DESC:AN IMPROVED PROCESS FOR THE PREPARATION OF LUMATEPERONE AND SALT THEREOF”

FIELD OF THE INVENTION

The present invention relates to a process for the preparation of Lumateperone of Formula (I) and salts thereof.

BACKGROUND OF THE INVENTION

Lumateperone tosylate, sold under the brand name Caplyta™, is an atypical antipsychotic medication of the butyrophenone class. It is approved for the treatment of schizophrenia as well as bipolar depression, as either monotherapy or adjunctive therapy (with lithium or valproate). It is developed by Intra-Cellular Therapies, licensed from Bristol-Myers Squibb. Lumateperone was approved for medical use in the United States in December 2019 with an initial indication for schizophrenia and became available in February 2020. It has since demonstrated efficacy in bipolar depression and received FDA approval in December 2021 for that indication as well.

Lumateperone tosylate is chemically known as the chemical name 4-((6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H,7H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxalin-8-yl)-1-(4-fluoro-phenyl)-butan-1-one 4-methylbenzenesulfonate and its represented by the following structure:

(Ia)

Lumateperone of Formula (I) and its tosylate salt of formula (Ia) were first described in U.S. Patent 7,183,282. The patent describes a process, as illustrated in Scheme-1, in which the compound of formula (IX) undergoes reduction with NaCNBH3 in presence of TFA / NH4OH to yield the compound of formula (IX-A). Further it reacts with CH3I in presence of NaH / DMF to yield the compound of formula (VII). The compound of formula (VII) is reduced with borane in THF to yield the compound of formula (VI), which is deprotected in presence of KOH/1-butanol to yield the compound of formula (V). The compound of formula (V) is reacted with the compound of formula (IVb) in presence of TEA, KI and dioxane to yield racemic Lumateperone, which is resolved using a chiral HPLC column to yield Lumateperone of Formula (I).

The process is schematically shown as below:

Scheme 1

The disadvantage associated with the above process is the resolution of racemic Lumateperone by using chiral HPLC, which requires exhaustive purification procedures such as chiral column chromatography to obtain enantiomeric pure product, which is industrially not viable. The further disadvantage of the above process is the use of excess reagents and reaction intermediates are required to obtain racemic compound , wherein such product is purified at the final step gives a maximum yield of 25-50%. Hence, there is a need for a more efficient process to make enantiomeric pure Lumateperone.

The process for the preparation of Lumateperone tosylate (Ia) disclosed in IN 202241021301 by MSN involves several steps, which is illustrated in the Scheme-2. First, the compound of formula (IX) undergoes reduction with NaBH4 in presence of TFA / MDC to yield the compound of formula (IX-A). Further it is reacted with CH3I in presence of potassium tert-butoxide / DMF / water to yield the compound (VII). The compound (VII) undergoes deprotection in the presence of KOH, n-butanol to yield the compound (XII). Compound (XII) is then treated with D-(-)-tartaric acid in the presence of MeOH to yield the compound (XIIa) and subsequently basified with NaOH to yield the compound (XIIb). Next, the compound (XIIb) is reduced with Borane-dimethylsulfide in the presence of THF to yield the compound (V). Compound (V) is then reacted with the compound (IVb) in the presence of TEA, KI, and 1,4-dioxane to obtain Lumateperone (I). Finally, the resulting compound is reacted with p-Toluenesulfonic acid in the presence of IPA to yield Lumateperone tosylate (Ia).

The process is schematically shown as below:

Scheme 2

The process for the preparation of Lumateperone tosylate (Ia) disclosed in IN 201911022605 involves several steps, as illustrated in Scheme-3. First, the compound (XIV) is reduced with NaBH3CN in the presence of TFA, which is again reduced with borane in THF in to yield the compound (XVI). The compound of formula (XVI) is reacted with compound (IVb) in the presence of TEA/KI in dioxane to yield the compound (XVII). Compound (XVII) is then treated (S)-mandelic acid in alcohol solvent and basified with aq. NaOH to yield the compound(XVIII), which is reacted with MeI in the presence of MDC and to yield a mixture of Lumateperone(I). Finally, Lumateperone is reacted with p-Toluenesulfonic acid in the presence of IPA to yield Lumateperone tosylate.

