INTRODUCTION:

Isomers are defined as by various instrumental method, molecules with same or identical atomic configuration, but with different three-dimensional arrangements or orientation of their atom in space i.e., isomers are two or more different molecules with the identical molecular formula but different structural arrangments.^1–3

Determination of Isomerism fonds importance in the field of pharmacology as different isomers unique in their pharmacokinetic and pharmacodynamic properties^4. Because of these majority of the molecules are marketed as single isomers. Isomerism in the field of pharmaceutical has opened a new era of research in the field of pharmacology, and it helps to understanding the mechanisms behind the adverse effects and the drug actions.⁵ Increasing knowledge of isomerism and their side effect can help in to introducing safer and effective drug alternatives of the emerging as well as existing drugs. Many existing marketed drugs have gone chiral switch i.e., one of its isomers from racemate mixture.⁶ Shift from Cetirizine to Levocetirizine is one such example where effective and safer drug was made available. On the other hand, chiral shift of Fenfluramine to Dexfenfluramine proved fatal.⁷

In order to guarantee the safety and quality of the drug, it is crucial to identify and quantify the isomeric impurities in the drug material during the API process development. It is always preferable to control or minimize the formation of the impurities during the reaction by understanding the kinetics of the reaction and root cause for the formation rather than multiple purifications at the end⁸.

Molecules that are similar in atomic bonding constitution but different in the three-dimensional arrangement of the atoms called stereoisomers. They have unique identical physical chemical properties except for optical rotatory and in a chiral environment. Appropriate manufacturing and control procedures should be used to assure stereoisomeric composition of a product, with respect to identity, strength, quality, and purity. Applications for enantiomeric and racemic drug substances should include a stereo chemically specific identity test and or a stereo chemically selective method. The choice of the controls should be based upon the substances and method of determination and stability characteristics.^9-14

The present work explains about the lurasidone hydrochloride manufacturing process free from optical isomers and focused on the root of formation of different isomers. Control strategy designed for KRM, KSM, intermediate and finished API. This work also explains the effectiveness of proposed control strategy from laboratory to commercial scale.

Introduction of Lurasidone Hydrochloride:

Lurasidone hydrochloride, (3aR, 4 S, 7 R, 7aS)− 2-((1 R, 2 R)− 2-[4-(1, 2-benzisothiazol-3-yl)piperazin-1-ylmethyl]cyclohexylmethyl)hexahydro-4, 7-methano-2H-isoindole-1, 3-dione hydrochloride (Figure.1), is an atypical antipsychotic drug approved by the U.S. Food and Drug Administration (FDA) for treatment of Schizophrenia . The lurasidone hydrochloride is an antipsychotic activity and it is mediated through a combination of central dopamine Type 2 (D2) and serotonin Type 2 (5-HT2A) receptor antagonism. Lurasidone hydrochloride contain a benzothiazole moiety who’s derivative and an atypical antipsychotic drug which is first time developed by Dainippon Sumitomo Pharma in collaboration with Merck Research Laboratories. US Food and drug administration approved Lurasidone hydrochloride (1) with the Brand name: Latuda in 2010 for the treatment of schizophrenia as an immediate release oral tablet. Lurasidone hydrochloride is chiral molecule containing of six chiral centres^15-17.

Figure.1: Lurasidone Hydrochloride(1)

Lurasidone hydrochloride(1) is manufactured by using three key starting materials (KSM) namely

i. KSM-01: (1R, 2R)-1, 2-cyclohexanedimethanol(13),

ii. KSM-02: 3-piperazin-1-yl-1, 2-benzisothiazole(7)

iii. KSM-03: (3aR, 4S, 7R, 7aS)-hexahydro-4, 7-methano-2H-isoindole-1, 3-dione(24) .

Isomerism in Lurasidone hydrochloride:

Lurasidone hydrochloride consists of six chiral centres, e. g. C1, C2, C11, C12, C15 and C16. Currently, the clinically used form is a single isomer. The crystal structure of the title compound is built up of discrete lurasidium anions and chloride cations⁸ (Figure.2).

Figure 2:- Lurasidone Hydrochloride chiral centres

Introduction of chirality in lurasidone hydrochloride:

The process Consist of synthesis of three Key staring material and two isolated intermediate out of those two key starting materials (1R, 2R)-1, 2-cyclohexane dimethanol (13) and 3aR, 4S, 7R, 7aS)-hexahydro-4, 7-methano-2H-isoindole-1, 3-dione (22) having chiral carbon, while 3-Piperazin-1-yl-1, 2-Benzisothiazole(7) does not impact the chirality in the lurasidone hydrochloride, (Figure 3). The ROS, brief manufacturing process and detailed discussion on isomers of trans (1R, 2R)-1, 2-cyclohexanedimethanol) and (3aR, 4S, 7R, 7aS)-hexahydro-4, 7-methano-2H-isoindole -1, 3-dione discussed in result and discussion section. (Figure.6).

Figure 3 KSM of Lurasidone HCl

MATERIALS:

Melting points were determined on Analab melting point apparatus, in open capillary tubes and are uncorrected. The 1H NMR and 13C NMR spectra were recorded on a Varian Gemini 400 MHz FT NMR spectrometer. Chemical shifts were reported in parts per million using tetramethyl silane as internal standard and are given in units. The solvents for NMR spectra were deuterochloroform and deuterodimethylsulfoxide unless otherwise stated. Infrared spectra were taken on Perkin Elmer Spectrum 100 in potassium bromide pallets unless otherwise stated. Hosli CH-Analyzer were used for elemental analyses and were performed on the results were within ±0.35% of the calculated values. High resolution mass spectra were obtained with a Shimadzu GC-MS QP mass spectrometer with an ionization potential of 70 eV. Reactions were monitored by High performance liquid chromatography on Agilent Technologies 1200 series. Gas chromatography on Agilent Technologies 7683B with head space was used for analysing the residual solvents. Reagent grade chemicals used were either commercially available and were used without additional purification or prepared by standard literature procedures. TLC was performed on silica-gel plates (60 F254; Merk), and TLC visualizations were performed with ultraviolet light.

METHODS:

Synthesis of Lurasidone Hydrochloride:

Lurasidone hydrochloride (1)is manufactured by using three key starting materials namely (1R, 2R)-1, 2-cyclohexane dimethanol (13), 3-Piperazin-1-yl-1, 2-Benzisothiazole(7) and (3aR, 4S, 7R, 7aS)-hexahydro-4, 7-methano-2H-isoindole-1, 3-dione(22) . After the evaluation of route of synthesis from the available literature^19-23, The process is evaluated with respect to process efficiency, process economy at industrial, ability to control process related and isomeric impurities, no of synthesis steps, reaction temperature, solvent volume, purification technique etc. Based on the available literature cost effective and efficient process for the synthesis of lurasidone is developed Presented in Roure of synthesis (Figure 4).

