DESC:Field of the Invention
The present invention relates to a process for preparation of apalutamide using novel intermediate i.e. alkyl or benzyl ester of N-[6-cyano-5-(trifluoromethyl)-3-pyridyl]carbamodithioic acid and a process for its preparation.

Background of invention
Apalutamide, chemically described as 4-[7-[6-cyano-5-(trifluoromethyl)pyridin-3-yl]-8-oxo-6-sulfanylidene-5,7-diazaspiro[3.4]octan-5-yl]-2-fluoro-N-methylbenzamide, is a non-steroidal antiandrogen (NSAA) used in the treatment of prostate cancer. It can be structurally represented as Formula (I).

(I)
It is particularly used in the treatment of patients with metastatic castration-resistant prostate cancer. The preparation of Apalutamide is known wherein 5-amino-3-(trifluoromethyl) pyridine-2-carbonitrile was reacted with thiophosgene to form 5-isothiocyanato-3-(trifluoromethyl)pyridine-2-carbonitrile.

Isothiocyanato-3-(trifluoromethyl)pyridine-2-carbonitrile formed was further coupled with 4-[(1-cyanocyclobutyl)amino]-2-fluoro-N-methyl-benzamide in a microwave at 80°C for 20 hours followed by hydrolysis and the yield obtained was 35-87%. The synthetic approach is very limited for industrial application as the heating in a microwave was not easy to apply in large scale synthesis and thus results in higher costs.
Known prior art involves coupling of 5-isothiocyanato-3-(trifluoromethyl)pyridine-2-carbonitrile with cyclobutanecarboxylic acid or derivative. Generation or preparation of 5-isothiocyanato-3-(trifluoromethyl)pyridine-2-carbonitrile requires use of noxious reagent such as thiophosgene, which generates high amount of poisonous phosgene gas and hence use of this intermediate at high scale is difficult and requires more labor and extreme care.
Although various approaches for preparing Apalutamide have been disclosed, there is still an unmet need for a more environmentally friendly, industrially practical, and economical process for preparation of Apalutamide. Thus the present invention addresses these needs.

Summary of the invention
In a general aspect, the present invention provides a process for preparation of Apalutamide of Formula (I).

(I)
The process comprises reacting a compound of Formula (II)

where R1 is (1-4C) alkyl, (1-4C) alkyl substituted by ethyl acetate or benzyl acetate, benzyl or benzyl substituted at ortho or para-positions by halo, NO2 or CN, with a compound of Formula (III)

at 60°C to 140°C in presence of a tertiary amine base and a solvent.
The tertiary amine base is selected from the group consisting of di-isopropyl ethylamine (DIPEA), triethylamine, trimethylamine, pyridine.
In an embodiment, the present invention comprises a process for preparing compound of Formula (II). The process comprises reacting a compound of Formula (A)

with carbon-di-sulfide at 10°C to 20°C in presence of an amidine base or a 1,4-diazabicyclo[2.2.2]octane (DABCO) or a DABCO derivative and a ketonic solvent at room temperature obtaining a compound of Formula (B); and reacting the compound of Formula (B) with an alkylating agent in presence of a polar aprotic solvent at room temperature.

The amidine base is selected from the group consisting of acetamidine, benzamidine, diazabicyclo[5.4.0]undec-7-ene (DBU), diazabicyclo[4.3.0]non-5-ene (DBN) and imidazolidine, wherein preferably the amidine base is 1,8 DBU. The ketonic solvent is selected from acetone, methyl ethyl ketone, methyl isobutyl ketone and the alkylating agent is selected from (1-4 C) alkyl halide, benzyl halide, o-nitro benzyl halide, p-nitrobenzyl haide, o-cyano benzyl halide, p-cyano benzyl halide chloro ethylacetate, bromo ethylacetate, iodo ethylacetate, chloro benzylacetate, bromo benzylacetate and iodo benzylacetate. The polar aprotic solvent is selected from N-methyl pyrrolidone, tetrahydrofuran, ethyl acetate, dimethylformamide, acetonitrile or dimethyl sulfoxide (DMSO).
The compound of Formula (B) is isolated as an amidine base complex or (1,4-diazabicyclo[2.2.2]octane) DABCO salt as a compound of Formula (IV).
.
In an embodiment, the present invention provides a compound of Formula (II) wherein the compound (II) is an alkyl or benzyl ester of N-[6-cyano-5-(trifluoromethyl)-3-pyridyl]carbamodithioic acid.
In another embodiment, the present invention provides a process for preparing compound of Formula (III).