The process is schematically shown as below:

Scheme 3

The prior art processes (schemes 1 and 2) first involve the reduction of the double bond compound (stage 1, compound I to II) followed by N-methylation to yield compound III. The major disadvantage associated with the above processes is the formation of more impurities during the reaction, which results the lesser yield of the final product Lumateperone tosylate.

The inventors of the present invention surprisingly developed an improved and efficient process for producing Lumateperone and its salts with higher yield and purity, which controls the impurities during the reduction step. Further, the resolution step is also industrially viable, which is performed in the presence of a mixture of solvents, rather than using column chromatography.

The present invention offers an improved process which demonstrates increased efficiency and economic viability at industrial scales. The process of the present invention achieves higher yield and purity of Lumateperone tosylate (Ia) with considerably lesser impurity.

SUMMARY OF THE INVENTION

The present invention relates to an improved process for the preparation of Lumateperone (I) and salts thereof with high yield and purity.

One aspect of the present invention provides, an improved process for the preparation of Lumateperone and salts thereof, which comprises the steps of:

a) reacting the compound of formula (IX) with a methylating agent in presence of a base and a suitable solvent to obtain the compound of formula (VIII);

b) treating the compound of formula (VIII) with a reducing agent in presence of an acid and a suitable solvent to obtain the compound of formula (VII);

c) reducing the amide carbonyl compound of formula (VII) with a Lewis acid in presence of a suitable solvent to obtain the compound of formula (VI);

d) deprotecting the compound of formula (VI) in presence of a base and a suitable solvent to obtain the compound of formula (V);

e) optionally the compound of formula (V) converts into salt compound of formula (Va);

Wherein the salt is selected from hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid, boric acid, formic acid, acetic acid, trifluoroacetic acid, propionic acid, butyric acid, oxalic acid, malonic acid, maleic acid, fumaric acid, succinic acid, citric acid, tartaric acid, benzoic acid, 4-hydroxybenzoic acid, mandelic acid, methanesulfonic acid, p-toluenesulfonic acid.

f) reacting the compound of formula (V) with the compound of formula (IVa) in presence of a base and mixture of suitable solvents to obtain the compound of formula (III);

wherein X is halogen or mesyl or tosyl.

g) treating the racemic compound of formula (III) with a chiral acid in presence of a mixture of suitable solvents to obtain the compound of formula (II);

h) basifying the compound of formula (II) in presence of a base and a suitable solvent to obtain Lumateperone (I); and

i) optionally reacting the Lumateperone (I) with an acid in presence of a suitable solvent to obtain Lumateperone acid salt (Ia).

Another aspect of the present invention provides, an improved process for the preparation of the compound of formula (VII), which comprises the steps of:

a) reacting the compound of formula (IX) with a methylating agent in presence of a base and a suitable solvent to obtain the compound of formula (VIII);

b) treating the compound of formula (VIII) with a reducing agent in presence of an acid and a suitable solvent to obtain the compound of formula (VII);

In another aspect of the present invention provides, an improved process for the preparation of Lumateperone (I), which comprises the steps of:

a) treating the racemic compound of formula (III) with a chiral acid in presence of a mixture of suitable solvents to obtain the compound of formula (II);

b) basifying the compound of formula (II) in presence of a base and a suitable solvent to obtain Lumateperone (I).

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to an improved process for the preparation of Lumateperone (I) and salts thereof with high yield and purity.

In a first embodiment, the present invention provides an improved process for the preparation of Lumateperone (I), which comprises the steps of:

a) reacting the compound of formula (IX) with a methylating agent in presence of a base and a suitable solvent to obtain the compound of formula (VIII);

b) treating the compound of formula (VIII) with a reducing agent in presence of an acid and a suitable solvent to obtain the compound of formula (VII);

c) reducing the amide carbonyl compound of formula (VII) with a Lewis acid in presence of a suitable solvent to obtain the compound of formula (VI);

d) deprotecting the compound of formula (VI) in presence of a base and a suitable solvent to obtain the compound of formula (V);

e) optionally the compound of formula (V) converts into salt compound of formula (Va);

f) reacting the compound of formula (V) with the compound of formula (IVa) in presence of a base and mixture of suitable solvents to obtain the compound of formula (III);

g) treating the racemic compound of formula (III) with a chiral acid in presence of a mixture of suitable solvents to obtain the compound of formula (II); and

h) basifying the compound of formula (II) in presence of a base and a suitable solvent to obtain Lumateperone (I).