Figure 4:- Route of Synthesis for Lurasidone Hydrochloride:

Manufacturing process of three key starting materials namely (1R, 2R)-1, 2-cyclohexane dimethanol (13), 3-Piperazin-1-yl-1,2-Benzisothiazole(7) and (3aR, 4S, 7R, 7aS)-hexahydro-4, 7-methano-2H-isoindole-1, 3-dione(22) and there control strategy to get desired quality of required isomers is designed using different process parameters like process efficiency, process economy at industrial, ability to control process related and isomeric impurities, no of synthesis steps, reaction temperature, solvent volume, purification technique etc. details manufacturing process and route od synthesis of each key starting material is discussed in preceding section

Synthesis of 3-piperazin-l-yl-l, 2-benzisothiazole hydrochloride (KSM-2)/7:- Synthesis of 3-piperazin-l-yl-l, 2-benzisothiazole hydrochloride involves the nucleophilic substitution reaction of anhydrous piperazine(6) with 3-chloro-l, 2-benzisothiazole(5) using tertiary butanol as solvent to be offered 3-piperazin-l-yl-l, 2-benz-isothiazole(3) as a freebase which was subsequently converted into its hydrochloride salt (Figure 5).

Figure 5: ROS of 3-piperazin-l-yl-l, 2-benzisothiazole hydrochloride(3)

3-piperazin-l-yl-l, 2-benzisothiazole hydrochloride (7) is contributing major component to lurasidone hydrochloride and one of active component to give efficacy of the molecule. It is a does not present any chiral carbon or geometrical isomerism, hence not responsible for isomerism in lurasidone hydrochloride.

Synthesis of trans (1R, 2R)-1, 2-cyclohexanedimethanol(KSM-1)/(13):- Manufacturing process of trans (1R, 2R)-1, 2-cyclohexanedimethanol (13) involves three chemical transformation and diastereomeric resolution. Cis-l, 2-cyclohexane dicarboxylic acid anhydride(8) is reflux in mixture of ethanol and toluene in presence of conc. H₂SO₄ to furnish cis-l, 2-cyclohexane dicarboxylic acid ethyl ester . The obtained mixture of isomers is further hydrolysed using potassium hydroxide to furnish mixture of cis-l, 2- cyclohexane dicarboxylic acid and trans-l, 2-cyclohexane dicarboxylic acid (9).Racemic trans-l, 2-cyclohexane dicarboxylic acid is further treated R -( + )-phenyl ethyl amine(10) in ethanol to furnish crude (1R, 2R)-1, 2-cyclohexane dicarboxylic acid-R-(+)-phenyl ethyl amine diastereomeric salt. The obtained crude salt is further crystallized using the mixture of ethanol and toluene to furnish pure (1 R, 2R)-1, 2-cyclohexane dicarboxylic acid R-(+)- phenyl ethyl amine diastereomeric salt, is then hydrolysed using. The desired product is finally extracted from aqueous phase using tertiary butyl methyl ether. (lR, 2R)-1, 2-cyclohexane dicarboxylic acid is converted to its corresponding dimethyl ester(12) in methanol in presence of thionyl chloride. The (1R, 2R)-1, 2-cyclohexanedimethanol(13) is synthesized using lithium chloride and potassium borohydride (Figure 6)

Figure 6: Route of Synthesis (ROS) for (1R, 2R)-1, 2-cyclohexanedimethanol (2):

Discussion on Stereoisomers in (1R, 2R)-1, 2-cyclohexanedimethanol (13):

Based on the evaluation of route of synthesis and brief manufacturing process for trans (1R, 2R)-1, 2-cyclohexanedimethanol (13) it is identified that there is possibility for presence of two isomers namely trans (1S, 2S)-1, 2-cyclohexanedimethanol(14) and cis 1-2-cyclohexane dimethanol(15 and16) in trans (1R, 2R)-1, 2-cyclohexanedimethanol (13). The possibility of formation of isomer and its controlling in the manufacturing process of trans (1R, 2R)-1, 2-cyclohexanedimethanol (13) is discussed in the proceeding part (Figure 7)

Figure 7: Stereoisomers of (1R, 2R)-1, 2-cyclohexanedimethanol

RESULTS AND DISCUSSION:

Control of isomeric impurities of (1R, 2R)-1, 2-cyclohexanedimethanol(13):

The control strategy for the content of other isomer in (1R, 2R)-1, 2-cyclohexanedimethanol is design by considering the purgability of each isomer in subsequent synthesis sequence. The content of trans (1S, 2S)-1, 2-cyclohexane dicarboxylic acid (11b)is monitored during the synthesis of Trans (1R, 2R)-l, 2-cyclohexane dicarboxylic acid dimethyl ester(12) with the limit of not more than 4.0% initially. Further the content of (1S, 2S)-1, 2-cyclohexane dimethanol and cis 1-2-cyclohexane dimethanol is monitored in (1R, 2R)-1, 2-cyclohexanedimethanol.additionally (1R, 2R)-1, 2-cyclohexanedimethanol and the content of cis 1, 2-cyclohexane dicarboxylic acid is monitored during the 1, 2- cyclohexane dicarboxylic acid as a racemic mixture (12) Further it is then monitored in the specification with the limit of not more than 1.0%. Trend data of for commercial batches of is provided in Table no 1.

Manufacturing process of (3aR, 4S, 7R, 7aS)-hexahydro-4, 7-methano-2H-isoindole-1, 3-dione (KSM-3) (22):

Manufacturing process of (3aR, 4S, 7R, 7aS)-hexahydro-4, 7-methano-2H-isoindole-1, 3-dione (22) involves two chemical transformation amidation of Exo isomer (20) using ammonium acetate to give Cis-exo-5-Norbornene-2, 3-dicarboximide (21).The product is treated with 10 % Palladium on carbon to give crude product which on purification with toluene give pure (3aR, 4S, 7R, 7aS)-hexahydro-4, 7-methano-2H-isoindole-1, 3-dione(22). The details of route of synthesis shown in (Figure 8)

Figure 8: Route of Synthesis for KSM(3)

Stereoisomers in (3aR, 4S, 7R, 7aS)-hexahydro-4, 7-methano-2H-isoindole-1, 3-dione (22): Based on the evaluation of route of synthesis and brief manufacturing process for (3aR, 4S, 7R, 7aS)-hexahydro-4, 7-methano-2H-isoindole-1, 3-dione (22) and its starting material Cis-5-norbornene-exo-2, 3-dicarboxylic anhydride (20), it is identified that there is possibility of presence of another isomer bicyclo-[2.2.1] heptane-2,3-di-endo-carboximide (24) in (3aR,4S,7R,7aS)-hexahydro-4,7-methano-2H-isoindole-1,3-dione (22). (Figure 9).

Figure 9:- Stereoisomers of KSM 3

Origin of Stereoisomers in 3aR,4S,7R,7aS)-hexahydro-4,7-methano-2H-isoindole-1,3-dione:

Synthesis of key starting material Cis-5-norbornene-Exo-2,3-dicarboxylic anhydride consist of reaction of Cyclopentadiene (17) is reacted with maleic anhydride (18) to form the Diels-Alder product Cis-5-norbornene-endo-2,3-dicarboxylic anhydride (Endo isomer) (19) which is further heated to furnish the thermodynamically stable product Cis-5-norbornene-Exo-2,3-dicarboxylic anhydride (Exo isomer) (20). Based on the evaluation of route of synthesis and brief manufacturing process for Cis-5-norbornene-Exo-2,3-dicarboxylic anhydride (Exo isomer ) (20), it is evident that during the Diels-alder reaction only two isomer namely Cis-5-norbornene-endo-2,3-dicarboxylic anhydride (Endo isomer)(19) which is kinetically stable and required isomer Cis-5-norbornene-Exo-2,3-dicarboxylic anhydride (Exo isomer) (20) which is thermodynamically stable.

