone base having HPLC purity 99.8%. However compound of formula III used herein is purified by different processes with losing substantial

yield around 40-42%. Further conversion of lurasidone base to lurasidone hydrochloride is also subject to additional yield loss. Hence the process is not economically viable.
Looking at the widely acclaimed therapeutic benefits attributed to Lurasidone hydrochloride, there clearly exists a need for a process which restricts the carryover of toxic impurities to the active drug substance while ensuring high purity without significant loss due to purifications.
Thus, present invention fulfills the need of the art and provides an efficient, economically viable and industrially applicable process for preparation of high purity Lurasidone and its therapeutically used salts such as hydrochloride in high yield.
OBJECT OF THE INVENTION
The object of the present invention is to provide an efficient, robust and industrially advantageous process for preparation of Lurasidone base by reacting chemical compounds bearing formula II and formula III and directly isolating Lurasidone base without any additional purifications.
Another object of the present invention is to provide a direct process for the preparation of Lurasidone hydrochloride of formula I from Lurasidone base with no mandatory purifications required to achieve critical quality attributes like assay or specific optical rotation.
Yet another object of the present invention is to provide substantially high purity Lurasidone base having any single impurity below 0.05%.
Yet another object of the present invention is to provide a process capable of providing Lurasidone base having any single impurity below 0.05%, without additional purification.

Yet another object of the present invention is to provide Lurasidone hydrochloride having any single impurity below 0.05%.
Yet another object of the present invention is to provide a process for the preparation of Lurasidone base and its corresponding pharmaceutically acceptable salts such as hydrochloride salt having any single impurity below 0.05%.
SUMMARY OF THE INVENTION
The present invention provides a process for the direct preparation of Lurasidone base having any single impurity below 0.05% comprising steps of:

a) reacting formula II and formula III in aromatic ether or dihydric alcohol or mixtures thereof in the presence of base without using any quaternary ammonium compound complex; and

b) isolating lurasidone base having purity greater than 99.8% and yield greater than 84% of theory.
The present invention provides a simple and industrially scalable process for direct isolation of lurasidone base after reacting compounds of formula II and formula III, comprising of the following steps:

a) treating the obtained residue of lurasidone base with suitable solvent below 70°C;
b) thereafter, cooling the process mass ;
c) isolating lurasidone base of formula la through conventional design .
The present invention provides a process for manufacturing lurasidone hydrochloride of formula I

having any single impurity below 0.05% by reacting lurasidone base with gaseous hydrogen chloride in suitable solvent.
The present invention provides a process for the preparation of lurasidone hydrochloride

having purity 99.9% and overall yield 80% based on input compound of formula III.
The present invention provides a process for the preparation of Lurasidone hydrochloride having any single organic impurity below 0.05% as per the Scheme-1.


BRIEF DESCRIPTION OF DRAWINGS:
FIG 1: HPLC chromatogram of lurasidone base of formula la
FIG 2: HPLC chromatogram of lurasidone hydrochloride of formula I
FIG 3: Compound mass spectrum report -MS
FIG 4: 1H NMR of Lurasidone hydrochloride of formula I
FIG 5: 13C NMR of Lurasidone hydrochloride of formula I
DETAILED DESCRIPTION OF THE INVENTION
All ranges cited herein include the endpoints, including those that recite a range "between" two values. Terms such as "about", "generally" and the like are to be construed as modifying a term or value such that it is not an absolute. Such terms will be defined by the circumstances and the terms that they modify as those terms are

understood by those skilled in the art. This includes, at the very least, the degree of expected experimental error, technique error and instrument error for a given technique used to measure a value.
According to one of the embodiment, present invention provides a process for the preparation of Lurasidone base having any single impurity below 0.05% comprising steps of:

a) reacting formula II and formula III in aromatic ether or dihydric alcohol or mixtures thereof in the presence of base without using any quaternary ammonium compound complex; and

b) isolating lurasidone base having purity greater than 99.8% and yield greater than
84%.
Surprisingly, the inventors of the present invention found the use of aromatic ether or dihydric alcohol in the condensation of formula II and formula III without using any quaternary ammonium compound complex leads to give lurasidone base having purity greater than 99.8% and having any single impurity below 0.05%.
In general, reaction step a) may be performed in one or more of aromatic ether or dihydric alcohol or mixtures thereof comprising of anisole, phenyl ethyl ether, phenyl propyl ether, substituted phenyl ether such as diphenyl ether and the like, dihydric

