FIELD OF THE INVENTION
The present invention relates to novel compounds of Formula I and process of preparation thereof
Formula I
The present invention further provides use of the compounds of Formula I in preparation of lumateperone of Formula II and pharmaceutically acceptable salts thereof,
Formula II
BACKGROUND OF THE INVENTION
Lumateperone (CAPLYTA) is an atypical antipsychotic approved for the treatment of schizophrenia in adults.
Lumateperone is chemically known as 4-((6bR,10aS)-3-methyl-2,3,6b, 9,10,10a-hexahydro-lH,7H-pyrido[3',4':4,5]pyrrolo[l,2,3-de]quinoxalin-8-yl)-l-(4-fluorophenyl)-butan-1-one represented by Figure II is disclosed in WO 2000/077001. The tosylate salt of lumateperone is represented by Formula Ha:
Formula Ha
PCT application WO 2000/077001 discloses process for the preparation of lumateperone as mentioned in the schemes 1 and 2 below:

Scheme 1:
Scheme 2:

WO2008/112280A1 discloses another process for the preparation of lumateperone as mentioned in the scheme-3 below:
Scheme 3:
Although there are certain processes known in the prior published references for the preparation of lumateperone, however, the present invention is focussed towards the development of an improved process for the preparation of lumateperone. Further, present invention is focussed to develop a process for the preparation of lumateperone using novel compounds as intermediates.
4

OBJECT OF THE INVENTION
The main object of the present invention is to provide novel compounds of Formula I as represented below:
Formula I
Another object of the present invention is to provide novel compounds that can be used in the preparation of the lumateperone and pharmaceutically acceptable salts thereof.
SUMMARY OF THE INVENTION
The main aspect of the present invention is to provide novel compounds of Formula I,
Formula I
isomers, or pharmaceutically acceptable salts thereof;
wherein,
A is selected from -CRi, -C(Ri)2, -N, -NRi, -CO, and -NOH;
Ri is independently selected from hydrogen, substituted or unsubstituted C1-C6 alkyl, and
amine protecting group; R2 is selected from hydrogen, azide, nitro, and halogen; R3 is
selected from hydrogen, substituted or unsubstituted C1-C6 alkyl group; or
R2 and R3 together form a saturated or unsaturated heterocyclic ring comprising one or
more heteroatoms selected from N, O, S, and is optionally substituted with one or more
substituents; and n is the integer selected from 0-2.
In another aspect, the present invention provides compounds of Formula I represented by following Formulae:

In another aspect, the present invention provides use of novel compounds of Formula I in preparation of lumateperone wherein said process comprises the steps of a) reacting compound of Formula XX with cyclopentanone to obtain compound of Formula III:
Formula XX Formula XXI
}
wherein R2 and R2' is selected from hydrogen, azide, nitro, substituted and unsubstituted
amine and halogen;
R2 is selected from hydrogen, azide, nitro, and halogen; R3 is selected from hydrogen,
substituted or unsubstituted C1-C6 alkyl group; or
R2 and R3 together form a saturated or unsaturated heterocyclic ring comprising one or
more heteroatoms selected from N, O, S, and is optionally substituted with one or more
substituents;
b) converting compound of Formula XXI into compound of Formula III by using suitable
oxidising agent;
Formula XXI Formula III
wherein R2 and R3 are as defined above;

c) converting compound of Formula III into compound of Formula XXII;
Formula III Formula XXII
wherein R2 and R3 are as defined above;
d) converting compound of Formula XXII to compound of Formula XXIII using suitable reducing agent;
Formula XXII Formula XXIII
wherein, R2 and R3 together form a saturated or unsaturated heterocyclic ring comprising one or more heteroatoms selected from N, O, S, and is optionally substituted with one or more substituents; and
e) converting compound of Formula XXIII to lumateperone of Formula II or pharmaceutically acceptable salts thereof.
DETAILED DESCRIPTION
Definitions:
"Pharmaceutically acceptable salts" as used in the context of the present invention refers to inorganic acids such as hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid salt; organic acids such as formic acids, acetic acid, diphenyl acetic acid, triphenylacetic acid, caprylic acid, dichloroacetic acid, trifluoro acetic acid, propionic acid, butyric acid, lactic acid, citric acid, gluconic acid, mandelic acid, tartaric acid, malic acid, adipic acid, aspartic acid, fumaric acid, glutamic acid, maleic acid, malonic acid, succinic acid, benzoic acid, /?-chlorobenzoic acid, nicotinic acid, o-hydroxybenzoic acid, p-hydroxybenzoic acid, l-hydroxy-naphthalene-2-carboxylic acid, hydroxynaphthalene-2-carboxylic acid, ethanesulfonic acid, ethane-1,2-disulfonic acid, 2-hydroxyethane sulfonic acid, methanesulfonic acid, (+)-camphor-10-sulfonic acid, benzenesulfonic acid, naphthalene-2-sulfonic acid, p-toluenesulfonic acid; pharmaceutically acceptable bases such as metal salts including alkali metal or alkaline earth metal salts for example sodium, potassium, magnesium, calcium or zinc salts, ammonium salts; and the like.

