DESC:Field of the invention:
The present invention relates to a process for the preparation of Lurasidone hydrochloride of formula-I.

Formula-I
Background of the invention:
Lurasidone hydrochloride is an atypical antipsychotic belonging to the chemical class of benzisothiazol derivatives. It is indicated for the treatment of patients with schizophrenia.
Lurasidone firstly reported in US patent no. 5,780,632. It discloses process for the preparation of Lurasidone and its hydrochloride salt.
US7605260B2 patent describes industrial feasible process for the preparation of Lurasidone hydrochloride by treating Lurasidone base with 1.8-5.0% aq. Hydrochoric acid solution in acetone.
WO20121331606A1 application discloses purification of Lurasidone base using Isopropyl alcohol and denatured spirit but, Lurasidone base has purity of 98.41% only. It also disclosed formation of Lurasidone hydrochloride from Lurasidone base by treating it with 7% aq. HCl and ethyl acetate. But, this process causes trapping of ethyl acetate in final Lurasidone hydrochloride crystal.
WO201319045A2 application discloses purification of Lurasidone base using various solvents example, ethyl acetate, methyl tert-butyl ether, IPA, acetone, methanol, methanol-acetonitrile mixture, methanol-acetonitrile-water mixture, acetonitrile-water mixture, acetone-water mixture. It also disclosed salification process for the preparation of Lurasidone hydrochloride using IPA-IPA-HCl, ethyl acetate-ethyl acetate-HCl, ethyl acetate- aq. HCl, ethyl acetate-IPA- HCl, acetone-IPA-HCl.
Although, prior art describes various processes for the purification of Lurasidone base and Lurasidone hydrochloride, its demerits encourage us to invent new process which has no solvent trapping in final product as well as devoid of genotoxic impurity in final Lurasidone hydrochloride product.
Summary of the invention:
An object of the present invention is to provide an excellent industrial process for producing Lurasidone hydrochloride of formula-I.
The present inventors have tenaciously studied the process for the preparation of Lurasidone hydrochloride from Lurasidone base in order to solve the problem of solvent trapping in final Lurasidone Hydrochloride and found that acetic acid is choice of solvent which is not entrapped itself into crystal lattice of Lurasidone hydrochloride.
Use of acetic acid as solvent has many advantages as mention below.
1) Lurasidone Hydrochloride and Lurasidone Base both are soluble in Acetic acid.
2) ICH limit of Acetic acid is 5000 ppm.
3) Acetic acid is miscible with water, so product can be precipitated by addition of water.
4) Very low OVI content in the final API.
5) Retention and Consistency of the desired polymorph.
6) Very effective purification solvent, give the final purity of API more than 99.9%.
7) Very low volume of solvent is used (3-4 volume).
All of these merits contribute to reducing the overall cost of the process, high purity product and making it commercially interesting and allowing it to be put into practice on an industrial level.
Details description of the invention:
The present invention is to provide an excellent industrial process for producing Lurasidone hydrochloride of formula-I.
A process for producing Lurasidone hydrochloride of formula-I,

which comprises providing solution of Lurasidone base of formula-II in acetic acid and reacting it with hydrogen chloride.
A process for the preparation of Lurasidone hydrochloride of formula-I comprising;
a. providing solution of Lurasidone base of formula-II in acetic acid;
b. adding hydrogen chloride into resulting solution of step-a;
c. adding water into resulting solution of step-b;
d. isolating Lurasidone hydrochloride.
Hydrogen chloride can be used in the form of concentrated hydrochloric acid or aqueous hydrochloric acid solution or hydrogen chloride gas.
An acetic acid is usually used in an amount of 1 to 50 times (by weight) of the amount of the Lurasidone hydrochloride (Formula-I), preferably in an amount of 2 to 25 times (by weight) of the amount of the Lurasidone hydrochloride (Formula-I) and more preferably in an amount of 3 to 10 times (by weight) of the amount of the Lurasidone hydrochloride (Formula-I).
The temperature for dissolving the Lurasidone hydrochloride in an acetic acid solvent is usually in the range of 0° C to a reflux temperature, preferably in the range of 25° C to reflux temperature, more preferably 25° to 35° C is used.