alcohol may be selected from mono ethylene glycol (MEG), diethylene glycol (DEG), poly ethylene glycol (PEG) such as PEG-200, PEG-300, PEG-2000, PEG-3000, PEG-6000, poly propylene glycol or mixtures thereof.
The base may be selected from the group consisting of inorganic base such as hydroxides, carbonates and bicarbonates of alkali or alkaline earth metals and organic base. In particular, the suitable base comprises of sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate and the like and triethylamine (TEA), diisopropylethylamine (DIPEA), diisopropylamine (DIPA).
This invention also relates to a high performance liquid chromatography (HPLC) method for identifying and separating the impurities formed during the synthesis of Lurasidone or its pharmaceutically acceptable salts; wherein, the impurities may be unreacted starting materials, by-products of the reaction, products of side reactions, isomeric impurities or degradation products.
Generally, impurities can be identified by its relative position in the chromatogram, where the position in a chromatogram is measure in minutes between time of injection of the sample on the column and the time of elution of the particular component through the detector. The relative position in the chromatogram is known as the "retention time." The convention uses retention time of the product (which is considered principal peak) as 1 and all related substances peaks appearing before and after the principal peaks at various time intervals can be termed as relative retention time with respect to the principal peak.
In HPLC analysis, retention time of a substance can vary depending on sensitivity of instrumentation, test conditions and a few other factors. To mitigate the effects of such variations upon accurate identification of an impurity, those skilled in the art use "relative retention time" (RRT) to identify impurities.

The aforesaid process involves providing Lurasidone base of formula la having any single impurity below 0.05% as cited in HPLC chromatogram of FIG 1.
According to another embodiment, present invention provides a process for the isolation of lurasidone base comprising the steps of:
a) treating the obtained residue of lurasidone base with suitable solvent at below 70°C;
b) cooling the reaction mixture;
c) isolating lurasidone base of formula la.
Surprisingly the inventors of the present invention have found that the isolation process of lurasidone base of formula la in very high purity is attainable by using specific combination of commercially available solvents as cited below.
In general, suitable solvent may be selected from hydrocarbon such as n-heptane, cyclohexane, iso-octane, mesitylene, tetralin, nitrile such as acetonitrile, halogenated solvent such as dichloromethane, chlorobenzene, fluorobenzene, alcohol such as methanol, ethanol, isobutanol, isopropanol ketone such as acetone, methyl isobutyl ketone, methyl ethyl ketone, ester such as ethyl acetate, isopropyl acetate, isobutyl acetate or mixtures thereof, such process may preferably employ a mixture of an alcohol such as ethanol, methanol or 2-propanol and a hydrocarbon such as hexane, heptane or cyclohexane optionally containing an ester or ketone as minor components of such solvent combinations.
Thus produced lurasidone base does not require any additional purification through solvent crystallization and thus leads to significantly improved yield of lurasidone base.
According to another embodiment, present invention provides a process for the preparation of lurasidone hydrochloride of formula I


having any single impurity below 0.05% by treating lurasidone base with gaseous hydrochloric acid in suitable solvent.
In general, suitable solvent may be selected from hydrocarbon solvent such as toluene, xylene, n-heptane, cyclohexane, iso-octane, mesitylene, tetralin or alkanol such as methanol, ethanol, isopropanol or halogenated solvent such as dichloromethane or ketone such as acetone or mixtures thereof.
The aforesaid process involves providing Lurasidone hydrochloride of formula I having any single impurity below 0.05% as cited in HPLC chromatogram of FIG 2.
HPLC Method and Analysis:
The method used for the analysis is a gradient HPLC method according to invention.
The experimental condition used are as follows.
Instrument : HPLC Equipped with UV/PDA detector and suitable software
Mobile phase A pH 2.0, Sodium perchlorate buffer
Mobile phase B Acetonitrile
Diluent Buffer and acetonitrile in the ratio of 70:30 (v/v)
Sample solution 1 mg/ml in diluent
Mode : Gradient
Column : Kromasil C8 (250 mm x 4.6 mm x 5 μ)
Flow rate : 1.4 ml/min
Wavelength : 210 nm
Injection volume : 40 μl
Column oven temp : 45°C
Auto sampler temp : . 10°C
Run time : 50 minute