The term "isomers" as used in the context of the present invention refers to all such compounds including tautomers, cis-and trans-isomers, R- and ^-enantiomers, diastereomers, D-isomers, L-isomers, and racemic mixtures of all the compounds herein described under the definitions of compound of Formula I.
"Suitable solvent" as used in the context of the present invention refers to solvents selected from, but not limited to, alcohols, hydrocarbons, halogenated solvents, esters, ethers, ketones, sulfoxides, formamide, amides, nitriles, pyrrolidines, carbonates, water and the like. Specifically, the suitable solvent as used in the present invention is selected from, but not limited to, tetrahydrofuran, toluene, o/m/p-xylene, 1,4-dioxane, dichloromethane, carbon tetrachloride, dichloroethane, dichlorobenzene, chlorobenzene, methanol, ethanol, isopropyl alcohol, acetonitrile, ethyl acetate, acetone, methyl ethyl ketone, 2-methyl tetrahydrofuran, butyl acetate, isobutyl acetate, t-butyl acetate, propyl acetate, propylene acetate, butanol, t-butanol, methyl t-butyl ketone, dimethyl sulfoxide, N-methyl pyrrolidine, dimethyl acetamide, dimethyl formamide, N-methyl acetamide, acetamide, acetone, methyl isobutyl ketone, acetonitrile, propionitrile, methyl ethyl ether, methyl tert-butyl ether, dimethyl ether, diethyl ether, cyclohexane, n-heptane, water and mixture thereof.
"Oxidising agent" as used in context of the present invention are selected from, but not limited to, selected from the group comprising 2,3-Dichloro-5,6-dicyano-l,4-benzoquinone (DDQ), Dess-Martin periodinane, pyridinium chloroformate and the like.
"Animating agent" as used in context of the present invention are selected from, but not limited to, selected from the group comprising hydroxylamine-o-sulfonic acid hydroxyl amine, hydrochlorate, n-hydroxy acetamide, ammonium sulphate and the like.
"Suitable base" as used in context of the present invention are selected from, but not limited to, selected from the group comprising organic and inorganic base selected from triethylamine, diisopropyl amine, diisopropyl ethyl amine, methyl amine, dimethyl aminoipyridine, alkali and alkaline earth metal hydroxides, alkali and alkaline earth metal carbonates and bicarbonates, pyridine, and the like.

"Reducing agent" as used in context of the present invention are selected from, but not limited to, selected from the group comprising of sodium cyanoborohydride, sodium borohydride, lithium aluminium borohydride, Pd/C, sodium borohydride, sodium triacetoxyborohydride and the like.
"Suitable acid" as used in context of the present invention are selected from, but not limited to, selected from the group comprising of trifluoroacetic acid, hydrochloric acid, sulfuric acid, formic acid, difluoroacetic acid, fluoroacetic acid, Titanium (IV) chloride, titanium isopropoxide and the like. The most preferred reducing agent is trifluoroacetic acid and the like.
The term "excipient" or "pharmaceutically acceptable excipient" means a component of a pharmaceutical product that is not an active ingredient, and includes but not limited to filler, diluent, disintegrant, glidants, stabilizers, surface active agents etc. The excipients that are useful in preparing a pharmaceutical composition are generally safe, non-toxic and neither biologically nor otherwise undesirable, and are acceptable for veterinary use as well as human pharmaceutical use. One excipient can perform more than one function.
The present invention will now be explained in details. While the invention is susceptible to various modifications and alternative forms, specific embodiment thereof will be described in detail below. It should be understood, however that it is not intended to limit the invention to the particular forms disclosed, but on the contrary, the invention is to cover all modifications, equivalents, and alternative falling within the scope of the invention as defined by the appended claims.
The steps of a method may be providing more details that are pertinent to understanding the embodiments of the present invention and so as not to obscure the disclosure with details that will be readily apparent to those of ordinary skill in the art having benefit of the description herein.
Further characteristics and advantages of the process according to the invention will result from the description herein below of preferred exemplary embodiments, which are given as indicative and non-limiting examples.

In one embodiment, the present invention provides novel compounds of Formula I, isomers, or pharmaceutical^ acceptable salts thereof;
Formula I
wherein,
A is selected from -CRi, -C(Ri)2, -N, -NRi, -CO, and -NOH;
Ri is independently selected from hydrogen, substituted or unsubstituted C1-C6 alkyl, and
amine protecting group; R2 is selected from hydrogen, azide, nitro, and halogen; R3 is
selected from hydrogen, substituted or unsubstituted C1-C6 alkyl group; or
R2 and R3 together form a saturated or unsaturated heterocyclic ring comprising one or
more heteroatoms selected from N, O, S, and is optionally substituted with one or more
substituents.
n is the integer selected from 0-2.
In another embodiment, the present invention provides novel compound of Formula I that is represented as compound of Formula III,
Formula III
wherein,
R2 is selected from hydrogen, azide, nitro, and halogen; R3 is selected from hydrogen,
substituted or unsubstituted C1-C6 alkyl group; or
R2 and R3 together form a saturated or unsaturated heterocyclic ring comprising one or
more heteroatoms selected from N, O, S, and is optionally substituted with one or more
substituents.
In another embodiment, the present invention provides novel compound of Formula I that is represented as compound of Formula IV,

Formula IV
wherein,
Ri is independently selected from hydrogen, substituted or unsubstituted C1-C6 alkyl, and
amine protecting group; R2 is selected from hydrogen, azide, nitro, and halogen; R3 is
selected from hydrogen, substituted or unsubstituted C1-C6 alkyl group; or
R2 and R3 together form a saturated or unsaturated heterocyclic ring comprising one or
more heteroatoms selected from N, O, S, and is optionally substituted with one or more
substituents.
In another embodiment, the present invention provides novel compound of Formula I that is represented as compound of Formula V,
Formula V
wherein,
A is selected from -CRi, -C(Ri)2, -N, -NRi, -CO, and -NOH;
Ri is independently selected from hydrogen, substituted or unsubstituted C1-C6 alkyl, and
amine protecting group; and
n is the integer selected from 0-2.
In another embodiment, the present invention provides novel compound of Formula I that is represented as compound of Formula VI,
Formula VI
wherein,