The process comprises reacting 4-bromo-2-fluoro-N-methylbenzamide (1) with 1-aminocyclobutane carboxylic acid or its ester (2) in presence of a solvent, cuprous halide, a base and a ligand,

wherein R is selected from OH and any good leaving group such as -OR’, wherein R’ is (1-4C) alkyl, benzyl, substituted alkyl group.
The base is alkali metal carbonate selected from sodium carbonate, potassium carbonate and calcium carbonate. The ligand is selected from N,N-dimethylaniline and its derivatives, 3-(dimethylamino)cyclohex-2-en-1-one, N,N-dimethyl-4-(phenylmethyl)benzenamine, 2-(4-N,N-dimethylaminophenyl) naphthalene, N,N-dimethylamino-4-cyclohexylbenzene, 1-(4-N,N-dimethylaminophenyl) naphthalene, 2-(N,N-dimethylamino)-1,4-benzoquinone. N,N-dimethylaniline derivative can be selected from O-halo-N,N-dimethylaniline, m-halo-N,N-dimethylaniline, p-halo-N,N-dimethylaniline, m-trifluoromethyl-N,N-dimethylaniline, p-Trifluoromethyl-N,N-dimethylaniline, o-trifluoromethyl-N,N-dimethylaniline, 4-benzhydryl-N,N-dimethylaniline, wherein halo is selected from Cl, Br, I and F. The solvent is selected from dimethyl formamide (DMF), dimethylacetamide, DMSO, Acetonitrile, N-methylpyrrolidone.

In an embodiment, a process for preparing Apalutamide further comprises, dissolving Apalutamide (I) in an alcoholic solvent and heating to a temperature of 55°C to 65°C to form a clear solution; and cooling the solution at a temperature of 0°C to 10°C and isolating pure Apalutamide. The pure Apalutamide is having 99.7% to 99.95% HPLC purity with 50% to 90% yield. The alcoholic solvent is selected from methanol, ethanol, isopropanol, butanol.

Description of the invention
The present invention provides a process for preparation of Apalutamide that obviates the need of using hazardous reagents like triphosgene and thiophosgene and is suitable for industrial production. Good yield of Apalutamide and better purity is an added advantage of the process of the present invention.
In an embodiment, an improved process for preparation of Apalutamide of Formula (I) from compound of Formula (II) is provided.

The process comprises reacting a compound of Formula (II),

where R1 is (1-4C) alkyl, (1-4C) alkyl substituted by ethyl acetate or benzyl acetate, benzyl or benzyl substituted at ortho or para-positions by halo, NO2 or CN; with a compound of Formula (III),

at a temperature of 60°C to 140°C in presence of a tertiary amine base in a solvent obtaining crude Apalutamide of Formula (I).

The reaction can be carried out at a temperature preferably at 90°C-130°C, most preferably at 110°C. The tertiary amine base can be selected from di-isopropyl ethylamine (DIPEA), triethylamine, trimethylamine, pyridine, preferably di-isopropylethylamine. The solvent can be selected from toluene, xylene, cyclohexane, chlorobenzene, dichlorobenzene, preferably toluene.

In an embodiment, the compound of Formula (II) is an ester of N-[6-cyano-5-(trifluoromethyl)-3-pyridyl]carbamodithioic acid and the compound of Formula (III) is 1-[3-fluoro-4-(methylcarbamoyl) anilino]cyclobutanecarboxylic acid.