The possibility of formation of isomer in (3aR,4S,7R,7aS)-hexahydro-4,7-methano-2H-isoindole-1,3-dione (22) is from the route of synthesis of (22) It is possible to have Carry over of endo derivatives (16) from Cis-5-norbornene-exo-2,3-dicarboxylic anhydride (19). This is Leeds to the formation of (23) and Bicyclo-[2.2.1] heptane-2, 3-di-endo-carboximide (24). The details of route of synthesis shown in (Figure 10)

Figure 10: Route of synthesis of (18)

The content of Cis-5-norbornene-endo-2,3-dicarboxylic anhydride (18) is monitored in the raw material specification of cis-5-norbornene-exo-2,3-dicarboxylic anhydride (20) with the limit of NMT 0.10%. The content of cis-5-norbornene-endo-2,3-dicarboxamide (23) is monitored in the specification of cis-exo-5-Norbornene-2,3-dicarboximide (21) and (3aR,4S,7R,7aS)-hexahydro-4,7-methano-2H-isoindole-1,3-dione (22) with the limit of NMT 0.10%

Table No.2 Content of Isomeric impurities in (22)

Impurity name	Limit	Observed result of Related substances by GC /HPLC
Impurity name	Limit	Batch no 1	Batch no 2
Cis-5-norbornene-endo-2,3-dicarboxylic anhydride (19)	NMT 0.10%	0.02%	0.02%
Cis-5-norbornene-endo-2,3-dicarboxamide (23)		0.02%	0.02%
Bicyclo-[2.2.1] heptane-2,3-di-endo-carboximide (24)		0.01%	0.01%

The content of bicyclo-[2.2.1] heptane-2,3-di-endo-carboximide (24) is monitored in the specification (3aR,4S,7R,7aS)-hexahydro-4,7-methano-2H-isoindole-1,3-dione (22) with the limit of NMT 0.10%. The content of isomeric impurities of (22) is controlled monitored and the data from the batches is presented in Table no.2

Isomers of Lurasidone Hydrochloride:

Lurasidone hydrochloride consists of six chiral centres, e. g. C1, C2, C11, C12, C15 and C16. The originality of chirality in lurasidone comes from isomerism of (3aR,4S,7R,7aS)-hexahydro-4,7-methano-2H-isoindole-1,3-dione (22) and trans (1R, 2R)-1,2-cyclohexanedimethanol (13) there is a possibility for formation of seven different isomer of Lurasidone hydrochloride(1), excluding Lurasidone hydrochloride. Mentioned in (Figure 11)

Figure 11:- Isomers of Lurasidone Hydrochloride

Manufacturing process of isomers of Lurasidone Hydrochloride:- The possibility for formation of different isomer is obvious, the present modified process is developed in such way that the recurrence of other isomer is controlled though process is possible as per ICH guidelines. No additional purification, precaution is required in modified process. The details of formation of isomer 1 to isomer 7, there manufacturing process and there controlled is established is discussed in (Figure 12) in Schematic Diagram for the formation of isomer-1 to isomer-8 .

Figure 12:- Schematic Diagram for the formation of isomer-1 to isomer-8:

Formation and control of isomers of Lurasidone Hydrochloride:

Isomer-1and isomer-7:- (3aR,4R,7S,7aS)-2-{(1R,2R)-2-[4-(1,2-benzisothiazol-3-yl)piperazin-1-ylmethyl]cyclohexyl methyl}hexahydro-4,7-methano-2H isoindole-1,3-dione (Trans R,R endo Lurasidone/ Isomer 1) (25) and (3aR,4R,7S,7aS)-2-{(1S, 2S)-2-[4-(1, 2-benzisothiazol-3-yl) piperazin-1-ylmethyl] cyclohexyl methyl}hexahydro-4,7-methano-2H isoindole-1,3-dione (Trans S,S endo Lurasidone/ Isomer 7) (31).This Formed when the trans (1S,2S)-1,2-cyclohexanedimethanol(13), it is then converted to corresponding Spiro Compound using (7)and finally reacted with (24)then this may lead to formation of isomer-1(25) and (1R,2R)-1,2-cyclohexanedimethanol(14), it is then converted to corresponding Spiro Compound using (7)and finally reacted with (24) then this may lead to formation of isomer-isomer-7(31) .

Isomer-2 and isomer-4:- (3aR,4R,7S,7aS)-2-{(1S, 2R)-2-[4-(1, 2-benzisothiazol-3-yl) piperazin-1-ylmethyl] cyclohexyl methyl} hexahydro-4, 7-methano-2Hisoindole-1, 3-dione (Cis S, R endo Lurasidone/ Isomer-2) (26).and (3aR,4R,7S,7aS)-2-{(1R,2S)-2-[4-(1,2-benzisothiazol-3-yl)piperazin-1-ylmethyl]cyclohexyl methyl}hexahydro-4,7-methano-2Hisoindole-1,3-dione (Cis R,S endo Lurasidone/ Isomer-4) (28). This Formed when the cis (1S,2R)-1,2-cyclohexanedimethanol(15), it is then converted to corresponding Spiro Compound using (7)and finally reacted with (24) then this may lead to formation of isomer-2(26) and cis (1R,2S)-1,2-cyclohexanedimethanol(16), it is then converted to corresponding Spiro Compound using (7)and finally reacted with (24) then this may lead to formation of isomer-isomer-4(28)

Table No.3: Content of Isomer 1 to Isomer 7 in Lurasidone hydrochloride(1)

Impurity name	Limit	Content of Isomer 1 to Isomer 7 by HPLC
Impurity name	Limit	Batch no 001	Batch no 002	Batch no 003
Isomer-1	NMT 0.15%	BQL	BQL	0.01%
Isomer-2		ND	ND	ND
Isomer-3		ND	BQL	ND
Isomer-4		0.04%	0.04%	0.05%
Isomer-5		ND	ND	ND
Isomer-6		BQL	BQL	BQL
Isomer-7		ND	ND	ND

* BQL = Below quantification limit, * BDL= Below detection limit * ND = Not detected

Isomer-3 and Isomer-5 (cis racemic exo lurasidone):

3aR,4S,7R,7aS)-2-{(1S, 2R)-2-[4-(1,2-benzisothiazol-3-yl)piperazin-1-ylmethyl]cyclohexyl methyl}hexahydro-4,7-methano-2Hisoindole-1,3-dione (Cis S,R exo Lurasidone) (27). This Formed when the cis (1S,2R)-1,2-cyclohexanedimethanol (15), it is then converted to corresponding Spiro Compound using (7)and finally reacted with (22)then this may lead to formation of isomer-3(27) and (3aR,4S,7R,7aS)-2-{(1R, 2S)-2-[4-(1, 2-benzisothiazol-3-yl) piperazin-1-ylmethyl] cyclohexyl methyl} hexahydro-4, 7-methano-2Hisoindole-1, 3-dione (Cis R, S exo Lurasidone) (29).This Formed when the cis (1R,2S)-1,2-cyclohexanedimethanol(16), it is then converted to corresponding Spiro Compound using (7)and finally reacted with (22)then this may lead to formation of isomer-5(29)

Isomer-6 :- (3aR,4S,7R,7aS)-2-{(1S,2S)-2-[4-(1,2-benzisothiazol-3-yl)piperazin-1-ylmethyl]cyclohexyl methyl}hexahydro-4,7-methano-2Hisoindole-1,3-dione (Trans S,S exo Lurasidone/ Isomer-6) (30).This Formed when the of trans (1S, 2S)-1,2-cyclohexane dimethanol(14), it is then converted to corresponding Spiro Compound using (7)and finally reacted with (22) then this may lead to formation of isomer-6 (30).