A is selected from -CRi, -C(Ri)2, -N, -NRi, -CO, and -NOH;
Ri is independently selected from hydrogen, substituted or unsubstituted C1-C6 alkyl, and
amine protecting group; and
n is the integer selected from 0-2.
In another embodiment, the present invention provides novel compounds as represented by following Formulae:
Formula IX , Formula XI ■ Formula XI1 , Formula XII
Formula XVI ■ Formula XVIII Formula XVIII1. <** Formula XIX
In another aspect, the present invention provides use of novel compounds of Formula I in preparation of lumateperone wherein said process comprises the steps of: a) reacting compound of Formula XX with cyclopentanone to obtain compound of Formula III:
Formula XX Formula XXI
wherein R2 and R2' is selected from hydrogen, azide, nitro, substituted and unsubstituted
amine and halogen;
R2 is selected from hydrogen, azide, nitro, and halogen; R3 is selected from hydrogen,
substituted or unsubstituted C1-C6 alkyl group; or
R2 and R3 together form a saturated or unsaturated heterocyclic ring comprising one or
more heteroatoms selected from N, O, S, and is optionally substituted with one or more
substituents;



b) converting compound of Formula XXI into compound of Formula III by using suitable oxidising agent;
Formula XXI Formula III
wherein R2 and R3 are as defined above;
c) converting compound of Formula III into compound of Formula XXII;
Formula III Formula XXII
wherein R2 and R3 are as defined above;
d) converting compound of Formula XXII in to compound of Formula XXIII using suitable
reducing agent;
o.
/ N\Rl H^N\Rl
\^N *" Ti H
R2 R3 R2 R3
Formula XXII Formula XXIII
wherein, R2 and R3 together form a saturated or unsaturated heterocyclic ring comprising one or more heteroatoms selected from N, O, S, and is optionally substituted with one or more substituents; and
e) converting compound of Formula XXIII to lumateperone of Formula II or
pharmaceutically acceptable salts thereof.
In another embodiment, the pure chiral lumateperone is prepared by resoluting compound of Formula XXIII or racemic lumaterperone in presence of suitable resolving agent selected from the group comprising of, but not limited to, tartaric acid, malic acid, dibenzoyl tartaric Acid, (R)-(+)-1,1′-Bi(2-naphthol), L-aspartic acid, (S)-1,4-benzodioxane-2-carboxylic acid, (1S)-(+)-3-bromocamphor-10-sulfonic acid hydrate , (1S)-(-)-camphanic acid, (1R,3S)-(+)-camphoric acid, (1R)-(-)-10-camphorsulfonic acid, (+)-2,3-dibenzoyl-D-tartaric acid, (-)-O,O′-dibenzoyl-L-tartaric acid mono(dimethylamide), di-p-toluoyl-D-tartaric acid monohydrate, (-)-O,O′-di-p-toluoyl-L-tartaric acid, D-glutamic acid, mandelic
13

acid, menthyloxyacetic acid, α-methoxy-α-trifluoromethylphenylacetic acid, mono-(1R)-
menthyl phthalate, (S)-(-)-N-[1-(1-naphthyl)ethyl]succinamic acid, (R)-(-)-5-
oxo-2-tetrahydrofurancarboxylic acid, (R)-(+)-N-(1-phenylethyl)phthalamic acid, (R)-
(+)-N-(1-phenylethyl)succinamic acid, (R)-(-)-2-Phenylpropionic acid, L-
pyroglutamic acid, D-(-)-quinic acid, D-valine and mixture thereof.
In one another embodiment, the present invention provides a process of preparation of lumateperone of Formula II by employing novel compounds of Formula IX, XI, and XII, wherein said process comprising of reaction steps as mentioned in the Scheme-4 below:
Scheme 4:


NH
HN Formula XIII
s'OH
Lumateperone Tosylate Formula DA
.

In one another embodiment, the present invention provides a process of preparation of lumateperone of Formula II by employing novel compounds of Formula XV, XVI, XVIII and XIX, wherein said process comprising of reaction steps as mentioned in the Scheme-5 below:
Scheme 5:
14

NH2HCI
NH O
NO,
Formula XTV

N02 Formula XV
O

Formula 11 Lumatepereone

N02 Formula XVI

-NH
-N H N02
Formula XVII

Lumateperone Tosylate Formula TTA

In one of the preferred embodiment, the pharmaceutically acceptable salt is tosylate salt. The lumateperone of Formula II is converted to lumateperone tosylate as represented below:

c

Formula II

Formula IIA

.