The ester of N-[6-cyano-5-(trifluoromethyl)-3-pyridyl]carbamodithioic acid of Formula (II) is an alkyl or benzyl ester of N-[6-cyano-5-(trifluoromethyl)-3-pyridyl]carbamodithioic acid. The alkyl ester of N-[6-cyano-5-(trifluoromethyl)-3-pyridyl]carbamodithioic acid is a methyl ester of N-[6-cyano-5-(trifluoromethyl)-3-pyridyl]carbamodithioic acid.

The present invention also provides a process for preparation of compound of Formula (II).
The process comprises reacting a compound of Formula (A)

with carbon-di-sulfide at 15°C to 20°C in presence of an amidine base or a 1,4-diazabicyclo[2.2.2]octane (DABCO) or DABCO derivative in a ketonic solvent at room temperature obtaining a compound of Formula (B):

The compound of Formula (B) can be reacted with an alkylating agent in presence of a solvent at room temperature to form Formula II.

In an embodiment, the compound of Formula (A) can be 5-amino-3-(trifluoromethyl)pyridine-2-carbonitrile and the compound of Formula (B) is [4-cyano-3-(trifluoromethyl)phenyl]carbamodithioic acid. The amidine base can be selected from acetamidine, benzamidine, diazabicyclo[5.4.0]undec-7-ene (DBU), diazabicyclo[4.3.0]non-5-ene (DBN) and imidazolidine. Preferably the amidine base is 1,8 DBU. The reaction can be preferably carried out in a ketonic solvent selected from acetone, methyl ethyl ketone, methyl isobutyl ketone, preferably acetone where the reaction can proceed at room temperature. The amount of amidine base or DABCO or DABCO derivative to ketonic solvent can be in the ratio 1 to 4 mole equivalent/volume.
The process for preparation of compound (II) involves reaction of carbonitrile compound A with carbondi-sulfide (CS2) which avoids use of thiophosgene and hence avoids formation of phosgene gas.
The alkylating agent can be selected from (1-4 C) alkyl halide, benzyl halide, o-nitro benzyl halide, p-nitrobenzyl haide, o-cyano benzyl halide, p-cyano benzyl halide chloro ethylacetate, bromo ethylacetate, iodo ethylacetate, chloro, benzylacetate, bromo, benzylacetate and iodo benzylacetate in a suitable solvent. The reaction can be carried out at a room temperature. The solvent can be selected from ketonic solvent, polar aprotic solvent or ethereal solvent. The ketonic solvent can be selected from acetone, methyl ethyl ketone or methyl isobutyl ketone. The polar aprotic solvent can be selected from N-methyl pyrrolidone, tetrahydrofuran, ethyl acetate, dimethylformamide, acetonitrile or dimethyl sulfoxide. The ethereal solvent can be selected from di-tert butyl ether, dibutyl ether, diethyl ether, diisopropyl ether, dimethoxy ethane, dimethoxymethane, 1,4-dioxane, methoxyethane, methyl tert-butyl ether, THF and 2-methyl THF. The amount of the alkylating agent to the solvent can be in the ratio of 0.65 to 2 mole equivalent/volume.
The acid compound of Formula (B) can be preferably isolated as an amidine base or a DABCO salt of [4-cyano-3-(trifluoromethyl)phenyl]carbamodithioic acid of Formula (IV).

The reaction of 5-amino-3-(trifluoromethyl)pyridine-2-carbonitrile of Formula (A) with carbondisulfide is carried out in presence of 1,8-DBU forming 1,8-DBU complex with [4-cyano-3-(trifluoromethyl)pyridyl]carbamodithioic acid of Formula (V).

The reaction of 5-amino-3-(trifluoromethyl)pyridine-2-carbonitrile of Formula (A) with carbondisulfide is carried out in presence of 1,4-diazabicyclo[2.2.2]octane (DABCO) to isolate DABCO salt of N-[6-cyano-5-(trifluoromethyl)-3-pyridyl]carbamodithioic acid of Formula (VI).