According to another embodiment, the inventors of the present invention found that Lurasidone hydrochloride having no detectable presence of impurity at RRT: 0.31 which is further characterized in having atomic mass: 346.2 (M+l) as depicted in the "Compound mass spectrum report -MS" of FIG 3. Moreover the very probable impurities of chemical compound inputs bearing formula II at RRT: 0.20 and formula III at RRT: 0.61 also remain below detection limit in the lurasidone base as well as lurasidone hydrochloride synthesized using the present inventive art.
According to another embodiment, present invention provides a process for the preparation of lurasidone hydrochloride

having purity 99.9% and overall high yield of 80% of theory based on input compound of formula III.
The invention is further defined by reference to the following example describing the preparation of the compounds of the invention. It will be apparent to those skilled in the art that many modifications, both to materials and methods, may be practiced without departing from the scope of the invention.

EXAMPLES:
EXAMPLE 1: PREPARATION OF LURASIDONE BASE
Mixture of formula II (41.2gm) and formula III (lOOgm) was charged into a stirred mixture of anisole (200ml), potassium carbonate (37.6gm) and polyethylene glycol-6000 (PEG-6000) in sub-stoichiometric amount under stirring. The whole mass was heated at 90-120°C and maintained for 2 to 4 hours by which time not less than 99 % of compound of formula (III) is converted. After cooling the reaction mass to ambient and diluting with water (300ml) to allow product migration, phases were separated by settling. The organic phase separated was treated with sufficient volume of sodium chloride brine and mixed well before settling for phase separation. The organic phase separated was vacuum distilled and the residue was diluted with Ethanol (200ml) and stirred overnight at 55-65°C. The process mass was cooled below 20°C, filtered, washed with chilled ethanol and dried to give lurasidone base (99.5gm -corresponding to 85.6% of theory) analyzed to have purity greater than 99.8% on HPLC, with no secondary peak found above 0.05 % (area,HPLC)
EXAMPLE 2: PREPARATION OF LURASIDONE BASE
Mixture of formula II (41.2gm) and formula III (lOOgm) was charged into the anisole (200ml), potassium carbonate (37.6gm) and PEG-6000 (5.0gm) under stirring. The reaction mixture was heated at temperature 110-120°C and maintained for 2-4 hours. After completion of reaction, the reaction mixture was cooled to 30°C and water (300ml) was added followed by stirring for 25-30 minutes and layers were separated. The obtained organic layer was mixed with 15% solution of sodium chloride (200gm) and stirred for 25-30 minutes. The organic layer was separated and organic layer was distilled under vacuum to get residue. Methanol (50 ml) and cyclohexane (450 ml) was added into the residue and stirred for about 60 minutes at 55-65°C. Cooled the reaction mixture at 0-5°C, filtered and dried to give lurasidone base (102.5gm -corresponding to 88% of theory) analyzed to have purity greater than 99.8% on HPLC, with no secondary peak found above 0.05 % (area,HPLC)

Spectroscopic Data: Infra-Red (cm"1) (KBr): 3439, 2941, 2920, 2841, 2858, 2808, 2798, 2788, 2772, 1978, 1770, 1700, 1591, 1560, 1490, 1446, 1364, 1290, 1259, 1190, 1170, 1144, 1006, 962, 903, 775, 744, 715, 679, 651, 619, 589.
EXAMPLE 3: PREPARATION OF LURASIDONE BASE
Mixture of formula II (41.2gm) and formula III (lOOgm) was charged into the anisole (200ml) and potassium carbonate (37.6gm) under stirring. The reaction mixture was heated at temperature 113-118°C and maintained for 6-12 hours. After completion of reaction, the reaction mixture was cooled to 30°C and water (300ml) was added followed by stirring for 25-30 minutes and layers were separated. The obtained organic layer was mixed with 15% solution of sodium chloride (200gm) and stirred for 25-30 minutes. The organic layer was separated and vacuum distilled to remove volatiles and get residue. Ethanol (200ml) was added to the residue and stirred for about 90 minutes at 55-65°C. Cooled the reaction mixture at 0-5°C, stirred to permit product separation, filtered and dried to give lurasidone base (98gm - corresponding to 84 % of theory) analyzed to have purity greater than 99.8% on HPLC, with no secondary peak found above 0.05 % (area,HPLC)
EXAMPLE 4: PREPARATION OF LURASIDONE HYDROCHLORIDE
Lurasidone base (lOOgm) was added into heptane (1000ml) under stirring. Hydrogen chloride was slowly introduced to the reaction mixture and continued till pH of reaction mixture achieved below 2. The reaction mixture was then stirred about 1 hour below 30°C and cooled to 0-5°C. The reaction mixture was filtered and washed with n-heptane followed by drying to give Lurasidone hydrochloride (lOO.gm -corresponding to 93 % of theory) analyzed to have purity 99.9% on HPLC, with no secondary peak found above 0.05 % (area,HPLC) Spectroscopic Data:
FIG 4: 'H NMR of Lurasidone hydrochloride of formula I FIG 5: 13C NMR of Lurasidone hydrochloride of formula I