In another embodiment, the present invention provides optically pure lumateperone, wherein said optically pure lumateperone is prepared by resolution of racemic lumateperone or by taking optically pure intermediate(s), such as (6bR,10aS)-8,9,10,10a-tetrahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline-2,7(3H,6bH)-dione as used in Scheme 4, or (6bR,10aS)-2,3,8,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxalin-7(6bH)-one as used in Scheme 5.
15

In another embodiment, the process for the preparation of Lumateperone includes preparation of intermediates wherein said intermediates may optionally be not isolated, or may be converted to suitable salts before proceeding to next step.
In one another embodiment, the process for the preparation of lumateperone includes preparation of intermediates wherein said intermediates may optionally be isolated as its pharmaceutically acceptable salts.
In further embodiment, present invention provides lumateperone of Formula II, wherein said lumateperone is substantially free of impurities of Formula A, B, C, D and E; wherein each impurity is less than about 0.3% w/w or total impurity less than about 1% w/w, more specifically less than about 0.15% w/w of any impurity;

Formula A > Formula B Formulae

Formula D • ** Formula E
In a preferred embodiment, the present invention provides a substantially pure amorphous form of lumateperone or its pharmaceutically acceptable salts, wherein said amorphous form is substantially free of any crystalline form.
In further embodiment, the present invention provides lumateperone or pharmaceutically acceptable salts thereof, characterized by particle size distribution wherein, d90 is between 0.1µm to 200µm.
In another preferred embodiment, the lumateperone or pharmaceutically acceptable salts thereof, is characterized by particle size distribution wherein, d90 is between 2.0 µm to 150µm.
16

In one another embodiment, the lumateperone or pharmaceutically acceptable salts thereof, prepared as per the process of the present invention is characterized with purity above 99%, preferably above 99.5%, and more preferably above 99.9%.
In further embodiment, the present invention provides a substantially pure crystalline form of lumateperone or pharmaceutically acceptable salts thereof.
In a preferred embodiment, the present invention provides a substantially pure crystalline form of lumateperone or its pharmaceutically acceptable salts, wherein said crystalline form is substantially free of amorphous form.
In another preferred embodiment, the present invention provides a solid dispersion of lumateperone its pharmaceutically acceptable salt together with a pharmaceutically acceptable carrier or polymer, processes for preparation thereof, and pharmaceutically compositions prepared therefrom.
In another embodiment, the present invention provides a process for the preparation of amorphous solid dispersion of lumateperone comprising the steps of:
a) providing a solution of lumateperone in a suitable solvent;
b) providing atleast one pharmaceutically acceptable excipient in a solvent and adding the solution obtained in step a); and
c) isolating the amorphous solid dispersion of lumateperone.
In one another embodiment, the present invention further provides a composition comprising lumateperone its pharmaceutically acceptable salt along with one or more pharmaceutically acceptable excipients.
The embodiments of the present invention are exemplified herein below:
EXAMPLES:
Example 1: Synthesis of 5-bromo-1,2,3,4-tetrahydrocyclopenta[b]indole of Formula VII:
17

2-bromophenylhydrazine hydrochloride (100g) was dissolved in a mixture of concentrated hydrochloric acid (10ml) and water (190ml) and cyclopentanone (45.0g) was added dropwise at room temperature. After that, the mixture was stirred for more than 5 h at 50-60 ºC. Reaction mixture was cooled to room temperature to get solid material. The mixture was filtered and the solid was washed with water until neutral pH obtained. The crude product was recrystallized in hexane to get 5-bromo-1,2,3,4-tetrahydrocyclopenta[b]indole of Formula VII (79.3g).
Example 2: Synthesis of 5-bromo-3,4-dihydrocyclopenta[b]indol-1(2H)-one of Formula VIII:
5-bromo-1,2,3,4-tetrahydrocyclopenta[b]indole of Formula VII (79.2g) was dissolved in tetrahydrofuran (214ml) and water (23ml) and then cooled to 0ºC. Charged 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone (84.0g) and stirred the reaction mixture for 2-3 hours. After completion, charged 5% sodium bisulphite solution in water and then tetrahydrofuran was distilled out completely. Aqueous layer was then extracted using dichloromethane (200*2) twice. Organic layer was distilled out completely and degassed to get 5-bromo-3,4-dihydrocyclopenta[b]indol-1(2H)-one of Formula VIII (58.8g).
Example 3: Synthesis of 6-azido-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-1-one of Formula IX:
5-bromo-3,4-dihydrocyclopenta[b]indol-1(2H)-one(58.8g) of Formula VIII and formic acid (95-97%) (176.0 ml) was dissolved in one flask and slowly charged over a solution of hydroxylamine-o-sulphonic acid (40g) in formic acid (95-97%) (100ml) at 20ºC over a period of 10 minutes. The reaction mixture is then heated under reflux for 3-7 hours. After cooling, it was quenched with ice water, neutralized with 5% sodium hydroxide. It was then extracted using dichloromethane (250*2) twice and distilled, degassed for 30 minutes. It was then taken up in DMSO (436ml) in a one litre RBF. Sodium azide (16.8g) was charged under argon atmosphere. The flask was placed in a 100ºC oil bath and stirred for 30 min. The reaction was cooled to room temperature and diluted with water (1000 mL), the suspended solid was then filtered. The solid was dissolved in DCM and dried on MgSO4. It was concentrated to saturation then crystallized with hexanes to get 6-azido-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-1-one of Formula IX (37.3g).
18