The amidine complex or DABCO salt of N-[6-cyano-5-(trifluoromethyl)-3-pyridyl]carbamodithioic acid further converts to alkyl or benzyl ester of N-[6-cyano-5-(trifluoromethyl)-3-pyridyl]carbamodithioic acid by reacting with alkylating agent. The alkylating agent can be selected from (1-4 C) alkyl halide, benzyl halide, o-nitro benzyl halide, p-nitrobenzyl haide, o-cyano benzyl halide, p-cyano benzyl halide chloro ethylacetate, bromo ethylacetate, iodo ethylacetate, chloro, benzylacetate, bromo, benzylacetate and iodo benzylacetate in a suitable solvent. The reaction can be carried out at a room temperature. The solvent can be selected from ketonic solvent, polar aprotic solvent or ethereal solvent. In the context of this embodiment, the ketonic solvent can be selected from acetone, methyl ethyl ketone or methyl isobutyl ketone. The polar aprotic solvent can be selected from N-methyl pyrrolidone, tetrahydrofuran, ethyl acetate, dimethylformamide, acetonitrile or dimethyl sulfoxide. The ethereal solvent can be selected from di-tert butyl ether, dibutyl ether, diethyl ether, diisopropyl ether, dimethoxy ethane, dimethoxymethane, 1,4-dioxane, methoxyethane, methyl tert-butyl ether, THF and 2-methyl THF. The amount of the alkylating agent to the solvent can be in the ratio of 0.65 to 2 mole equivalent/volume.

In another embodiment, a process for preparation of compound of Formula (III) is provided.

The process comprises reacting 4-bromo-2-fluoro-N-methylbenzamide (1) with 1-aminocyclobutane carboxylic acid or its ester (2) in presence of a solvent, cuprous halide, a base and a ligand

wherein R is selected from OH and any good leaving group such as -OR’, wherein R’ is (1-4C) alkyl, benzyl, substituted alkyl group.
The reaction of 4-bromo-2-fluoro-N-methylbenzamide (1) with 1-aminocyclobutanecarboxylic acid or its ester (2) can be carried out in presence of a solvent, cuprous halide, a base and a ligand. The reaction can be carried out in a solvent selected from dimethyl formamide (DMF), dimethylacetamide, DMSO, Acetonitrile, N-methylpyrrolidone. The cuprous halide used in the reaction can be selected from cuprous chloride, cuprous bromide, cuprous iodide, preferably cuprous chloride. The base used can be an alkali metal carbonate selected from sodium carbonate, potassium carbonate and calcium carbonate. The ligand can be selected from N,N-dimethylaniline and its derivatives, 3-(dimethylamino)cyclohex-2-en-1-one, N,N-dimethyl-4-(phenylmethyl)benzenamine, 2-(4-N,N-dimethylaminophenyl) naphthalene, N,N-dimethylamino-4-cyclohexylbenzene, 1-(4-N,N-dimethylaminophenyl)naphthalene, 2-(N,N-dimethylamino)-1,4-benzoquinone. N,N-dimethylaniline derivative can be selected from O-halo-N,N-dimethylaniline, m-halo-N,N-dimethylaniline, p-halo-N,N-dimethylaniline, m-Trifluoromethyl-N,N-Dimethylaniline, p-Trifluoromethyl-N,N-Dimethylaniline, o-Trifluoromethyl-N,N-dimethylaniline, 4-benzhydryl-N,N-dimethylaniline, wherein halo is selected from Cl, Br, I and F.
The reaction can be preferably carried out in DMF and in presence of cuprous chloride, potassium carbonate and N,N-dimethylaniline.

In this embodiment, the process for preparation of compound of Formula (III) comprises reacting 4-bromo-2-fluorobenzoic acid (C) with thionyl chloride in presence of mixture of a ketonic solvent and a polar aprotic solvent at a temperature of 60°C to 85°C obtaining 4-bromo-2-fluorobenzoyl chloride (D); amination of compound (D) with an aminating agent in presence of a solvent forming 4-bromo-2-fluoro-N-methylbenzamide (1); followed by reacting compound (1) with 1-aminocyclobutanecarboxylic acid or its ester (2) in presence of a solvent, cuprous halide, a base and a ligand.