In an embodiment of the present invention, the step (a) involves reacting the compound of Formula (IX) with a methylating agent in the presence of a base and a suitable solvent, thereby yielding the compound of Formula (VIII). The reaction is conducted at a temperature ranging from 20 to 40°C, preferably maintained between 25 and 30°C.

In another embodiment of the present invention, step (b) comprises the reduction of the compound of formula (VIII) in the presence of a reducing agent, an acid, and a suitable solvent to obtain the compound of formula (VII). In yet another embodiment, the temperature during step (b) is maintained in the range of -10°C to 10°C, preferably between -5°C and 0°C.

In another embodiment of the present invention, step (c) involves reacting the compound of formula (VII) with a Lewis acid in the presence of a suitable solvent to obtain the compound of formula (VI). In yet another embodiment, the reaction is carried out at a temperature in the range of 70-75°C, preferably at 60-65°C.

In another embodiment of the present invention, the step (d) involves the compound of formula (VI) undergoing deprotection in the presence of a base and a suitable solvent to yield the compound of formula (V). The reaction is carried out at a temperature ranging from 100°C to 130°C, preferably maintained at 110°C to 115°C.

In another embodiment of the present invention, the step (f) comprises reacting the compound of formula (V) with the compound of formula (IVa) in the presence of a base and a mixture of suitable solvents to obtain the compound of formula (III). The reaction temperature for step (f) is maintained in the range of 90-110°C, and preferably at 95-100°C.

In another embodiment of the present invention, the step (g) comprises treating the racemic compound of formula (III) with a chiral acid in presence of a mixture of suitable solvents to obtain the compound of formula (II). The reaction temperature of the step (g) is in the range of 20-80°C.

In another embodiment of the present invention, the process comprises step (h), wherein compound (II) is treated with a base in the presence of a suitable solvent at 10-15°C to yield Lumateperone of Formula (I).

In another embodiment, Lumateperone of Formula (I) is reacted with an acid in a suitable solvent to obtain a Lumateperone salt. In one embodiment, Lumateperone of Formula (I) is reacted with p-toluenesulfonic acid in a suitable solvent at 20-40°C to obtain the Lumateperone tosylate salt of formula (Ia).

In a second embodiment, the present invention provides an improved process for the preparation of the compound of formula (VII), which comprises the steps of:

a) reacting the compound of formula (IX) with a methylating agent in presence of a base and a suitable solvent to obtain the compound of formula (VIII); and

b) treating the compound of formula (VIII) with a reducing agent in presence of an acid and a suitable solvent to obtain the compound of formula (VII).

In another embodiment, the compound of formula (VII) is further converted to Lumateperone (I) or salts thereof.

In the third embodiment, the present invention provides an improved process for the preparation of Lumateperone (I), which comprises the steps of:

a) treating the racemic compound of formula (III) with a chiral acid in presence of a mixture of suitable solvents to obtain the compound of formula (II); and

b) basifying the compound of formula (II) in presence of a base and a suitable solvent to obtain Lumateperone (I).

According to an embodiment of the present invention, wherein methylating agent is selected from methyl chloride, methyl bromide and methyl iodide, methyl lithium, methyl methane sulfonate, dimethyl sulfate, N-methyl-N-nitrosourea, tetramethyltin, dimethylzinc, or trimethylaluminium.

According to an embodiment of the present invention, wherein reducing agent is selected from sodium borohydride, sodium cyano borohydride, lithium borohydride or lithium triethylborohydride.

According to an embodiment of the present invention, wherein lewis acid is selected from AlCl3 (Aluminium chloride), BF3 (boron trifluoride), Br2 (dibromine), AlF3 (aluminum fluoride), CO2 (carbon dioxide), SO2 (Sulfur dioxide), SO3 (sulfur trioxide), SiBr4 (silicon tetrabromide) or SiF4 (silicon tetrafluoride).