Example 4: Synthesis of 6-amino-2,3,4,5-tetrahydro-lH-pyrido[4,3-b]indol-l-one of Formula X:
6-azido-2,3,4,5-tetrahydro-lH-pyrido[4,3-b]indol-l-one of Formula IX (37.3g) was charged in a RBF. Charged zinc dust (16.Og), ammonium formate (31.05g) and methanol (373ml). The reaction mixture was stirred for one hour at room temperature. After reaction completion, reaction mixture was filtered out. And methanol was distilled out. It was again taken up in MDC and washed with saturated brine to remove ammonium formate. Distilled out dichloromethane completely and degassed to get 6-amino-2,3,4,5-tetrahydro-lH-pyrido[4,3-b]indol-l-one of Formula X (23.1 lg).
Example 5: Synthesis of 9,10-dihydro-lH-pyrido[3',4':4,5]pyrrolo[l,2,3-de]quinoxaline-2,7(3H,8H)-dione of Formula XI:
Charged 6-amino-2,3,4,5-tetrahydro-lH-pyrido[4,3-b]indol-l-one of Formula X (23.1 lg), ethyl bromoacetate (15.0ml), sodium carbonate and potassium iodide (11.3g) in acetone (550 mL) was refluxed for 16 hours. Acetone was removed under vacuum and the residue was diluted with dichloromethane (700ml) and then washed with water (500ml) and brine (200 ml) and dried over sodium sulphate. Evaporation of the solvent gave oil which was then dissolved in TUF (150ml). Then 2N HC1 (51ml) was added in portions at room temperature. After 1.5 hour, THF was distilled under reduced pressure and residue was treated with IN HC1 (75ml). After filtration, the resulting brown solid was dissolved in dichloromethane (250ml) and washed with brine (150ml). Evaporated the solvents and purified the compound through column chromatography to get 9,10-dihydro-lH-pyrido[3',4':4,5]pyrrolo[l,2,3-de]quinoxaline-2,7(3H,8H)-dione of Formula XI (12.5g).
Example 6: Synthesis of 8,9,10,10a-tetrahydro-lH-pyrido[3',4':4,5] pyrrolo[l,2,3-de]quinoxaline-2,7(3H,6bH)-dione of Formula XII:
9,10-dihydro-lH-pyrido[3',4':4,5]pyrrolo[l,2,3-de]quinoxaline-2,7(3H,8H)-dione of
Formula XI (12.5g), trifluoroacetic acid (125ml) was charged in a RBF and stirred. Lot wise charged sodium cyanoborohydride (5.2 g) at 0-5°C with vigorous stirring. After addition, the reaction mixture was stirred at room temperature for 30 minutes. After completion, reaction was slowly poured over ammonium hydroxide solution (300.0ml)

containing ice. The reaction mixture was then basified using IN sodium hydroxide to make the mixture basic. The reaction mixture was extracted twice using dichloromethane and then washed using DM water. Distilled out organic layer completely and degassed to get 8,9,10,10a-tetrahydro-lH-pyrido[3',4':4,5]pyrrolo[l,2,3-de]quinoxaline-2,7(3H,6bH)-dione of Formula XII (11.3g).
Example 7: Synthesis of 2,3,6b,7,8,9,10,10a-octahydro-lH-
pyrido[3',4':4,5]pyrrolo[l,2,3-de]quinoxaline of Formula XIII:
A solution of borane in THF (l.OM) (71.0ml) was added dropwise to stirred solution of 8,9,10,10a-tetrahydro-lH-pyrido[3',4':4,5]pyrrolo[l,2,3-de]quinoxaline-2,7(3H,6bH)-dione of Formula XII in anhydrous THF (54.0ml) under nitrogen atmosphere. After addition, the mixture was stirred and heated at reflux for an hour. After completion, cooled to room temperature and charged 6N HC1 (32.2ml). The mixture was again heated to reflux for 30 minutes. Distilled and dried under reduced vacuum. Residue was taken up in minimum quantity of water and then solution was basified with IN sodium hydroxide and then extracted with dichloromethane twice. The combined organic layer was washed with DM water and distilled under reduced pressure to get 2,3,6b,7,8,9,10,10a-octahydro-lH-pyrido[3',4':4,5]pyrrolo[l,2,3-de] quinoxaline of Formula XIII (8.99g).
Example 8: Synthesis of l-(4-fluorophenyl)-4-(2,3,6b,9,10,10a-hexahydro-lH-pyrido[3',4,:4,5]pyrrolo[l,2,3-de]quinoxalin-8(7H)-yl)butan-l-one of Formula XIV:
Added 2,3,6b,7,8,9,10,10a-octahydro-lH-pyrido[3',4':4,5]pyrrolo[l,2,3-de]quinoxaline of Formula XIII (8.99g), 4-chloro-4'-fluoro-butyrophenone(l 1.4g), triethylamine (23.Og) and KI (9.68g) in dioxane (50ml) and toluene (50ml) and refluxed for 7 hours. After filtration and evaporation of the solvent, MDC (200ml) was added to dissolve the residue. The dichloromethane solution was washed with brine (2*200ml), dried over anhydrous sodium sulphate and concentrated to approximately 55ml and added dropwise to a 0.5N HC1 ether solution (600ml). The resulting brown solid was filtered out, washed with ether and then dissolved in water. The aqueous layer was basified with 2N NaOH and extracted with DCM (2* 100ml). The combined organic phase was washed with brine (2*200ml) and dried over sodium sulphate. Evaporated the solvent and crystallized the compound so obtained in