The compound of Formula (III) is 1-[3-fluoro-4-(methylcarbamoyl)anilino]cyclobutanecarboxylic acid.
The process of reacting 4-bromo-2-fluorobenzoic acid (C) with thionyl chloride can preferably be carried out in a solvent selected from toluene, ethyl acetate, dichloromethane. The reaction can be carried out in presence of catalytic amount of suitable amide selected from dimethyl formamide and dimethyl acetamide at 60-85°C, preferably at 70-75°C. The 4-bromo-2-fluorobenzoyl chloride (D) obtained is taken as is in the next reaction without isolation. Compound (D) can be reacted with an aminating agent selected from monomethylamine obtaining compound (1) and preferable 40% solution of monomethylamine can be used. The said reaction can be carried out at room temperature in presence of a solvent selected from toluene, ethyl acetate, dichloromethane.

In another embodiment the present invention provides a process for obtaining pure Apalutamide of Formula (I). The process comprises, dissolving Apalutamide (I) prepared by the process of the present invention in an alcoholic solvent and heating to a temperature of 55°C to 65°C to form a clear solution; and cooling the solution at a temperature of 0°C to 10°C and isolating pure Apalutamide having 99.7 % to 99.95 % HPLC purity with 50% to 90 % yield. The alcoholic solvent is selected from methanol, ethanol, isopropanol, butanol.

In the context of the present invention, the process of the present invention is an eco-friendly, industrially practical, and economical process. The process of the present invention advantageously avoids use of hazardous reagents like triphosgene, and thiophosgene. The process for preparation of Apalutamide is simple and does not involve multiple work up steps and also does not require additional time. The process of the present invention results in high yield of the end product of the present invention with maximum HPLC purity.
EXAMPLES
Example and implementation is provided herein below for illustration of the invention. Variations, modifications, and enhancements to the described examples and implementations and other implementations can be made based on what is disclosed.

Example 1
Preparation of 4-Bromo-2-fluoro-N-methylbenzamide (1)

Dimethyl formamide (DMF) (1 ml) was charged to the mixture of 4-bromo-2-fluoro benzoic acid (100 g) (C) and toluene (200 ml) with stirring at 30-35°C. The temperature of the reaction mixture was raised to 65-70°C. Thionyl chloride (100 g) was added slowly to the mass at 65-70°C. The mass was stirred for 1-2 hours to get clear solution. The mass was cooled to 10-15°C. The mass comprising intermediate compound 4-bromo-2-fluorobenzoyl chloride (D) was obtained. The mass was slowly added to the 40% solution of monomethylamine (281 ml) previously cooled to 15°C. The mixture was stirred for 1 hour at 10-15°C. The mass was filtered under vacuum. The reaction mass was washed with Toluene (50 ml) followed by washing with water (100 ml). The product was dried in hot air oven at a temperature from about 60°C to about 65°C to get dry weight (100 g) having a purity of 99.44%.

Example 2
Preparation of 1-{[3-fluoro-4-(methylcarbamoyl)phenyl]amino}cyclobutanecarboxylic acid (Formula III)

Under argon atmosphere, copper chloride (12.8 gm) was charged to N,N’-dimethyl Formamide (600 ml) at 75-80°C. 4-bromo-2-fluoro-N-methylbenzamide (100 g) was charged to the mixture followed by addition of N,N-dimethylaniline (8.35 gm). The reaction mixture was stirred for 15-20 minutes. 1-aminocyclobutane carboxyclic acid (74.4gm) was added and again the mixture was stirred for 15-20 minutes at 75-80°C. Powdered potassium carbonate (148 gm) was added and stirred for 15 minutes. Water (10 ml) was added and the temperature of the mass was raised to 110°C and stirred for 4-5 hours. The mass was cooled to 30-35°C and filtered, and washed with dimethyl formamide. Dimethyl formamide was distilled under vacuum and the mass was cooled. Water (700 ml) was added to the mass and pH was adjusted to 13.5 - 14 by using 10% sodium hydroxide solution. MDC (300 ml) was added to the reaction mass and stirred. The layers were separated and aqueous layer was extracted with MDC (300 ml). MDC layer was separated and washed with water (300 ml). All the aqueous layers were combined and pH was adjusted to 2.5-3 by HCl to precipitate out the product. The mass was stirred and filtered under vacuum. The precipitate was washed with water (100 ml) and suck dried well. The material was dried under vacuum at 55-60°C. The dried product 1-{[3-fluoro-4-(methylcarbamoyl) phenyl]amino}cyclobutanecarboxylic acid (135g) was isolated. Thereafter, the product is tested for HPLC purity which was observed to be 99.75%.
Example 3
Preparation of 5-amino-3-(trifluoromethyl) pyridine-2-carbonitrile 1,8-diazabicyclo[5.4.0] undec-7-en (1,8 DBU) (Formula V).