All the above discussion reviled that there is possibility of formation of seven different isomer of Lurasidone during the manufacturing of Lurasidone hydrochloride with usage of two different key starting material (3aR,4S,7R,7aS)-hexahydro-4,7-methano-2H-isoindole-1,3-dione and (1R,2R)-1,2-cyclohexanedimethanol. All isomers of Lurasidone hydrochloride are monitored in the Lurasidone hydrochloride with limit of not more than 0.15% and the obtained results for isomers are tabulated in Table No.3.

EXPERIMENTAL SECTION:

All reagents, solvents, and processing aids were purchased from commercial source obtained and used as received. The reactor used were Glass-lined, Stainless steel reactor, and Gas induction reactor having variable rate agitation and a −10 to 150°C jacket temperature range were used for reactions to conduct on a pilot scale. ¹H NMR and ¹³C NMR spectra were recorded on a Bruker 300 MHz FT spectrometer in CDCl₃and DMSO as solvent. All chemical shifts are reported in δ ppm relative to tetramethyl silane used as an internal standard. Purity of compounds was assessed by HPLC on an Agilent Technologies 1200 series.

Method developed at Megafine Pharma (P) Ltd were used for HPLC Method for Calculating Chemical, Assay, and Chiral Purity and Related substances of Lurasidone Hydrochloride (1) and were estimated by a gradient HPLC analysis. (a) Kromasil C8, (250 × 4.6 mm ID), 5 μ column; Mobile phase-A comprising a mixture of phosphate buffer (5.75 g ammonium dihydrogen orthophosphate) in HPLC grade water (1000 mL) were used to determine the related substances of Lurasidone Hydrochloride (1) and was estimated using, sonicate to dissolve, add 1ml triethylamine and filter through 0.45 μm nylon filter and degas. Mobile phase-B Acetonitrile; gradient elution: time (min)/A (v/v): B (v/v), T0.0/70:30, T5.0/ 70:30, T30.0/45:55, T35.0/35:65, T42.0/35:65, T45.0/70:30; T50.0/70:30; flow rate 1.0 mL/min column temperature 35 °C, wavelength 225 nm.

Synthesis of (lR,2R)-1,2-cyclohexane dicarboxylic acid(9):

Cis-l,2-cyclohexane dicarboxylic acid anhydride (100 gm) (8) is reflux in mixture of ethanol and toluene(300 ml and 150 ml) in presence of conc. H₂SO_4,(1ml) to furnish cis-l,2-cyclohexane dicarboxylic acid ethyl ester. The obtained cis-l,2-cyclohexane dicarboxylic acid ethyl ester is isomerized in presence of sodium ethoxide(14 gm) to obtain mixture of cis-l,2-cyclohexane dicarboxylic acid ethyl ester and trans-l,2-cyclohexane dicarboxylic acid ethyl ester. The obtained mixture of isomers is further hydrolysed using potassium hydroxide (150 gm) to furnish mixture of cis-l,2- cyclohexane dicarboxylic acid and trans-l,2-cyclohexane dicarboxylic acid. The obtained mixture of dicarboxylic acid is finally crystallized from water(710, ml) to obtain trans-l,2- cyclohexane dicarboxylic acid as a racemic mixture Purity by GC >97.00 The FT-IR spectrum of (lR,2R)-1,2-cyclohexane dicarboxylic acid(9) was recorded in the solid state KBr dispersion medium using Shimadzu model Spectrum8400 series FT-IR· spectrophotometer 1696.89 cm^-1(C=O), 1412.19 cm^-1(C-O-H), 2952.81cm^-1 (C-H) The ¹H NMR was recorded on 400MHz NMR Spectrometer in DMSO₃: o 12.09 (s, 2H), 2.34 (bs, 2H), 1.68 and 1.91- 1.93 (bs, 4H), 1.23 (s,4H) The ESI +ve ionization of (lR,2R)-1,2-cyclohexane dicarboxylic acid, displayed deprotonated molecular ion mlz = 171.0 which corresponds to of molecular formula C₁₂H₈O₄.

Synthesis of (lR,2R)-1,2-cyclohexane dicarboxylic acid dimethyl ester(12):

Racemic trans-l,2-cyclohexane dicarboxylic acid(100 gm)(9) is further treated R(+)-phenyl ethyl amine (56 gm) (10) in ethanol (800 ml) to furnish crude (1R,2R)-1,2-cyclohexane dicarboxylic acid-R-(+)-phenyl ethyl amine diastereomeric salt. The obtained crude salt is further crystallized using the mixture of ethanol and toluene (500 ml) to furnish pure (1 R,2R)-1,2-cyclohexane dicarboxylic acid R-(+)- phenyl ethyl amine diastereomeric salt. The obtained pure (1R,2R)-1,2-cyclohexane dicarboxylic acid-R-(+)-phenyl ethyl amine diastereomeric salt is then hydrolysed using Con.HCI(48 ml) to furnish (lR,2R)-1,2-cyclohexane dicarboxylic acid(11a). The desired product is finally extracted from aqueous phase using tertiary butyl methyl ether(1000 ml). (lR,2R)-1,2-cyclohexane dicarboxylic acid is converted to its corresponding dimethyl ester (95-110 gm) (12)in methanol (500 ml) in presence of thionyl chloride(152 gm).

The FT-IR spectrum of (1R,2R)-1,2-cyclohexane dicarboxylic acid dimethyl ester was recorded in the solid state KBr dispersion medium using Shimadzu model Spectrum 8400 series FT-IR· spectrophotometer 1736.67 cm^-1(C=O), 1253.22 cm^-1(C-O-H), 2941.63cm^-1 (C-H) The ¹H NMR was recorded on 400MHz NMR Spectrometer in DMSO : δ 3.65 (s, 6H), 2.59-2.61(q, 2H), 2.03-2.06 (d, 2H), 1.76-1.78 (d, 2H), 1.24-1.36 (m, 4H), ¹³C NMR (400 MHz, DMSO): δ 175.18, 51.47, 44.48, 28.62, 24.90 The ESI +ve ionization of (1R,2R)-1,2-cyclohexane dicarboxylic acid dimethyl ester, displayed deprotonated molecular ion mlz = 201.0 which corresponds to of molecular formula C₁₀H₁₆O₄.