isopropanol to get l-(4-fluorophenyl)-4-(2,3,6b,9,10,10a-hexahydro-lH-
pyrido[3',4':4,5]pyrrolo[l,2,3-de]quinoxalin-8(7H)-yl)butan-l-oneofFormulaXIV(8.5g).
Example 9: Synthesis of Lumateperone of Formula II:
Example 9a: Sodium hydride (1.27g of 60% dispersion in mineral oil) was washed with hexane and suspended in anhydrous DMF (5ml), the suspension was added to a stirred solution of l-(4-fluorophenyl)-4-(2,3,6b,9,10,10a-hexahydro-lH-pyrido [3',4':4,5] pyrrolo [l,2,3-de]quinoxalin-8(7H)-yl)butan-l-one of Formula XIV in anhydrous DMF (50ml) under nitrogen atmosphere. After the gas evolution had subsided, the mixture was cooled in an ice water bath and treated with methyl iodide (3.55g). The mixture was stirred at room temperature for an hour and then concentrated. The residue was treated with water and extracted with DCM twice. Distilled and degassed the organic phase to get racemic mixture of Lumateperone (6.20g).
Example 9b: Racemic mixture of Lumateperone as obtained in Example 9a was further separated into its corresponding enantiomers by HPLC utilizing a chiralcel AD column with 50%) ethanol/methanol solvent system. Enantiomerically pure Lumateperone of Formula II (2.4g).
Example 10: Synthesis of l-(4-fluorophenyl)-4-(6bR,10aS)-(2,3,6b,9,10,10a-hexahydro-lH-pyrido[3',4,:4,5]pyrrolo[l,2,3-de]quinoxalin-8(7H)-yl)butan-l-one of Formula XlVa:
l-(4-fluorophenyl)-4-(2,3,6b,9,10,10a-hexahydro-lH-pyrido [3',4':4,5] pyrrolo[ 1,2,3-
de]quinoxalin-8(7H)-yl)butan-l-one of Formula XIV (5g) was resolved to give
enantiomerically pure l-(4-fluorophenyl)-4-((6bR,10aS)-2,3,6b,9,10,10a-hexahydro-lH-
pyrido[3',4':4,5]pyrrolo[l,2,3-de]quinoxalin-8(7H)-yl) butan-1-one of Formula XIV by
forming diastereomeric salt with (S) - mandelic acid with >99%> excess, in alcohol solvent
and pure salt so obtained was basified with aq. NaOH to get enantiomerically pure l-(4-
fluorophenyl)-4-((6bR,10aS)-2,3,6b,9,10,10a-hexahydro-lH-pyrido [3',4':4,5]
pyrrolo[l,2,3-de]quinoxalin-8(7H)-yl)butan-l-one of Formula XIVa(1.5 g).
Example 11: Synthesis of Lumateperone of Formula II:

Lumateperone of Formula II was prepared by using l-(4-fluorophenyl)-4-((6bR,10aS)-2,3,6b,9,10,10a-hexahydro-lH-pyrido[3',4':4,5]pyrrolo[l,2,3-de]quinoxalin-8(7H)-yl)butan-l-one of Formula XlVa following the method as disclosed in Example-9a.
Example 12: Synthesis of 5-nitro-l,2,3,4-tetrahydrocyclopenta[b]indole of Formula XV:
2-nitrophenylhydrazine (100.Og) was dissolved in a mixture of concentrated hydrochloric acid (10ml) and water (190ml) and then cyclopentanone (53.Og) was added dropwise at room temperature. After that, the mixture was stirred for more than 5 h at 50-60 °C. When the reaction cooled to room temperature solid appeared in the system. The mixture was filtered and the solid was washed with enough water until neutral. The crude product was recrystallized in hexane to get 5-nitro-l,2,3,4-tetrahydrocyclopenta[b]indole of Formula XV(74.81g).
Example 13: Synthesis of 5-nitro-3,4-dihydrocyclopenta[b]indol-l(2H)-one of Formula XVI:
5-nitro-l,2,3,4-tetrahydrocyclopenta[b]indole of Formula XV (74.81g) was dissolved in tetrahydrofuran (214ml) and water (23ml) and then cooled to 0°C. Charged 2,3-Dichloro-5,6-dicyano-l,4-benzoquinone (92.4g) and stirred reaction mixture for 2-3 hours. After completion, charged sodium bisulphite solution in water (5%) and then tetrahydrofuran was distilled out completely. Aqueous layer was then extracted using dichloromethane (200*2) twice. Organic layer was distilled out completely and degassed to get 5-nitro-3,4-dihydrocyclopenta[b]indol-l(2H)-one of Formula XVI (56.Og).
Example 14: Synthesis of 6-nitro-2,3,4,5-tetrahydro-lH-pyrido[4,3-b]indol-l-one of Formula XVII:
5-nitro-3,4-dihydrocyclopenta[b]indol-l(2H)-one (56.Og) of Formula XVI and formic acid (95-97%) (176.0ml) was dissolved in one flask and slowly charged over a solution of hydroxylamine-o-sulphonic acid (44g) in formic acid (95-97%) (100ml) at 20°C over a period of 10 minutes. The reaction mixture is then heated under reflux for 3-7 hours. After