5-amino-3-(trifluoromethyl) pyridine-2-carbonitrile (100 g) was added to acetone (200 ml) at 25-30°C. The reaction mixture was cooled to 10 to 20°C, preferable the reaction mixture was cooled to 15-20°C. 1,8-DBU (244 g) was added slowly to the reaction mass at a temperature from about 15°C to about 20°C and carbon disulfide (211 gm) was added drop wise at a temperature from about 15°C to about 20°C. The reaction mass was maintained for 3-4 hours at 25-30°C. The product was precipitated out and the mixture was stirred for 1 hour after precipitation. The reaction mass was quenched in water (3L). The mass was maintained for 30 minutes at a temperature from about 25°C to about 30°C. The reaction mass was filtered under vacuum and wet cake washed with DM water (100 ml). The cake was suck dried and further dried under vacuum at 40°C to isolate 5-amino-3-(trifluoromethyl) pyridine-2-carbonitrile 1,8-Diazabicyclo[5.4.0]undec-7-en complex (210 g). Thereafter, the product is tested for HPLC purity and LCMS purity such that HPLC purity was observed to be 77.84% and LCMS purity was observed to be 70.15%, [M+1] = 417.

Example 4
Preparation of methyl-[6-cyano-5-(trifluoromethyl)pyridin3-yl] carbamodithioate (Formula II)
5-amino-3-(trifluoromethyl)pyridine-2 carbonitrile 1,8-Diazabicyclo [5.4.0]undec-7-en (100 g) was charged to dimethyl formamide (200 ml) at 25-30°C. The reaction mixture was cooled to 10-15°C. Methyl iodide (44.30 g) was added drop wise to the reaction mixture. The mass was stirred for 30 minutes at a temperature from about 15°C to about 20°C. Water (3 L) was added to the reaction mass and stirred for 20-30 minutes. The product methyl-[6-cyano-5-(trifluoromethyl) pyridin 3-yl]carbamodithioate was separated by filtration under vacuum and washed with water (100 ml). The product was suck dried and further dried under vacuum at a temperature of 50°C to about 55°C to isolate preparation of methyl-[6-cyano-5-(trifluoromethyl)pyridin3-yl] carbamodithioate (62 gm). Thereafter, the product is tested for HPLC purity which was observed to be 80%.

Example 5
Purification of methyl-[6-cyano-5-(trifluoromethyl)pyridin 3-yl ]carbamodithioate
Methyl-[6-cyano-5-(trifluoromethyl)pyridin-3-yl]carbamodithioate (100 g) was added to the mixture of toluene (390 ml) and methanol (10 ml) at a temperature from about 25°C-30°C to form a slurry. The temperature of reaction mass was raised to 70-75°C till reaction mass becomes clear. The mass was filtered and washed with Toluene (25 ml). The reaction mass was cooled at 10-15°C and stirred for 1 hour. The mass was filtered and washed with cool toluene (25 ml). The precipitate was suck dried and further dried under vacuum at 55-60°C for 6-7 hours. After cooling below 35°C, pure methyl-[6-cyano-5-(trifluoromethyl)pyridin-3-yl]carbamodithioate (61 gm) was obtained with HPLC purity 98.05%.