The equivalent of hydrogen chloride to be used is usually in the range of 0.9 to 3 equivalents, preferably in the range of 1.0 to 2.0 equivalents, more preferably in the range of 1.0 to 1.3 equivalents, to one equivalent of the Lurasidone base.
The temperature of treating of the Lurasidone base of formula-II with concentrated hydrochloric acid in acetic acid is usually in the range of 0° C to a reflux temperature, preferably in the range of 25° C to reflux temperature, more preferably 30±5° C is used.
The time of treating hydrochloric acid with Lurasidone base of formula-II is in the range of one minute to 2 hours, preferably in the range of from 10 minute to 1 hour.
The crystal of Lurasidone hydrochloride is precipitated by adding water into the mixture of Lurasidone hydrochloride in acetic acid. Precipitated product can be separated by a conventional method, for example, by filtration.
Drying of Lurasidone hydrochloride can be done under reduced pressure or drying under atmospheric pressure or drying under atmosphere of inert gas such as nitrogen or air flow. The drying temperature is in the range of 40° to 80° C, preferably in the range of 50° to 70° C.
A detailed process for the preparation of Lurasidone hydrochloride is described in scheme-1.
The starting materials of present invention are prepared by following scheme 2.


The following examples illustrate the invention further. It should be understood, however, that the invention is not confined to the specific limitations set forth in the individual examples but rather to the scope of the appended claims.
Examples:
Stage-I: Preparation of (1R, 2R)-Cyclohexane-1, 2-diyldimethanediyldimethanesulfonate. (Formula- VI)
Methylene dichloride (1 L) and (1R,2R)-1,2-cyclohexanedimethanol (100 g) (Formula- VII) were charged in RBF at 25±5°C under nitrogen atmosphere. Resulting reaction mass was stirred for 5 to 10 min at 25±5°C under nitrogen atmosphere. Triethylamine (154.37 g) was added into this reaction mixture. After stirring this reaction mixture, it was cooled to 0-10 °C under nitrogen atmosphere. Methane sulfonyl chloride (158.86 g) was added drop wise to the reaction mixtures at 0-15°C under nitrogen atmosphere. Resulting reaction mixture was heated up to 22±2°C and maintained the temperature for 1hr. Water was added into reaction mixture at 25±5°C and stirred the reaction mixture for 5-10 min. settled the reaction mixture and collected the organic layer which was washed with water at least 2-3 times. Organic layer was distilled out under vacuum at 37±2°C. Methylene dichloride was added into reaction mass at 37±2°C and cooled the reaction mass up to 25±5°C. Cyclohexane was added slowly to reaction mass at 25±5°C. Reaction mass was stirred for 1 hr at 25±5°C and filter the solid at 25±5°C. Resulting wet cake was washed with cyclohexane (2* 100 ml) at 25±5°C. Dry the solid in VTD at 40±2°C for 6 hrs
Stage-II: Preparation of (3aR, 7aR)-4’-(benzo[d]isothiazol-3-yl)-octahydro-spiro[isoindole-2,1’-piperazin]-1’-ium mesylate
Acetonitrile (1.0 L) and (1R, 2R)-Cyclohexane-1,2-diyldimethanediyldimethanesulfonate (100 g) was charged into RBF at 30±5°C. Reaction mixture was stirred for 5-10 min at 30±5°C. 3-(1-Piperazinyl)-1,2-benzothiazole (73.00 g) was added into this reaction mixture. Na2C03 (35.29 g) and tetra butyl ammonium hydrogen sulphate (5.65 g) were added into this reaction mixture at 30±5°C. Resulting reaction mixture was stirred for 5-10 min at 30±5°C and heated up to at 83±2°C for 6 hrs. The reaction mass was cooled up to 73±2°C and Na2C03 (35.29 g) was charged into it and heated upto 83±2°C for 9 hrs. Acetonitrile (500 ml) was charged at 70±5°C and reaction mixture was stirred for 30 min at 76±2°C. Wet cake was collected by filtration. Ethyl acetate (100 ml) was added to the reaction mixture at 45±2°C. Organic layer was distilled out under vacuum at 45±2°C. Resulting crude mass was again washed with ethyl acetate (100 ml) at 30±5°C. Suck dry the solid till completely removal of filtrate ml. The solid was dried in VTD at 55±2°C for 8 hrs.