Synthesis of (lR,2R)-1,2-cyclohexanedimethanol/(13):

Charge(THF)tetra hydrofuran (700 ml) to the reactor containing (1R,2R)-1,2-cyclohexane dicarboxylic acid dimethyl ester (12) (100 gm), Charge lithium chloride(63gm) is reduced in presence of potassium borohydride (80 gm ), Stir the reaction mixture for 14-16 hrs at 25-30°C .completion of reaction checked by HPLC. Add slowly 1N HCl(50 ml) solution to the reaction mass till to achieve pH between 3-4. Add ammonia solution (45 ml) to the reaction mass till to achieve pH between 8-9 and extracted product in methylene dichloride (500 ml), distilled out under vacuum to get syrup,charged (DIPE) Disiopropylether (150 ml) to get cleat solution at 50-55°C Chill the mixture to -10 to -15°C Filter the precipitated product drying under vacuum at temp between 35-40°C to get dry (65 gm) (2). FT-IR· spectrophotometer 3319.86 cm^-1(-OH), 2930.83cm^-1(C-H), 1449.87cm^-1 (C-H) The ¹H NMR was recorded on 400MHz NMR Spectrometer in DMSO : δ 3.59 - 3.62 (dd, 2H), 3.49 - 3.53(dd, 2H), 3.26 (d, 2H), 3.26 (s, 2H), 1.67 - 1.78 (m, 2H), 1.58 - 1.62(dd, 2H), 0.96 - 1.35(m, 6H), The ESI +ve ionization of (1R,2R)-1,2-cyclohexanedimethanol, displayed deprotonated molecular ion mlz = 145.0 which corresponds to of molecular formula C₈H₁₆O₂.

Synthesis of Cis-exo-5-Norbornene-2,3-dicarboximide (17):

Charge(300 ml) acetic acid into the reactor, Charge (100 gm) Exo-isomer (20), Charge ammonium acetate(70 gm), Heat the reaction mass to 105 - 110℃, Maintain the reaction mass for 20-24 hrs, check completion of reaction by HPLC,after reaction completion . Distilled out acetic acid completely under vacuum at below 70°C charge purified water(200 ml) Filter the reaction mass Wash the solid with purified water Dry the material (21)under vacuum at 50-55°C. Dry weight = (85 - 90 gm) .The FT-IR spectrum of Cis-exo-5-Norbornene-2,3-dicarboximide. was recorded in the solid state KBr dispersion medium using Shimadzu model Spectrum 8400 series FT-IR· spectrophotometer 3169.57 cm^-1(N-H), 1715.97 cm^-1(C=O), 2972.77 cm^-1 (C-H) The ¹H NMR was recorded on 400MHz NMR Spectrometer in CDCl₃ : δ 7.88 (s, 1H), 6.27 - 6.28 (t, 2H), 3.28 - 3.30 (t, 2H), 2.72 (d, 2H), 1.44 - 1.56 (dt, 2H), The ESI +ve ionization, displayed deprotonated molecular ion M/Z = 164.0 which corresponds to of molecular formula C₉H₉NO.

Synthesis of (3aR,4S, 7R, 7aS)-bexabydro-4, 7-metbano-2H-isoindole-l,3- dione (22)

Charge(1300 ml) Methanol into the reactor, Charge (100 gm) Cis-exo-5-Norbornene-2,3-dicarboximide(21) Charge 10 % Palladium on carbon (15 gm), start purging of hydrogen gas at 28-35℃, Maintain the reaction mass for 3-5 hrs, check completion of reaction by HPLC,after reaction completion, filter the catalyst,distilled out methanol completely under vacuum charge purified water(100 ml) Filter the reaction mass Wash the solid with purified water dry the material under vacuum at 50-55°C. to get crude product which on purification with toluene at 80-85 ℃ get clear solution, Cool the reaction mass to 25-30°C further it was cool to 0-5°C. Filter the reaction mass. Dry the material under vacuum for 4-5 hrs at 50-55°C Dry wt.: (85 to 90 gm).

The FT-IR spectrum of (3aR,4S,7R,7aS)-hexahydro-4,7-methano-2H-isoindole- 1,3-dione (22). was recorded in the solid state KBr dispersion medium using Shimadzu model Spectrum 8400 series FT-IR· spectrophotometer 3200.95 cm^-1(N-H), 1785.15 cm^-1(C=O), 2962.88 cm^-1 (C-H) The ¹H NMR was recorded on 400MHz NMR Spectrometer in CDCl₃ : δ 7.97 (s, 1H), 2.70 - 2.71 (m, 2H), 2.64 - 2.65 (d, 2H), 1.64 - 1.69 (m, 2H), 1.25 - 1.38 (m, 4H), The ESI +ve ionization, displayed deprotonated molecular ion M/Z = 166.0 which corresponds to of molecular formula C₉H₁₁N₂O.

Synthesis of 3-piperazin-l-yl-l,2-benzisothiazole hydrochloride(7):

Synthesis of 3-piperazin-l-yl-l,2-benzisothiazole hydrochloride involves the nucleophilic substitution reaction of anhydrous piperazine(6)(254 gm) with 3-chloro-l,2-benzisothiazole(5) (100 gm)using tertiary butanol(100 ml) as solvent at Maintain the reaction mass at 120 ℃ for 24-26 hrs. Completion of reaction is monitored using HPLC, charged purified water(600 ml) and product is extracted in toluene. Distilled out toluene to offered 3-piperazin-l-yl-l,2-benz-isothiazole as a freebase which was subsequently converted into its hydrochloride salt using concentrated Hydrochloric acid (40 ml )in methanol (350 ml)to get dry product after drying at 50 -55℃. Wt.:- 95-100 gm. The FT-IR spectrum of 3-piperazin-l-yl-l,2-benzisothiazole hydrochloride. was recorded in the solid state KBr dispersion medium using Shimadzu model Spectrum 8400 series FT-IR· spectrophotometer 3445.85cm^-1(N-H), 1590.13, 1559.80 and 1483.29cm^-1(C=C), 1114.50cm^-1 (C-N) The ¹H NMR was recorded on 400MHz NMR Spectrometer in CDCl₃ : δ 7.88 -7.91 (dt, 1H), 7.78 -7.81 (dt, 1H), 7.43 -7.47 (td, 1H), 7.32 -7.36 (td,1H), 3.47 - 3.50 (m, 4H), 3.08 - 3.11 (m, 4H). The ESI +ve ionization of 3-piperazin-1-yl-1,2-benisothiazole, displayed deprotonated molecular ion M/Z = 220.0 which corresponds to of molecular formula C₁₁H₁₃N₃S. HCl.

Synthesis of trans-l,2-bis(methanesulfonyloxymethyl) cyclohexane (2):

(1R, 2R)-1,2-cyclohexanedimethanol 100 gm (13) is reacted with methane sulfonyl chloride 162 gm in the presence of triethylamine 210 gm as base in dichloromethane as solvent 1300 ml, at -5 to -10 ℃ and further maintaining at 0-5 ℃ .The completion of reaction is monitored by HPLC, after reaction completion. Reaction mass was quenched with purified water 1000 ml and after water workup organic layer was separated, after distillation of organic layer below 40 ℃ to furnishes trans-l,2- bis (Methanesulfonyloxymethyl) cyclohexane (2), as oil which is then further crystallise to obtained solid using isopropyl alcohol. the wet solid was dried at 50-55 ℃ under vacuum for 4-5 hrs to obtained dry solid 135 to 165 gm.