Example 6
Preparation of Apalutamide (Formula I)

1-{[3-fluoro-4-(methylcarbamoyl)phenyl]amino} cyclobutanecarboxylic acid(100 g) was added to Toluene (500 ml) at a temperature from about 30°C to about 35°C. Di-isopropyl ethylamine (97.1 g) was added to the reaction mixture. Methyl-[6-cyano-5-(trifluoromethyl)pyridin 3-yl] carbamodithioate (156.2 g) was charged to the reaction mass followed by addition of phenol (106 g) at 30-35°C. The reaction mass was heated to 108-112°C and water was distilled azeotropically. After completion of the reaction, the mass was cooled to a temperature from about 55°C to about 60°C. Toluene was distilled under vacuum. The mass was cooled to 30-35°C. MDC (600 ml) was charged to the reaction mass and stirred for 30 to 40 minutes. 10% sodium hydroxide solution was charged to the mass and stirred for 30-35 minutes. The mass was filtered and organic layer was separated and 10% sodium hydroxide (100 ml) was charged and stirred for 15-20 minutes. The layers were separated and 10% HCl (300 ml) was added and stirred for 15-20 minutes. The layers were separated and water (250 ml) was charged to the organic layer and stirred for 15-20 minutes. The MDC layer was distilled out at 55 to 60°C. IPA (100 ml) was charged and was distilled under vacuum at 55-60°C. The oily mass was cooled to 30-35°C and IPA (500 ml) was charged. The solid mass was stirred for 60-70 minutes at 30-35°C. The solid mass was filtered and washed with IPA. The precipitate was suck dried and further dried under vacuum at 50-60°C for 6-7 hours. The material was cooled and Apalutamide (125 g) was unloaded with HPLC purity 97.11%.

Example 7
Purification of Apalutamide
Crude Apalutamide (100 gm) obtained was charged to methanol (1000 ml) at room temperature. The temperature of the mixture was raised to 55-65°C. Activated charcoal (5 gm) was added to the clear solution, filtered through hyflo and washed with methanol at 55-65°C. The mass was cooled to 0 to 10°C and stirred for 1 hour. The mass was filtered and washed with cool methanol. Pure Apalutamide (55 gm) was isolated after drying, with HPLC purity 99.90%.

The foregoing description of specific embodiments of the present invention has been presented for purposes of illustration and description. They are not intended to be exhaustive or to limit the present invention to the precise forms disclosed, and obviously many modifications and variations are possible in light of the above teaching.

The embodiments were chosen and described in order to best explain the principles of the present invention and its practical application, to thereby enable others, skilled in the art to best utilize the present invention and various embodiments with various modifications as are suited to the particular use contemplated.

It is understood that various omission and substitutions of equivalents are contemplated as circumstance may suggest or render expedient, but such are intended to cover the application or implementation without departing from the spirit or scope of the present invention.
,CLAIMS:

1. A process for preparation of Apalutamide of Formula (I), comprising:

reacting a compound of Formula (II)

where R1 is (1-4C) alkyl, (1-4C) alkyl substituted by ethyl acetate or benzyl acetate, benzyl or benzyl substituted at ortho or para-positions by halo, NO2 or CN,
with a compound of Formula (III)

at 60°C to 140°C in presence of a tertiary amine base and a solvent.

2. The process as claimed in claim 1, wherein the tertiary amine base is selected from the group consisting of di-isopropyl ethylamine (DIPEA), triethylamine, trimethylamine, pyridine.

3. The process as claimed in claim 1 and 2, wherein the tertiary amine base is di-isopropylethylamine.

4. The process as claimed in claim 1, wherein the solvent is selected from toluene, xylene, cyclohexane, chlorobenzene, dichlorobenzene.

5. A process for preparing compound of Formula (II), comprises;
(i) reacting a compound of Formula (A)

with carbon-di-sulfide at 10°C to 20°C in presence of an amidine base or a 1,4-diazabicyclo[2.2.2]octane (DABCO) or a DABCO derivative and a ketonic solvent at room temperature obtaining a compound of Formula (B); and

(ii) reacting the compound of Formula (B) with an alkylating agent in presence of a polar aprotic solvent at room temperature.