cooling it was quenched with ice water, neutralized with 5% sodium hydroxide. It was then extracted using Dichloromethane (250*2) twice and distilled, degassed for 30 minutes to get 6-nitro-2,3,4,5-tetrahydro-lH-pyrido[4,3-b]indol-l-one of Formula XVII (41.92g).
Example 15: Synthesis of 6-amino-2,3,4,5-tetrahydro-lH-pyrido[4,3-b]indol-l-one of Formula X:
6-nitro-2,3,4,5-tetrahydro-lH-pyrido[4,3-b]indol-l-one of Formula XVII (41. Og), methanol (410ml) and palladium on carbon (10%) (4.10g) was charged in a hydrogenator. The reaction mixture was hydrogenated at 10 kg pressure at 50°C in 2 hours. After reaction completion, filtered out the reaction mixture. Distilled out methanol completely and degassed to get 6-amino-2,3,4,5-tetrahydro-lH-pyrido[4,3-b]indol-l-one of Formula X (28.54g).
Example 16: Synthesis of 9,10-dihydro-lH-pyrido[3',4':4,5]pyrrolo[l,2,3-de]quinoxalin-7-(8H)-one of Formula XVIII:
6-amino-2,3,4,5-tetrahydro-lH-pyrido[4,3-b]indol-l-one (28.Og), ethanol (280ml) and Chloroacetaldehyde (13.03g) was charged in a four neck round bottom flask. Stirred for 10 minutes at room temperature. Charged triethylamine (15.62g) and heated to 100°C. Stirred for 2 hour at same temperature and cooled down to room temperature. Filtered out the reaction mixture and washed with DM water (300ml). Dried in a hot air oven for 4-6 hrs to get 9,10-dihydro-lH-pyrido[3',4':4,5]pyrrolo[l,2,3-de]quinoxalin-7-(8H)-one of Formula XVIII(21.94g).
Example 17: Synthesis of 2,3,8,9,10,10a-hexahydro-lH-
pyrido[3',4':4,5]pyrrolo[l,2,3-de]quinoxalin-7(6bH)-one of Formula XIX:
9,10-dihydro-lH-pyrido[3',4':4,5]pyrrolo[l,2,3-de]quinoxalin-7-(8H)-one of Formula XVIII (21.0g), trifluoroacetic acid (218ml) was charged in a RBF and stirred at room temperature. Lot wise charged sodium cyanoborohydride (18.5g) at 0-5°C with vigorous stirring. After addition, the reaction mixture was stirred at room temperature for 30 minutes. After completion, reaction was slowly poured over ammonium hydroxide solution (1000ml) containing ice. Reaction mixture was then basified using IN sodium hydroxide

to make the mixture basic. The mixture was extracted twice using dichloromethane and then washed using DM water. Distilled out organic layer completely and degassed to get 2,3,8,9,10,10a-hexahydro-lH-pyrido[3',4':4,5]pyrrolo[l,2,3-de]quinoxalin-7(6bH)-one of Formula XIX(19.23g).
Example 18: Synthesis of 2,3,6b,7,8,9,10,10a-octahydro-lH-
pyrido[3',4':4,5]pyrrolo[l,2,3-de]quinoxaline of Formula XIII:
A solution of borane in THF (1.0M)(120.0ml) was added dropwise to stirred solution of 2,3,8,9,10,10a-hexahydro-lH-pyrido[3',4':4,5]pyrrolo[l,2,3-de]quinoxalin-7(6bH)-one of Formula XIX (19.Og) in anhydrous THF(90.0ml) under nitrogen atmosphere. After addition, the mixture was stirred and heated at reflux for an hour. After completion, reaction mixture was cooled to room temperature and charged 6N HC1 (54.14ml). The mixture was again heated to reflux for 30 minutes. Distilled and dried under reduced vacuum. Residue was taken up in minimum quantity of water and then solution was basified with IN sodium hydroxide and then extracted with dichloromethane twice. The combined organic layer was washed with DM water and distilled under reduced pressure to get 2,3,6b,7,8,9,10,10a-octahydro-lH-pyrido[3',4':4,5]pyrrolo[l,2,3-de] quinoxaline of Formula XIII (14.27g).
Example 19: Synthesis of l-(4-fluorophenyl)-4-(2,3,6b,9,10,10a-hexahydro-lH-pyrido[3',4,:4,5]pyrrolo[l,2,3-de]quinoxalin-8(7H)-yl)butan-l-one of Formula XIV:
Added 2,3,6b,7,8,9,10,10a-octahydro-lH-pyrido[3',4':4,5]pyrrolo[l,2,3-de]quinoxaline of Formula XIII (14.Og), 4-chloro-4'-fluoro-butyrophenone(18g), triethylamine (35.89g) and KI (15.07g) in 1,4-dioxane (75ml) and toluene (75ml) and refluxed for 7 hours. After filtration and evaporation of the solvent, MDC (250ml) was added to dissolved the residue. The dichloromethane solution was washed with brine (2*250ml), dried over anhydrous sodium sulphate and concentrated to approximately 55ml and added dropwise to a 0.5N HC1 ether solution (720ml). The resulting brown solid was filtered out, washed with ether and then dissolved in water. The aqueous layer was basified with 2N NaOH and extracted with DCM (2* 150ml). The combined organic phase was washed with brine (2*250ml) and dried over sodium sulphate. Evaporation of the solvent and crystallisation in isopropanol give l-(4-fluorophenyl)-4-(2,3,6b,9,10,10a-hexahydro-lH-pyrido[3',4':4,5]pyrrolo[l,2,3-de]quinoxalin-8(7H)-yl)butan-l-one of Formula XIV (13.7g).