According to an embodiment of the present invention, wherein the chiral acid is selected from tartaric acid, dibenzoyl-L-tartaric acid, mandelic acid, (-)-Di-p-toluoyl-L-tartaric acid, (-)-Di-p-anisoyl-L-tartaric Acid, (-)-Diacetyl-L-tartaric Acid, diisopropyl D-(-)-tartrate, D- (+)-malic acid, dimethyl L-(+)-tartrate and L-valine, (-)-dibenzoyl-L-tartaric acid mono(dimethylamide) or (+)-dibenzoyl-D-tartaric acid mono(dimethylamide).

According to an embodiment of the present invention, wherein base is organic or inorganic base. The organic base selected from triethylamine, diisopropylethylamine, tert-butylamine, pyridine, or piperidine, diazabicycloundecane (DBU). The inorganic base selected from sodium hydride, potassium hydride, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, caesium carbonate, sodium bicarbonate or potassium bicarbonate.

According to an embodiment of the present invention, wherein the suitable solvent is selected sulfoxides such as dimethyl sulfoxide and diethyl sulfoxide; alcohols such as methanol, ethanol, n-propanol, isopropyl alcohol, n-butanol, isobutanol, tert-butanol; nitriles such as acetonitrile and propionitrile; ether solvent such as tetrahydrofuran, diisopropylether, diethyl ether, 2-methyltetrahydrofuran, cyclopentyl methyl ether, methyl tert-butyl ether, dioxane; amides such as N,N-dimethylformamide and N,N-dimethylacetamide; and aromatic hydrocarbons such as toluene, anisole, heptane and xylene; esters such as ethylacetate, methylacetate, butyl acetate, isopropyl acetate, methoxy ethyl acetate; ketones such as acetone, methylisobutyl ketone, 2-pentanone, ethylmethylketone, diethylketone; halogenated hydrocarbons such as chloroform, dichloromethane; water; cyclohexane and N-methyl-2-pyrrolidone or mixtures thereof.

According to an embodiment of the present invention, wherein the acid selected from but not limited to "inorganic acids" such as hydrofluoric acid, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, boric acid, perchloric acid, carbonic acid; and "organic acids" such as formic acid, acetic acid, trifluoroacetic acid, propionic acid, butyric acid, valeric acid, capric acid, oxalic acid, malonic acid, maleic acid, fumaric acid, lactic acid, succinic acid, citric acid, uric acid, tartaric acid, benzoic acid, 4-hydroxybenzoic acid, salicylic acid, oleic acid, octanoic acid, stearic acid, mandelic acid, adepic acid, pivalic acid, camphorsulfonic acid, substituted/unsubstituted alkyl/aryl sulfonic acids such as methanesulfonic acid, ethanesulfonic acid, propanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid or naphthalenesulfonic acid.

The present invention has several advantages over the prior arts. It achieves controlled impurity levels by performing N-methylation i.e. conversion of compound (IX) to compound (VIII), prior to the reduction step i.e. reduction of compound (VIII) to compound (VII). Furthermore, the resolution step utilizes a mixture of solvents and involves reacting compound (III) with an enantiomer of chiral acid to form compound (II), followed by basifying the compound (II) to obtain Lumateperone (I). This resolution step is crucial in significantly increasing the purity of Lumateperone (I) and its tosylate salt (Ia).

The present disclosure is further described considering the following experiments which are set forth for illustration purpose only and not to be construed for limiting the scope of the disclosure. The following experiments can be scaled up to industrial/commercial scale and the results obtained can be extrapolated to the industrial scale.

EXAMPLES

Example 1: Preparation of Ethyl 3-methyl-2-oxo-2,3,9,10-tetrahydro-1H-pyrido[3',4':4,5] pyrrolo[1,2,3-de]quinoxaline-8(7H)-carboxylate

Ethyl 2-oxo-2,3,9,10-tetrahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline-8 (7H)-carboxylate (100 g) in N,N-Dimethylacetamide (100 ml), sodium hydroxide (20 g) were added to round bottom flask. The mixture was maintained at 0-5°C for 30-45 minutes. Then, methyl iodide (56.9g) was added, and the reaction temperature was raised to 25-30°C and stirred for 1-2 hours. After completion of the reaction, the reaction mixture was cooled to 0-10°C. Purified water (2000ml) was added, and the mixture was stirred for another 1-2 hours. The precipitated solid was filtered at 25-30°C, washed with purified water, and dried at 50-55°C to yield ethyl 3-methyl-2-oxo-2,3,9,10-tetrahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline-8(7H)-carboxylate.