6. The process as claimed in claim 5, wherein the amidine base is selected from the group consisting of acetamidine, benzamidine, diazabicyclo[5.4.0]undec-7-ene (DBU), diazabicyclo[4.3.0]non-5-ene (DBN) and imidazolidine.

7. The process as claimed in claim 5, wherein the amidine base is 1,8 DBU.

8. The process as claimed in claim 5, wherein the ketonic solvent is selected from acetone, methyl ethyl ketone, methyl isobutyl ketone.

9. The process as claimed in claim 5, wherein the alkylating agent is selected from (1-4 C) alkyl halide, benzyl halide, o-nitro benzyl halide, p-nitrobenzyl haide, o-cyano benzyl halide, p-cyano benzyl halide chloro ethylacetate, bromo ethylacetate, iodo ethylacetate, chloro benzylacetate, bromo benzylacetate and iodo benzylacetate.

10. The process as claimed in claim 5, wherein the polar aprotic solvent is selected from N-methyl pyrrolidone, tetrahydrofuran, ethyl acetate, dimethylformamide, acetonitrile or dimethyl sulfoxide (DMSO).

11. The process as claimed in claim 5, wherein the compound of Formula (B) is isolated as an amidine base complex or (1,4-diazabicyclo[2.2.2]octane) DABCO salt as a compound of Formula (IV)
.

12. A compound of Formula (II) prepared by the process as claimed in claim 5, is an alkyl or benzyl ester of N-[6-cyano-5-(trifluoromethyl)-3-pyridyl]carbamodithioic acid,

wherein R1 is (1-4C) alkyl, (1-4C) alkyl substituted by ethyl acetate or benzyl acetate, benzyl or benzyl substituted at ortho or para-positions by halo, NO2 or CN.

13. A process for preparing compound of Formula (III), comprising, reacting 4-bromo-2-fluoro-N-methylbenzamide (1) with 1-aminocyclobutane carboxylic acid or its ester (2) in presence of a solvent, cuprous halide, a base and a ligand,

wherein R is selected from OH and any good leaving group such as -OR’, wherein R’ is (1-4C) alkyl, benzyl, substituted alkyl group.

14. The process as claimed in claim 13, wherein the base is alkali metal carbonate selected from sodium carbonate, potassium carbonate and calcium carbonate.

15. The process as claimed in claim 13, wherein the ligand is selected from N,N-dimethylaniline and its derivatives, 3-(dimethylamino)cyclohex-2-en-1-one, N,N-dimethyl-4-(phenylmethyl)benzenamine, 2-(4-N,N-dimethylaminophenyl) naphthalene, N,N-dimethylamino-4-cyclohexylbenzene, 1-(4-N,N-dimethylaminophenyl) naphthalene, 2-(N,N-dimethylamino)-1,4-benzoquinone. N,N-dimethylaniline derivative can be selected from O-halo-N,N-dimethylaniline, m-halo-N,N-dimethylaniline, p-halo-N,N-dimethylaniline,m-trifluoromethyl-N,N-dimethylaniline, p-Trifluoromethyl-N,N-dimethylaniline, o-trifluoromethyl-N,N-dimethylaniline, 4-benzhydryl-N,N-dimethylaniline, wherein halo is selected from Cl, Br, I and F.

16. The process as claimed in claim 13, wherein the solvent is selected from dimethyl formamide (DMF), dimethylacetamide, DMSO, Acetonitrile, N-methylpyrrolidone.

17. A process for preparing Apalutamide as claimed in claim 1, further comprises, dissolving Apalutamide (I) in an alcoholic solvent and heating to a temperature of 55°C to 65°C to form a clear solution; and cooling the solution at a temperature of 0°C to 10°C and isolating pure Apalutamide having 99.7 % to 99.95 % HPLC purity with 50 % to 90 % yield.

18. The process as claimed in claim 17, wherein the alcoholic solvent is selected from methanol, ethanol, isopropanol, butanol.