Example 20: Synthesis of Lumateperone of Formula II:
l-(4-fluorophenyl)-4-(2,3,6b,9,10,10a-hexahydro-lH-pyrido [3*,4*:4,5] pyrrolo[l,2,3-de]quinoxalin-8(7H)-yl)butan-l-one of Formula XIV (5g) was resolved to give enantiomerically pure l-(4-fluorophenyl)-4-((6bR,10aS)-2,3,6b,9,10,10a-hexahydro-lH-pyrido[3',4':4,5]pyrrolo[l,2,3-de]quinoxalin-8(7H)-yl)butan-l-one of Formula XIV by forming diastereomeric salt with (S) - mandelic acid with >99% excess, in alcohol solvent and pure salt was basified with aq. NaOH to get enantiomerically pure l-(4-fluorophenyl)-4-((6bR,10aS)-2,3,6b,9,10,10a-hexahydro-lH-pyrido[3',4':4,5]pyrrolo[l,2,3-de] quinoxalin-8(7H)-yl)butan-l-one of Formula XlVa (1.5 g).
Example 21: Synthesis of Lumateperone tosylate of Formula IIA:
To a solution of lumateperone free base of Formula II (400g) in ethanol (3000 ml) was added, a solution 175.3g of p-toluene sulfonic acid monohydrate. The reaction mixture was stirred at room temperature for approx. 1 hour, and then the internal temperature was reduced to 2-4°C, with an ice bath. The reaction mixture was stirred at same temperature for one more hour and the batch becomes brownish white slurry. To this added heptane (6000 ml) in approximately 3 hours. The resultant mixture was stirred at 2-4°C for another one hour and then hold for 15 hours, protected from light. The reaction mixture was then filtered, and the solid is rinsed with heptane (1000ml). After drying in a vacuum oven at 35 to 40°C for 4 hours Lumateperone tosylate of Formula IIA (345.8g) as tan brown solid was obtained.

WE CLAIM
1. A compounds of Formula I, isomers, or pharmaceutical^ acceptable salts thereof;
Formula I
wherein,
A is selected from -CRi, -C(Ri)2, -N, -NRi, -CO, and -NOH;
Ri is independently selected from hydrogen, substituted or unsubstituted C1-C6 alkyl, and
amine protecting group; R2 is selected from hydrogen, azide, nitro, and halogen; R3 is
selected from hydrogen, substituted or unsubstituted C1-C6 alkyl group; or
R2 and R3 together form a saturated or unsaturated heterocyclic ring comprising one or
more heteroatoms selected from N, O, S, and is optionally substituted with one or more
substituents;
n is the integer selected from 0-2.
2. The compounds as claimed in claim 1, wherein said compounds are selected from
Formula IX , Formula XI ■ Formula XI' , Formula XII
Formula XVI ' Formula XVIII Formula XVni'. ^ Formula XIX
3. A process for the preparation of lumateperone and pharmaceutically acceptable salts thereof, wherein said process comprises the steps of:
a) reacting compound of Formula XX with cyclopentanone to obtain compound of Formula III;

Formula XX Formula XXI
wherein R2 and R2' is selected from hydrogen, azide, nitro, substituted and unsubstituted
amine and halogen;
R2 is selected from hydrogen, azide, nitro, and halogen; R3 is selected from hydrogen,
substituted or unsubstituted C1-C6 alkyl group; or
R2 and R3 together form a saturated or unsaturated heterocyclic ring comprising one or
more heteroatoms selected from N, O, S, and is optionally substituted with one or more
substituents;
b) converting compound of Formula XXI into compound of Formula III by using suitable
oxidising agent;
Formula XXI Formula III
wherein R2 and R3 are as defined above;
c) converting compound of formula III into compound of formula XXII;
Formula III Formula XXII
wherein R2 and R3 are as defined above;
d) converting compound of Formula XXII in to compound of Formula XXIII using suitable reducing agent;
Formula XXII Formula XXIII
wherein, R2 and R3 together form a saturated or unsaturated heterocyclic ring comprising one or more heteroatoms selected from N, O, S, and is optionally substituted with one or more substituents; and

e) converting compound of Formula XXIII in to Lumateperone of Formula II or pharmaceutically acceptable salts thereof.
4. The process as claimed in claim 3, wherein said lumateperone is prepared by resoluting compound of Formula XXIII or racemic lumaterperone in presence of suitable resolving agent.
5. The process as claimed in claim 4, wherein said resolving agent is selected from tartaric acid, malic acid, dibenzoyl tartaric acid, (R)-(+)-l,l'-Bi(2-naphthol), L-aspartic acid, (S)-l,4-benzodioxane-2-carboxylic acid, (lS)-(+)-3-bromocamphor-10-sulfonic acid hydrate , (lS)-(-)-camphanic acid, (lR,3S)-(+)-camphoric acid, (lR)-(-)-10-camphorsulfonic acid, (+)-2,3-dibenzoyl-D-tartaric acid, (-)-0,0'-dibenzoyl-L-tartaric acid mono(dimethylamide), di-p-toluoyl-D-tartaric acid monohydrate, (-)-0,0'-di-p-toluoyl-L-tartaric acid, D-glutamic acid, mandelic acid, menthyloxyacetic acid, a-methoxy-a-trifluoromethylphenylacetic acid, mono-(lR)-menthyl phthalate, (S)-(-)-N-[l-(l-naphthyl)ethyl]succinamic acid, (R) - (-) -5-oxo-2-tetrahydrofurancarboxylic acid, (R)-(+)-N-(l-phenylethyl)phthalamic acid, (R)-(+)-N-(l-phenylethyl)succinamic acid, (R)-(-)-2-Phenylpropionic acid, L-pyroglutamic acid, D-(-)-quinic acid, D-valine, chiralcel AD column and mixture thereof.
6. The process as claimed in claim 3, wherein said lumateperone or its pharmaceutically acceptable salts is characterized by particle size D90 less than about 200um.
7. Substantially pure Lumateperone of Formula II and pharmaceutically acceptable salts thereof wherein said lumateperone and its salts are substantially free of impurities of Formula A, B, C, D and E wherein each impurity is less than about 0.3% w/w,

wherein said lumateperone is isolates with purity of 99.9% and above.
8. A composition comprising Lumateperone of Formula II or pharmaceutically acceptable salts thereof, and optionally one or more pharmaceutically acceptable excipients, wherein said lumateperone is prepared by a process as claimed in claim 3.