Yield: 93.4% (97.7 g)

Example 1a: Preparation of Ethyl 3-methyl-2-oxo-2,3,9,10-tetrahydro-1H-pyrido[3',4':4,5] pyrrolo [1,2,3-de]quinoxaline-8(7H)-carboxylate

Ethyl 2-oxo-2,3,9,10-tetrahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline-8 (7H)-carboxylate (120 g) in N,N-Dimethylacetamide (1200 ml), sodium hydride (19.2 g, 60% dispersion in mineral oil) were added to round bottom flask at 0-5°C, and the mixture was maintained for 30-45 min under nitrogen atmosphere. Methyl iodide (71.1 g) was then added at 0-5°C. The reaction mixture temperature was raised to 25-30°C, stirred for 1-2 hours. After completion of the reaction, cooled the reaction mass to 0-10°C. Purified water (2400 ml) was added to the reaction mixture then stirred for 1-2 hrs. Filtered the precipitated solid at 25-30°C and washed the wet cake with purified water (360 ml) then dried at 50-55°C to yields Ethyl 3-methyl-2-oxo-2,3,9,10-tetrahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline- 8(7H)-carboxylate.

Yield: 99.58% (125 g)

Example-2: Preparation of Ethyl 3-methyl-2-oxo-2,3,6b,7,10,10a-hexahydro-1H-pyrido [3',4' :4,5] pyrrolo [1,2,3-de] quinoxaline-8(9H)-carboxylate

Ethyl 3-methyl-2-oxo-2,3,9,10-tetrahydro-1H-pyrido [3',4':4,5] pyrrolo[1,2,3-de] quinoxaline-8(7H)-carboxylate (50 g), acetonitrile (250 ml) was added into a round bottom flask and cooled to -5°C to 0°C. At the same temperature, trifluoroacetic acid (75 ml), sodium borohydride (7.9 g) were added lot wise to the obtained reaction mixture which was then stirred for 1-2 hours. After completion of the reaction, methanol (75 ml) was added to the reaction mass at -5°C to 5°C and stirred for 10-15 min. The pH was adjusted to 9.0-10.0 with 10% aqueous sodium hydroxide solution (380 ml). followed by addition of toluene (500 ml) to the reaction mixture, raised the reaction mass temperature to 25-30°C. Separated the toluene layer and aqueous layer at 25-30°C, then extracted the product with toluene (250 ml) from aqueous layer and washed the combined toluene layer with 10% sodium chloride solution (250 ml). Concentrated the toluene layer at below 45°C. n-Heptane (250 ml) was added to the concentrated mass at 25-30°C and stirred for 1-2 hrs. Filtered the solid at 25-30°C and washed the wet cake with n-heptane (50 ml) then dried at 50-55°C to yield Ethyl 3-methyl-2-oxo-2,3,6b,7,10,10a-hexahydro-1H-pyrido [3',4':4,5] pyrrolo[1,2,3-de] quinoxaline-8(9H)-carboxylate.

Yield: 90.6% (45.3g)

Example 3: Preparation of ethyl 3-methyl-2,3,6b,7,10,10a-hexahydro-1H-pyrido[3',4':4,5] pyrrolo[1,2,3-de] quinoxaline-8(9H)-carboxylate

Ethyl 3-methyl-2-oxo-2,3,6b,7,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de] quinoxaline-8(9H)-carboxylate (120 g) was dissolved in tetrahydrofuran (600 ml) at 25-30°C , and cooled to 10-15°C. 1.0 M solution of borane in tetrahydrofuran (761 mL) was added to the reaction mixture at 10-15°C. The reaction mixture temperature was then raised to 60-65°C, stirred for 1-2 hours. After completion, the reaction mass was cooled to 0-5°C. 6N hydrochloric acid (360 ml) was then added and raised the reaction mass temperature to 60-65°C, and maintained for 1-2 hours. Dichloromethane (600 ml) and purified water (600 ml) were added to the reaction mixture, the reaction mixture was concentrated at 25-30°C, and pH was adjusted to 9.0-10 with 8% sodium hydroxide solution (1080 ml) at 0-10°C. Separated the dichloromethane layer and washed with purified water (600 ml) and then concentrated to yield ethyl 3-methyl-2,3,6b,7,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de] quinoxaline-8(9H)-carboxylate.