The FT-IR spectrum of (lR,2R)-1,2-cyclohexane dicarboxylic acid was recorded in the solid state KBr dispersion medium using Shimadzu model Spectrum 8400 series FT-IR· spectrophotometer 3020.15 and 2940.61 cm^-1(C-H), 1349.42 cm^-1(S=O), 1173.54 cm^-1 (S-O) The ¹H NMR was recorded on 400MHz NMR Spectrometer in CDCl₃: δ 4.276-4.311 (m, 2H), 4.167-4.199 (m, 2H), 3.038 (s, 6H), 1.783-1.827 (m,4H) 1.700-1.712 (m,2H) 1.270-1.290(m,4H). The ¹³C NMR was recorded on 400MHz NMR Spectrometer in CDCl₃: δ 71.876, 38.003, 36.735, 28.810, 24.939.The ESI +ve ionization of (lR,2R)-1,2-cyclohexane dicarboxylic, displayed deprotonated molecular ion m/z = 323.2 which corresponds to the adduct of sodium with the molecular formula C₁₀H₂₀O₆S₂Na.

Synthesis of 4' -(1,2-benzisothiazol-3-yl)-(3aR,7aR)-octahydro-spiro [2H -isoindole-2,1 'piperazinium ]methanesulfonate (Spiro Compound )(3):

The obtained (100 gm) trans-l,2-bis(methanesulfonyloxymethyl)cyclohexane(2) is condensed of with (69 gm) 3- piperazin-l-yl-l,2-benisothiazole (7) in the presence of sodium carbonate (350 gm) as a base and isopropyl alcohol (1.0 lit) as solvent at 78-82°C for 18-20 hrs . The reaction progress was monitored by HPLC, after completion of reaction distilled out IPA completely and charge ethyl acetate (2.0 lit) and heating at 50 -55 for 1.0 hrs further cool to RT, after filtration to furnish the 4'-(1,2-benzisothiazol-3-yl)-(3aR,7aR)-octahydro-spiro[2Hisoindole- 2,1'-piperazinium]methanesulfonate (Spiro compound/7),at the obtained solid is purified, and isolated using ethyl acetate the wet solid were dried at 50-55 ℃ under vacuum for 4-5 hrs to obtained dry solid 105 to 120 gm.

The FT-IR spectrum of (lR,2R)-1,2-cyclohexane dicarboxylic acid was recorded in the solid state KBr dispersion medium using Shimadzu model Spectrum8400 series FT-IR· spectrophotometer 2990.73,2932.17 cm^-1(C-H), 1651.45, 1591.24, 1562.33 cm^-1(C=C), 1491.41 cm^-1 (CH₂), 1209.14(S=O) The ¹H NMR was recorded on 400MHz NMR Spectrometer in DMSO: δ 8.11 - 8.20 (dd, 2H), 7.46 -7.62 (t, 2H), 3.93 - 3.98 (m, 2H), 3.66 - 3.80 (m,8H), 3.18 - 3.24(t, 2H), 2.28(s,2H), 1.77 1.90 (m,6H), 1.16 - 1.25(m,4H), The ESI +ve ionization, displayed deprotonated molecular ion mlz = 328.4 which corresponds to of molecular formula C₁₉H₂₆N₃S.

Synthesis of Lurasidone hydrochloride (1):

(100 gm) 4'-(1,2-benzisothiazol-3-yl)-(3aR, 7aR)-octahydro-spiro[2H-isoindole-2, 1 '- piperazinium ]methanesulfonate (3) is condensed with (428 gm) (3aR,4S, 7R, 7aS)-hexahydro-4, 7 -methano-2Hisoindole- l,3-dione(22) in the presence of (358 gm) potassium carbonate as a base and toluene (800 ml) as solvent at 105-110 ℃, reaction completion monitored by HPLC, after reaction completion reaction mass col to RT, purified water (1.0 lit) charged,settled and separated organic layer,distilled out organic layer to furnish the Lurasidone base(4). The obtained Lurasidone base is isolated using acetone and finally it is purified using mixture of toluene and methanol to furnish lurasidone base pure. the wet solid was dried at 50-55 ℃

For 4-5 hrs to obtained dry solid 80 to 100 gm. The Lurasidone base(4) 100 gm charged in GLR, charged acetone 1500 ml heated the reaction mass to 50-55℃, filter the hot reaction mass through 0.2-micron filter, added dilute IPA.HCl solution at 50-55℃ to converted to corresponding hydrochloride salt, further cool the reaction mass to 0-5℃ and the solid was isolated using filtration, the wet solid were dried at 50-55 ℃

For 3-9 hrs to obtained dry solid 85 to 90 gm. The FT-IR spectrum of ((3aR,4S,7R,7aS)-2-[((1R,2R)-2-{4-(l,2-benzothiazol-3-yl) piperazin-l-yl]methyl }cyclohexyl) methyl]hexahydro-4, 7-methano-2H-isoindol-1,3-dione hydrochloride was recorded in the solid state KBr dispersion medium using Shimadzu model Spectrum8400 series FT-IR· spectrophotometer 1687.31cm^-1(C=O), 1367.04 cm^-1(CH₂), 2889.93, 2831.25, 2873.06cm^-1 (C-H) The ¹H NMR was recorded on 400MHz NMR Spectrometer in DMSO: δ 7.82-7.85 (t, 2H), 7.51-7.53 (t, 1H), 7.27-7.41 (t, 1H), 4.08-4.38 (m,4H), 3.44-3.59 (m, 5H ) 3.18 (m,5H ), 2.87(t, 1H), 2.65-2.69 (dd,4H), 2.31(dd,1H), 1.60-1.79 (m, 7H), 1.06-1.36 (m, 8H) . The ¹³C NMR was recorded on 400MHz NMR Spectrometer in DMSO: δ 179.39, 161.61, 152.90, 127.88, 127.35, 124.37, 123.30, 120.67, 61.71, 52.80, 49.97, 48.60, 46.18, 41.66, 39.68, 34.51, 33.28, 31.27, 29.78, 27.93, 24.27 The ESI +ve ionization displayed deprotonated molecular ion M/Z = 493 which corresponds to of molecular formula C₂₈H₃₆N₄O₂S.

Synthesisof(3aR,4R,7S,7aS)-2-[((R,2R)-2-{4-(l,2-benzothiazol-3-yl)piperazin-l-yl]methyl} cyclohexyl) methyl] hexahydro-4,7-methano-2H-isoindol-l,3-dione(25) And (3aR,4R,7S,7aS)-2-[((S,2S)-2-{4-(l,2-benzothiazol-3-yI) piperazin-l-yl] methyl} cyclohexyl) methyl] hexahydro-4, 7 -methano-2H-isoindol-l,3-dione(31) Mixture of isomer-1 and isomer-7:-

(43 gm) Trans- racemic derivatives of (13) is condensed with (18.43 gm) endo isomer (24) in the presence of potassium carbonate (15.4) gm as a base and toluene (340 ml) as solvent at 105-110 ℃, reaction completion monitored by TLC, after reaction completion reaction mass cool to RT, purified water (400 ml) charged,settled and separated organic layer,distilled out organic layer to furnish the Trans racemic Lurasidone base The obtained Trans Lurasidone base is isolated using acetone and finally it is purified using mixture of toluene and methanol to furnish lurasidone base pure. the wet solid was dried at 50-55 ℃. Trans racemic endo lurasidone base is converted to corresponding hydrochloride salt using IPA-HCl and acetone as solvent to achieve lurasidone salt i.e., mixture of isomer 1 and 7 which is further converted into free base with help of aqueous ammonia in MDC.