Stage-III: Preparation of (3aR,4S,7R,7aS)-2-{(1R,2R)-2-[4-(1,2-Benzisothiazol-3- yl)piperazin-1-ylmethyl] cyclohexylmethyl}hexahydro-4,7-methano-2H- isoindole-1,3-dione
Toluene (1500 ml) and (3aR, 7aR)-4’-(benzo[d]isothiazol-3-yl)-octahydro-spiro[isoindole-2,1’-piperazin]-1’-ium mesylate (100 g) into RBF at 30±5°C. Into above reaction mixture, (3aR,4S,7R,7aS)-4,7-methano-1H-isoindole-1,3(2H)-dione (RM-II) (42.90 g), Potassium carbonate (39.16 g) and 18-crown-6-ether (3.12 g) were charged and stirred it for 5-10 min 30±5°C. Resulting reaction mixture was heated to 110±2°C for 4 hrs. Reaction mass was cooled to 30±5°C and filtered it. Wet cake was collected and washed it with toluene (100 ml) at 30±5°C. Water (300 ml) was added to reaction mass at 30±5°C and organic layer was collected. Water (300 ml) was again added to organic layer and stirred the reaction mass for 5-10 min at 30±5°C and aqueous layer was discarded and organic layer was collected into this organic layer activated carbon (5.0 g) was added at 30±5°C. Reaction mass was stirred for 30 min at 30±5°C and it was filtered through hyflo at 30±5°C and hyflo was washed with toluene (100 ml) at 30±5°C. Organic layer was distilled out under vacuum at 50±2°C. denatured alcohol (with 2.8-3.8 % Cyclohexane) was added (100 ml) at 50±2°C and stirred it for 10-15 min at 50±2°C. denatured alcohol (with 2.8-3.8 % Cyclohexane) was distilled out and again it was washed with denatured alcohol (with 2.8-3.8 % Cyclohexane) (1800 ml) at 50±2°C and reaction mass was heated up to 78±2°C for 10 min and it was cooled gradually to 27±2°C in 1 - 2 hours. Reaction mass was stirred for 1 hr and solid was collected by filtration at 27±2°C and wet cake was washed with denatured alcohol (with 2.8-3.8 % Cyclohexane) (100 ml). Dry the solid under vacuum at 60±5°C for 8 hrs.
Stage-IV: Preparation of (3aR,4S,7R,7aS)-2-{(1R,2R)-2-[4-(1,2-benzisothiazol-3-yl)piperazin-1-ylmethyl]Cyclohexylmethyl}hexahydro-4,7-methano-2H-isoindole-1,3-dione hydrochloride
Acetic acid (300ml) and Lurasidone base were charged (100 g) at 30±5°C. Reaction mass was stirred until clear solution was observed visually at 30±5°C. Activated carbon was added (5.0 g) to reaction mass at 30±5°C and was stirred for 10-15 min a at 30±5°C. Reaction mass was filtered through hyflo bed at 30±5°C and was washed it with acetic acid (100 ml) at 30±5°C. Conc. HCl was added to reaction mass at 30±5°C and was stirred 30 min at 30±5°C. Water (1000 ml) was slowly added to the reaction mixture at 30±5°C and was stirred it for 2 hr at 30±5°C. Solid was filtered at 30±5°C. The wet cake was washed with Water (2*100 ml). The solid was suck dried till complete removal of filtrate. Resulting solid was Dried under vacuum at 60±2°C for 8 hrs.
,CLAIMS:1. A process of Lurasidone hydrochloride of formula-I

Formula-I
comprising, reacting Lurasidone base with hydrogen chloride in presence of acetic acid.
2. A process according to claim 1, wherein hydrogen chloride can be in the form of concentrated hydrochloric acid, hydrogen chloride gas or aqueous hydrochloric acid.
3. A process according to claim 1, wherein Lurasidone hydrochloride is precipitated by adding water into a mixture of Lurasidone hydrochloride and acetic acid.