Yield: 96.49% (110 g)

Example 4: Preparation of 3-Methyl-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido [3',4':4,5] pyrrolo[1,2,3-de] quinoxaline

Ethyl 3-methyl-2,3,6b,7,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de] quinoxaline-8(9H)-carboxylate (100 g) was dissolved in n-butanol (600 ml) at 25-30°C. Following the addition of sodium hydroxide powder (53 g) to the mixture. The mixture was heated to 110-115°C for 6-8 hours. After completion of the reaction. The reaction mixture was cooled to 80-85°C and distilled the n-butanol solvent completely from the reaction mass under vacuum. Purified water (500 ml) was added to the reaction mixture and cooled to 10-15°C. The pH was adjusted to 6.0-6.50 using 6N hydrochloric acid solution (230 ml) at 10-15°C and stirred for 30 min. Dichloromethane (500 ml) was added to the reaction mixture, maintained for 10-20 min at 10-15°C and again pH was adjusted to 10.0-10.5 using 10% sodium hydroxide solution (210 ml). Separated the dichloromethane layer and extracted with dichloromethane (500 ml) from the aqueous layer, washed with purified water (500 ml), concentrated to yield 3-Methyl-2,3,6b,7,8,9, 10,10a-octahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de] quinoxaline.

Yield: 88.15% (67 g)

Example 5: Preparation of 3-Methyl-6b,7,8,9,10,10a-hexahydro-1H-pyrido [3',4' :4,5] pyrrolo [1,2,3-de]quinoxalin-2(3H)-one

Ethyl 3-methyl-2-oxo-2,3,6b,7,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de] quinoxaline-8(9H)-carboxylate (115 g) was suspended in n-butanol (1150 mL) at 25-30°C. Potassium hydroxide powder (224.6 g) was then added, and the mixture was heated to 115-120°C for 1-2 hours. After completion of the reaction, the reaction mass was cooled to 10-15°C. Purified water (575 mL) was added, and the pH was adjusted to 10-10.5 with 6N hydrochloric acid. The n-butanol layer was separated from the mixture, and the product was extracted from the aqueous layer with n-butanol (2 x 230 mL). The n-butanol layer was washed with 10% aqueous sodium chloride solution (575 mL) and concentrated to obtain 3-Methyl-6b,7,8,9,10,10a-hexahydro-1H-pyrido[3',4':4,5] pyrrolo[1,2,3-de]quinoxalin-2(3H)-one.

Yield: 87.1 g

Example 6: Preparation of 3-Methyl-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido [3',4':4,5] pyrrolo[1,2,3-de] quinoxaline

3-Methyl-6b,7,8,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxalin-2(3H)-one (25g) was dissolved in tetrahydrofuran (125 mL). Under a nitrogen atmosphere, 1.0 M borane in tetrahydrofuran (159 mL) was added at 10-15°C. The reaction mixture was heated to 60-65°C and stirred for 1-2 hours, the reaction mixture was cooled to 0-5°C. 6N hydrochloric acid (75 mL) was added, and the reaction mixture was heated to reflux. The reaction mixture was stirred at reflux for half an hour, and the solvent was distilled out under reduced pressure. Dichloromethane (125 mL) and purified water (125 mL) were added to the concentrated residue at 25-30°C. The pH was adjusted to 8.0-9.0 with 2N sodium hydroxide solution (235 mL) at 0-10°C. After stirring for 30 minutes, the organic layer was separated and washed with purified water (125 mL). The organic layer was concentrated to obtain 3-Methyl-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline as a residue.

Yield: 21.5 g,

Example 7: Preparation of 1-(4-Fluorophenyl)-4-(3-methyl-2,3,6b,7,10,10a-hexa hydro-1H-pyrido [3',4':4,5] pyrrolo[1,2,3-de]quinoxalin-8(9H)-yl)butan-1-one