The FT-IR spectrum of (3aR,4R,7S,7aS)-2-[((R,2R)-2-{4-(l,2-benzothiazol-3-yl)piperazin-l-yl]methyl} cyclohexyl) methyl] hexahydro-4,7-methano-2H-isoindol-l,3-dione(25) And (3aR,4R,7S,7aS)-2-[((S,2S)-2-{4-(l,2-benzothiazol-3-yI) piperazin-l-yl] methyl} cyclohexyl) methyl] hexahydro-4, 7 -methano-2H-isoindol-l,3-dione(31) Mixture of isomer-1 and isomer-7. was recorded in the solid state KBr dispersion medium using Shimadzu model Spectrum 8400 series FT-IR· spectrophotometer 1178.46 cm^-1(C-C), 1362.01cm^-1(CH₂), 1768.07 and 1698.01 cm^-1 (C=O), 1591.04, 1562.97 and 1490.39 (C=C).The ¹H NMR was recorded on 400MHz NMR Spectrometer in CDCl₃ : δ 7.90-7.90 (d, 2H), 7.78-7.80 (d, 1H), 7.42-7.46 (td, 1H), 7.32-7.36 (td, 1H), 3.90-3.95 (dd, 1H), 3.50-3.52 (t, 4H), 3.27-3.33(dd, 1H), 2.74(s, 2H), 2.58-2.68(m, 5H), 2.21-2.25(dd, 1H), 1.86-1.89 (t, 1H), 1.52-1.66 (m, 8H), 0.99-1.40(m, 7H), The ^l3C NMR was recorded on 100 MHz NMR Spectrometer in DMSO. Chemical shifts was recorded on 8 scale in ppm relative to TMS ( δ 0.00) as a internal standard. 178.61, 163.89, 152.48, 127.89, 127.29, 123.79, 120.34, 63.36, 53.28, 49.98, 48.55 and 48.62, 42.26, 42.04, 40.47, 38.90, 37.25, 30.44, 29.63, 25.17, 24.81, 24.49. The ESI +ve ionization, displayed deprotonated molecular ion M/Z = 492.67 which corresponds to of molecular formula C₂₈H₃₆N₄O₂S.

Synthesis of (3aR,4R, 7S, 7 as)-2-[(( S,2R)-2-{ 4-(1,2-benzothiazol-3-yl) piperazin-l-yl] methyl}cyclohexyl) methyl] hexahydro-4, 7 -methano-2H-isoindol-l,3-dione(26) And (3aR,4R, 7S, 7 as)-2-[( (IR,2S)-2-{4-(1,2-benzothiazol-3-yl) piperazin-l-yl] methyl}cyclohexyl)methyl] hexahydro-4, 7 -methano-2H-isoindol-l,3-dione(28) Mixture of isomer-2 and isomer-4:- (30 gm) Cis- racemic derivatives of (13) is condensed with (12.86) gm endo isomer (24) in the presence of potassium carbonate (10.75 gm) as a base and toluene 240 ml as solvent at 105-110 ℃, reaction completion monitored by TLC, after reaction completion reaction mass col to RT, purified water (300 ml) charged,settled and separated organic layer,distilled out organic layer to furnish the Cis racemic Lurasidone base The obtained Lurasidone base is isolated using acetone and finally it is purified using mixture of toluene and methanol to furnish lurasidone base pure. the wet solid was dried at 50-55 ℃ Cis racemic endo lurasidone base is converted to corresponding hydrochloride salt using IPA-HCl and acetone as solvent to achieve lurasidone salt i.e., mixture of isomer 2 and 4 which is further converted into free base with help of aqueous ammonia in MDC.

The FT-IR spectrum of (3aR,4R, 7S, 7 as)-2-[(( S,2R)-2-{4-(1,2-benzothiazol-3-yl) piperazin-l-yl] methyl} cyclohexyl)methyl] hexahydro-4, 7 -methano-2H-isoindol-l,3-dione (26 ) And (3aR,4R, 7S, 7 as)-2-[( (IR,2S)-2-{4-(1,2-benzothiazol-3-yl) piperazin-l-yl] methyl}cyclohexyl)methyl] hexahydro-4, 7 -methano-2H-isoindol-l,3-dione(28) was recorded in the solid state KBr dispersion medium using Shimadzu model Spectrum 8400 series FT-IR· spectrophotometer 1169.37 cm^-1(C-C), 1375.93 cm^-1(CH₂), 1760.92 and 1700.63 cm^-1 (C=O), 1592.76, 1560.45 and 1490.49 (C=C).The 1H NMR was recorded on 400MHz NMR Spectrometer in CDCl3 : δ 7.89-7.91 (d, 1H), 7.78-7.80 (d, 1H), 7.42-7.46 (td, 1H), 7.32-7.36 (td, 1H), 3.51-3.58 (m, 5H), 3.37-3.41 (dd, 1H), 3.04-3.05(m, 2H), 2.74(s, 2H), 2.58-2.69(m, 4H), 2.34-2.47(dd, 2H), 2.03-2.08 (m, 1H), 1.90-1.91 (m, 1H), 1.20-1.68(m, 14H), The l3C NMR was recorded on 100 MHz NMR Spectrometer in DMSO. Chemical shifts were recorded on 8 scale in ppm relative to TMS ( δ 0.00) as a internal standard. 178.51 and 178.57, 163.92, 152.53, 127.94, 127.32, 123.86, 123.68, 120.38, 58.72, 53.34, 50.04, 48.55 and 48.68, 42.05, 39.41, 38.97, 36.59, 35.23, 27.01 and 27.50, 24.82, 24.52, 23.39, 23.18. The ESI +ve ionization, displayed deprotonated molecular ion M/Z = 493 which corresponds to of molecular formula C₂₈H₃₆N₄O₂S.

Synthesis of (3aR,4S,7R,7aS)-2-[((S,2R)-2-{4-(1,2-benzothiazol-3-yI) piperazin-l-yl] methyl} cyclohexyl)methyl] hexahydro-4, 7 -methano-2H-isoindol-l,3-dione(27) And (3aR,4S, 7R, 7aS)-2-[( (lR,2S)-2-{4-(1,2-benzothiazol-3-yl) piperazin-l-yl] methyl} cyclohexyl)methyl] hexahydro-4, 7 -methano-2H-isoindol-l,3-dione(29) Mixture of isomer-3 and isomer-5: Cis- racemic derivatives of (15 and 16) 30 gm is condensed with endo isomer 12.86 gm (22) in the presence of potassium carbonate 10.75 gm as a base and toluene 240 ml as solvent at 105-110 ℃, reaction completion monitored by TLC, after reaction completion reaction mass col to RT, purified water 300 ml charged,settled and separated organic layer,distilled out organic layer to furnish the Cis racemic Lurasidone base The obtained Cis-Lurasidone base is isolated using acetone and finally it is purified using mixture of toluene and methanol to furnish lurasidone base pure. the wet solid was dried at 50-55 ℃. Cis racemic endo lurasidone base is converted to corresponding hydrochloride salt using IPA-HCl and acetone as solvent to achieve lurasidone salt i.e., mixture of isomer 2 and 4 which is further converted into free base with help of aqueous ammonia in MDC.