EXAMPLE 5: PREPARATION OF LURASIDONE HYDROCHLORIDE
Lurasidone base (lOOgm) was added into dichloromethane (900ml) under stirring. Hydrochloric acid gas was passed slowly into the reaction mixture till at least one or more mole equivalent of hydrogen chloride is absorbed in the mass. The reaction mixture was then stirred below 30°C for 30 minutes or longer and cooled to 0-5°C. Water (100ml) was carefully added to dilute the reaction mixture and stirred for 15-20 minutes below 20°C before settling and separating phases. The organic phase separated was stripped to get solid residue. Dichloromethane (100ml) and acetone (200ml) were added to the residue and stirred for 25-30 minutes at 25-30°C. The reaction mixture was then cooled to 0-5°C, filtered and dried to give Lurasidone hydrochloride (100.5gm - corresponding to 94 % of theory) analyzed to have purity 99.9% on HPLC, with no secondary peak found above 0.05 % (area,HPLC).

WE CLAIM:
1. A process for the preparation of Lurasidone base having any single impurity below 0.05% comprising steps of:

a) reacting formula II and formula III in an ether or dihydric alcohol or mixtures thereof in the presence of base without using any quaternary ammonium compound complex; and

b) directly isolating lurasidone base in chromatographic purity exceeding 99.8% and isolated yield as at the least 84% of theory.
2. The process according to claim 1, wherein the ether used is selected from the group consisting of anisole, phenyl ethyl ether, phenyl propyl ether, diphenyl ether or mixtures thereof.
3. The process according to claim 1, wherein dihydric alcohol is selected from the group consisting of mono ethylene glycol (MEG), diethylene glycol (DEG), any poly ethylene glycol (PEG) having estimated atomic mass in the range of 200-6000 unit, poly propylene glycol or mixtures thereof.
4. The process according to claim 1, wherein base is selected from group consisting of inorganic base such as hydroxides, carbonates and bicarbonates of alkali or alkaline earth metals and organic base. In particular, the suitable base comprises of sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate,

potassium carbonate, sodium bicarbonate, potassium bicarbonate and the like and secondary or tertiary amines such as triethyl amine (TEA), diisopropylethylamine (DIPEA), diisopropylamine (DIPA).
5. The process according to claim 1, wherein isolation of lurasidone base comprising
the steps of:
a) the obtained residue of lurasidone base is treated with suitable solvent at below 70°C;
b) cooling the resulting mass;
c) isolating lurasidone base of formula la.

6. The process according to claim 5, wherein suitable commercial solvent is selected from hydrocarbon such as n-heptane, cyclohexane, iso-octane, mesitylene, tetralin, nitriles including nitrile such as acetonitrile, halogenated solvents such as dichloromethane, chlorobenzene, fluorobenzene, mono or polyhydroxy solvents such as methanol, ethanol, isobutanol, isopropanol and similar, ketones such as acetone, methyl isobutyl ketone, methyl ethyl ketone, esters such as ethyl acetate, isopropyl acetate, isobutyl acetate or mixtures thereof; such process may preferably employ a mixture of an alcohol such as ethanol, methanol or 2-propanol and a hydrocarbon such as hexane, heptane or cyclohexane optionally containing an ester or ketone as minor components of such solvent combinations.
7. A process for the preparation of lurasidone hydrochloride of formula I

having any single impurity below 0.05% by reacting lurasidone base with gaseous hydrogen chloride in suitable commercial solvent. 8. The process according to claim 7, wherein suitable solvent is selected from hydrocarbon solvent such as toluene, xylene, n-heptane, cyclohexane, iso-octane,

mesitylene, tetralin or alkanol such as methanol, ethanol, isopropanol or halogenated solvent such as dichloromethane or ketone such as acetone or mixtures thereof. 9. Lurasidone hydrochloride of formula I having any single impurity below 0.05%.