4-Chloro-1-(4-fluorophenyl)butan-1-one (85 g), triethylamine (122.3 g) and potassium iodide (72 g) were added to the round bottom flask. 3-Methyl-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido [3',4':4,5] pyrrolo[1,2,3-de] quinoxaline (66 g), mixture of 1,4-dioxane (363 ml) and toluene (363 ml) were added to the reaction mixture. The reaction mixture was heated to 95-100°C for 12-15 hours. After completion of the reaction, it was cooled to 25-30°C and filtered the unwanted solid. Purified water (330 ml) was added to the filtrate and stirred for 10-20 mins at 25-30°C, then layer was separated. Purified water (330 ml) was added, and pH was adjusted to 1.0-2.0 with 6N hydrochloric acid (198 ml) at 10-15°C, followed by stirred for 30-45 min at 25-30°C. The aqueous layer contained product was separated and washed with toluene (2x330 ml). Toluene (330 ml) was added to the aqueous layer contained product, and the pH was adjusted to 8.0-9.0 with 10% aqueous sodium hydroxide solution (240 ml) at 10-15°C. Separated the layers, the product was extracted with toluene (330 ml) from the and washed the combined toluene layer with purified water (330 ml). Toluene layer was treated with a mixture of activated carbon (3.3 g) and silica gel (13.2 g) at 25-30°C for 20-30 min, then filtered and concentrated to yield 1-(4-Fluorophenyl)-4-(3-methyl-2,3,6b,7,10,10a-hexahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2,3-de] quinoxalin-8(9H)-yl) butan-1-one.

Yield: 83.11% (93.8 g)

Example 8: Preparation of 1-(4-Fluorophenyl)-4-((6bR,10aS)-3-methyl-2,3,6b,7, 10,10a-hexahydro-1H-Pyrido [3',4':4,5] pyrrolo[1,2,3-de] quinoxalin-8(9H)-yl)butan-1-one (2R,3R)-2,3-bis((4-methylbenzoyl)oxy)succinate

1-(4-Fluorophenyl)-4-(3-methyl-2,3,6b,7,10,10a-hexahydro-1H-pyrido [3',4':4,5] pyrrolo[1,2,3-de] quinoxalin-8(9H)-yl) butan-1-one (50 g), mixture of toluene (150 ml) and acetonitrile (100 ml) were added into a reaction flask at 25-30°C. (-)-Di-p-toluoyl-L-tartaric acid (63.8 g) in acetonitrile (250 ml) was added to the obtained reaction mixture at 25-30°C, and the mixture was stirred at 25-30°C for 2 hrs, and the reaction mixture was heated to 60-65°C for 1 hr. The mixture was cooled to 25-30°C and stirred for 1-2 hours. The wet cake was washed the with acetonitrile (50 ml) and dried to give 1-(4-Fluorophenyl)-4-((6bR,10aS)-3-methyl-2,3,6b,7,10,10a-hexahydro-1H-Pyrido [3',4':4,5] pyrrolo [1,2,3-de] quinoxalin-8(9H)-yl)butan-1-one (2R,3R)-2,3-bis((4-methyl benzoyl)oxy)succinate

Yield: 40.8 g

Example-9: Preparation of 4-((6bR,10aS)-3-Methyl-2,3,6b,9,10,10a-hexahydro-1H,7H-pyrido [3',4':4,5] pyrrolo [1,2,3-de]quinoxalin-8-yl)-1-(4-fluoro-phenyl)-butan-1-one 4-methylbenzenesulfonate

1-(4-Fluorophenyl)-4-((6bR,10aS)-3-methyl-2,3,6b,7,10,10a-hexahydro-1H-Pyrido [3', 4':4,5]pyrrolo[1,2,3-de]quinoxalin-8(9H)-yl)butan-1-one (2R,3R)-2,3-bis((4-methyl benzoyl)oxy)succinate (20 g) was suspended in dichloromethane (300 mL) and purified water (260 mL). The pH was adjusted to 9.0-10.0 with 7.5% aqueous sodium hydroxide solution (40 mL) at 10-15°C. The dichloromethane layer and aqueous layer were separated at 25-30°C. The product was extracted with dichloromethane (2 x 60 mL). The combined dichloromethane layer was washed with purified water (100 mL) and concentrated at below 32°C under reduced pressure. The resulting residue was dissolved in isopropyl alcohol (40 mL) at 25-30°C. Activated carbon (0.8 g) was added, and the mixture was treated for 20-30 minutes. The reaction mixture was filtered through a Hyflo bed, and the hyflo bed was washed with isopropyl alcohol (16 mL). p-Toluenesulfonic acid monohydrate (3.9 g) was dissolved in isopropyl alcohol (24 mL) at 25-30°C and filtered. This isopropyl alcohol solution containing p-toluene sulfonic acid monohydrate was added to the isopropyl alcohol solution containing the product at 25-30°C, and the mixture was stirred for 30 hours at the same temperature. The solid mass was filtered at 25-30°C, and the wet cake was washed with isopropyl alcohol.
,CLAIMS:We claim:

1. An improved process for the preparation of Lumateperone (I) and salts thereof comprising:
a) reacting the compound of formula (IX) with a methylating agent in presence of a base and a suitable solvent to obtain the compound of formula (VIII);

b) treating the compound of formula (VIII) with a reducing agent in presence of an acid and a suitable solvent to obtain the compound of formula (VII);

c) reducing the amide carbonyl compound of formula (VII) with a Lewis acid in presence of a suitable solvent to obtain the compound of formula (VI);

d) deprotecting the compound of formula (VI) in presence of a base and a suitable solvent to obtain the compound of formula (V);

e) optionally the compound of formula (V) converts into salt compound of formula (Va);

f) reacting the compound of formula (V) with the compound of formula (IVa) in presence of a base and mixture of suitable solvents to obtain the compound of formula (III);

wherein X is halogen or mesyl or tosyl.

g) treating the racemic compound of formula (III) with a chiral acid in presence of a mixture of suitable solvents to obtain the compound of formula (II);

h) basifying the compound of formula (II) in presence of a base and a suitable solvent to obtain Lumateperone (I).

i) optionally reacting the Lumateperone (I) with an acid in presence of a suitable solvent to obtain Lumateperone acid salt (Ia).

2. The process as claimed in claim 1, wherein methylating agent is selected from methyl chloride, methyl bromide and methyl iodide, methyl lithium, methyl methane sulfonate, dimethyl sulfate, N-methyl-N-nitrosourea, tetramethyltin, dimethylzinc, or trimethylaluminium.

3. The process as claimed in claim 1, wherein reducing agent is selected from sodium borohydride, sodium cyano borohydride, lithium borohydride or lithium triethylborohydride.

4. The process as claimed in claim 1, wherein lewis acid is selected from AlCl3 (Aluminium chloride), BF3 (boron trifluoride), Br2 (dibromine), AlF3 (aluminum fluoride) , CO2 (carbon dioxide), SO2 (Sulfur dioxide), SO3 (sulfur trioxide), SiBr4 (silicon tetrabromide) or SiF4 (silicon tetrafluoride).

5. The process as claimed in claim 1, wherein base is organic or inorganic base, wherein the organic base selected from triethylamine, diisopropylethylamine, tert-butylamine, pyridine, piperidine, diazabicycloundecane (DBU) and the inorganic base selected from sodium hydride, potassium hydride, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, caesium carbonate, sodium bicarbonate or potassium bicarbonate.

6. An improved process for the preparation of Lumateperone (I) comprising:

a) treating the racemic compound of formula (XIII) with a chiral acid in presence a mixture of suitable solvents to obtain the compound of formula (XIX);

b) basifying the compound of formula (XIX) in presence of a base and suitable solvent to yields Lumateperone.

7. The process as claimed in claim 1 and 6, wherein chiral acid is selected from tartaric acid, dibenzoyl-L-tartaric acid, mandelic acid, (-)-Di-p-toluoyl-L-tartaric acid, (-)-Di-p-anisoyl-L-tartaric Acid, (-)-Diacetyl-L-tartaric Acid, diisopropyl D-(-)-tartrate, D-(+)-malic acid, dimethyl L-(+)-tartrate and L-valine, (-)-dibenzoyl-L-tartaric acid mono(dimethylamide) and (+)-dibenzoyl-D-tartaric acid mono(dimethylamide).

8. The process as claimed in claim 1 and 6, wherein suitable solvent is selected dimethyl sulfoxide, methanol, ethanol, n-propanol, isopropyl alcohol, n-butanol, isobutanol, tert-butanol, acetonitrile, propionitrile, tetrahydrofuran, diisopropylether, diethyl ether, methyl tert-butyl ether, dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, toluene, 1,4-dioxane, heptane, xylene, ethylacetate, isopropyl acetate, acetone, chloroform, dichloromethane, water, cyclohexane and N-methyl-2-pyrrolidone and or mixtures thereof.