The FT-IR spectrum of (3aR,4S,7R,7aS)-2-[((S,2R)-2-{4-(1,2-benzothiazol-3-yI) piperazine-l-yl] methyl} cyclohexyl)methyl] hexahydro-4, 7 -methano-2H-isoindol-l,3-dione(27). And (3aR,4S, 7R, 7aS)-2-[( (lR,2S)-2-{4-(1,2-benzothiazol-3-yl) piperazine-l-yl] methyl} cyclohexyl)methyl] hexahydro-4, 7 -methano-2H-isoindol-l,3-dione(29) was recorded in the solid state KBr dispersion medium using Shimadzu model Spectrum 8400 series FT-IR· spectrophotometer 1177.05 cm^-1(C-C), 1377.56 cm^-1(CH₂), 1762.68 and 1698.0 cm^-1 (C=O), 1594.62, 1574.13 and 1490.44 (C=C).The ¹H NMR was recorded on 400MHz NMR Spectrometer in CDCl3 : δ 7.88-7.90 (d, 2H), 7.78-7.80 (d, 1H), 7.42-7.46 (td, 1H), 7.31-7.35 (td, 1H), 3.51-3.56 (m, 5H), 3.38-3.42 (d, 1H), 2.58-2.68(m, 8H), 2.31-2.46(m, 2H), 2.02-2.05(m, 1H), 1.88(bs, 1H), 1.10-1.66(m, 14H), The ^l3C NMR was recorded on 100 MHz NMR Spectrometer in DMSO. Chemical shifts were recorded on 8 scale in ppm relative to TMS ( δ 0.00) as a internal standard. 179.03, 163.88, 152.52, 127.92, 127.30, 123.83, 123.66, 120.36, 58.69, 53.30, 50.01, 48.37 and 48.48, 39.48, 39.54 and 39.58, 36.40, 35.07, 33.05, 27.88 and 27.91, 27.51, 26.99, 23.35, 23.20. The ESI +ve ionization, displayed deprotonated molecular ion M/Z = 493 which corresponds to of molecular formula C₂₈H₃₆N₄O₂S

Synthesis of (3aR,4S,7R,7aS)-2-[((1R,2R)-2-{4-(1,2-benzothiazol-3-yI) piperazin-l-yl] methyl} cyclohexyl)methyl] hexahydro-4, 7 -methano-2H-isoindol-l,3-dione(1) And (3aR,4S,7R,7aS)-2-[((S,2S)-2-{4-(1,2-benzothiazol-3-yl) piperazine-l-yl] methyl} cyclohexyl)methyl] hexahydro-4, 7 -methano-2H-isoindol-l,3-dione(30) Mixture of Lurasidone and isomer 6:- Trans- racemic derivatives of (13 and14) 43 gm is condensed with (3aR,4S, 7R, 7aS)-bexabydro-4, 7-metbano-2H-isoindole-l,3- dione (22) 18.43 gm in the presence of potassium carbonate 15.4 gm as a base and toluene 340 ml as solvent at 105-110 ℃, reaction completion monitored by TLC, after reaction completion reaction mass col to RT, purified water 400 ml charged,settled and separated organic layer,distilled out organic layer to furnish the Trans racemic Lurasidone base The obtained Trans Lurasidone base is isolated using acetone and finally it is purified using mixture of toluene and methanol to furnish lurasidone base pure. the wet solid was dried at 50-55 ℃.

The FT-IR spectrum of (3aR,4S,7R,7aS)-2-[((R,2R)-2-{4-(1,2-benzothiazol-3-yI) piperazin-l-yl] methyl} cyclohexyl)methyl] hexahydro-4, 7 -methano-2H-isoindol-l,3-dione(1) And

(3aR,4S,7R,7aS)-2-[((S,2S)-2-{4-(1,2-benzothiazol-3-yl) piperazin-l-yl] methyl} cyclohexyl)methyl] hexahydro-4, 7 -methano-2H-isoindol-l,3-dione(30) was recorded in the solid state KBr dispersion medium using Shimadzu model Spectrum 8400 series FT-IR· spectrophotometer 1189.44 cm^-1(C-C), 1363.81cm^-1(CH₂), 1771.36 and 1697.51 cm^-1 (C=O), 1591.67, 1562.86 and 1491.73 (C=C).The 1H NMR was recorded on 400MHz NMR Spectrometer in CDCl₃ : δ 7.88-7.90 (d, 2H), 7.77-7.79 (d, 1H), 7.42-7.46 (td, 1H), 7.31-7.35 (td, 1H), 3.49-3.51 (t, 4H), 3.27-3.33 and 3.89-3.93 (dd, 2H), 2.58-2.69(m, 9H), 2.19-2.24(dd, 1H), 0.97-1.88(m, 16H), The ^l3C NMR was recorded on 100 MHz NMR Spectrometer in DMSO. Chemical shifts were recorded on 8 scale in ppm relative to TMS ( δ 0.00) as a internal standard. 178.84, 163.60, 152.24, 127.64, 127.06, 123.56, 123.43, 120.12, 63.17, 53.05, 49.75, 48.14 and 48.19, 42.18, 40.17, 39.25 and 39.28, 37.07, 32.87, 30.30, 29.38, 27.64 and 27.69, 25.02, 24.63. The ESI +ve ionization, displayed deprotonated molecular ion M/Z = 493 which corresponds to of molecular formula C₂₈H₃₆N₄O₂S.

CONCLUSION:

Process for the Practical synthesis of Lurasidone hydrochloride (1) is established by identifying the isomeric impurities. The control strategy to mitigate/elimination of these isomeric impurities in Lurasidone hydrochloride (1) to acceptable ICH limit is developed by optimizing reaction condition for the transformation so as to obtain cost effective and commercially viable and suitable process for scale up of Lurasidone hydrochloride (1) with the overall yield of 65 % and 99.95 purity by HPLC. Practical synthesis approaches also identified to synthesized isomeric impurities (21-27) . The extent of cost effectiveness and productivity of developed process was evaluated and found significantly improved over the reported processes.

CONFLICT OF INTEREST:

The authors have no conflicts of interest regarding this publication.

ACKNOWLEDGMENTS:

The authors are grateful to the Management of Megafine Pharmaceuticals (P) Ltd., for supporting this work. We also thank colleagues of Analytical Research and Development Department, Megafine Pharmaceuticals (P) Ltd., for valuable cooperation in developing the chromatographic methods for establishing the process and identifying the impurities.

CONFLICT OF INTEREST:

The author declares no competing financial interest.

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Received on 08.12.2024 Revised on 01.03.2025

Accepted on 07.05.2025 Published on 02.08.2025

Available online from August 08, 2025

Research J. Pharmacy and Technology. 2025;18(8):3749-3760.

DOI: 10.52711/0974-360X.2025.00540

This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License. Creative Commons License.

Impurity name [%]	Limit	Batch 01	Batch 02	Batch 03	Batch 04
Trans (1S, 2S)-1, 2-cyclohexane dicarboxylic acid(11 a)	NMT 4.0%	2.70%	2.0%	1.40%	1.15%
Cis 1, 2-cyclohexane dicarboxylic acid(11 b)	NMT 4.0%	1.40%	0.79%	ND	0.79%
Cis 1-2-cyclohexane dimethanol (15and16)	NMT 1.0%	0.11%	ND	ND	0.05%
Trans (1S, 2S)-1, 2-cyclohexane dimethanol (Trans (1S,2S) (14)	NMT 1.0%	0.05%	0.04%	0.07%	ND