DESC:CROSS-REFERENCE TO RELATED APPLICATIONS
This application, in its entirety, claims the benefit of earlier Indian provisional patent application No. 4469/CHE/2014 filed on September 12, 2014.
BACKGROUND OF THE INVENTION
FIELD OF THE INVENTION
The present disclosure relates generally to the field of pharmaceutical sciences and more specifically to a process for the preparation of enzalutamide.

BACKGROUND OF THE INVENTION
Enzalutamide, chemically known as 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)-2-fluoro-N-methylbenzamide, has the following chemical formula:

Enzalutamide is an androgen receptor antagonist drug marketed as XTANDI® in the United States by Astellas Pharma US, Inc. and is indicated for use as treatment of metastatic castration-resistant prostate cancer.
U.S. Patent No. 7,709,517, which is hereby incorporated by reference, discloses a series of compounds with strong antagonistic activity at the androgen receptor.

U.S. Patent Application Publication No. 20130034501, which is hereby incorporated by reference, discloses a process for the preparation of enzalutamide.
There is a need to provide an improved process for the preparation of enzalutamide which avoids the use of expensive and hazardous chemicals as well reduces impurities in the final product. The present disclosure provides a novel process for the preparation of enzalutamide which is industrially viable.

SUMMARY OF THE INVENTION
One aspect of the present disclosure provides a process for the preparation of enzalutamide which may be carried out according to the set of steps shown below.
According to the present disclosure, formula 4 may be prepared by the following steps:
a) converting formula 1 to formula 2;

b) reducing formula 2 to formula 3; and

c) treating formula 3 with trimethylsilyl cyanide to give formula 4.

According to the preset disclosure, formula 6 may separately be prepared by reacting formula 5 with thiophosgene to give formula 6.

According to the present disclosure, formula 4 may then be reacted with formula 6 to give crude enzalutamide.

Within the context of the present invention, crude enzalutamide may optionally be purified to provide substantially pure enzalutamide.
DETAILED DESCRIPTION OF THE INVENTION
It is to be understood that the description of the present invention has been simplified to illustrate elements that are relevant for a clear understanding of the invention, while eliminating, for purposes of clarity, other elements that may be well known.
The present invention provides an improved process for the preparation of enzalutamide.
One aspect of the present invention provides a process for the preparation of enzalutamide, which may be carried out by reacting formula 4 (N-methyl-2-fluro-4-(1,1 dimethyl-cynomethyl)aminobenzamide) with formula 6 (4-isothiocyanato-2-(trifluoromethyl) benzonitrile) to form enzalutamide.
Another aspect of the present invention provides a process for the preparation of enzalutamide, which may be carried out by first preparing formula 4 (N-methyl-2-fluro-4-(1,1 dimethyl-cynomethyl)aminobenzamide), and, in a separate set of steps, preparing formula 6 (4-isothiocyanato-2-(trifluoromethyl) benzonitrile). Within the context of the invention, formula 4 and formula 6 may then be reacted to form enzalutamide.
According to the present invention, formula 4 may be prepared by the following set of steps:
a) converting formula 1 to formula 2;

b) reducing formula 2 to formula 3; and

c) treating formula 3 with trimethylsilyl cyanide to give formula 4.

According to the preset invention, formula 6 may separately be prepared by reacting formula 5 with thiophosgene to give formula 6.

According to the present invention, formula 4 may then be reacted with formula 6 to give crude enzalutamide.

Within the context of the present invention, crude enzalutamide may optionally be purified to give substantially pure enzalutamide.
According to the present invention, formula 4 and formula 6, which may be reacted to form the final enzalutamide product, may be prepared via independent reaction processes. The processes of the present invention that may be employed to synthesize formula 4 will be described, followed by a description of the processes of the present invention that may be employed to synthesize formula 6.
According to the present invention, formula 4 may be prepared by the following processes. First formula 1 may be converted to formula 2. Within the context of the present invention, the conversion of formula 1 to formula 2 may be achieved by reacting formula 1 with an alkyl amine compound to obtain formula 2. Examples of suitable alkyl amine compounds include methylamine, ethylamine, n-propylamine, isopropylamine, butylamine, and mixtures thereof. In some embodiments of the present invention, methylamine has been found to be a particularly useful alkyl amine compound for reacting with formula 1.
According to the present invention, formula 2 may then be reduced to obtain formula 3. Formula 2 may be reduced in the presence of an organic solvent using a reducing agent, for example, palladium/carbon. Suitable organic solvents include, for example, alcoholic solvents. Examples of suitable alcoholic solvents include methanol, ethanol, isopropanol, and mixtures thereof. One of skill in the art will be able to identify other suitable reducing agents and solvents that may be used within the context of the present invention.
According to the present invention, formula 3 may then be treated with trimethylsilyl cyanide (TMSCN) to obtain formula 4. Within the context of the present invention, this reaction may occur in the presence of an acid and an organic solvent. Suitable acids include, for example, acetic acid. The organic solvent may be a ketone, for example, acetone. One of skill in the art will be able to identify other suitable acids and solvents that may be used to achieve this particular step.
Turning to preparation of formula 6, the following series of steps may be employed. Formula 5 (4-amino-2-(trifluoromethyl) benzonitrile) may be reacted with thiophosgene obtain formula 6. Within the context of the present invention, this reaction may occur in the presence of an organic solvent. The organic solvent may be an alkane, for example, hexane or heptane. One of skill in the art will be able to identify other suitable organic solvents that may be used to achieve this particular step.
According to the present invention, formula 4 may be reacted with formula 6 to obtain crude enzalutamide. Within the context of the present invention, this reaction may occur in the presence of a solvent. Suitable solvents include alcoholic solvents, organic aromatic solvents, dimethylacetamide, or mixtures thereof. In some embodiments of the present invention, pyridine, dimethylacetamide, or mixtures thereof was particularly useful for carrying out this step. Suitable alcoholic solvents include methanol, ethanol, isopropanol, and mixtures thereof. Suitable organic aromatic solvents include xylene, toluene, pyridine, and mixtures thereof. In other embodiments, isopropanol, toluene, or mixtures thereof was useful for carrying out this step. In some embodiments of the present invention, xylene may also be used. Within the context of the present invention, the crude enzalutamide may then (optionally) be purified, for example, by dissolving the crude enzalutamide in a solvent, for example, isopropanol. One of skill in the art will be able to identify other suitable alcohols and aromatic organic solvents that may be used to achieve this particular step.
The enzalutamide disclosed herein formulated in an oral dosage form, such as a capsule. Within the context of the present invention, lomitapide mesylate may be incorporated into dosage forms with a variety of excipients well known in the art, for example, caprylocaproyl polyoxylglycerides, butylated hydroxyanisole, butylated hydroxytoluene, gelatin, sorbitol sorbitan solution, glycerin, purified water, titanium dioxide, and black iron oxide. One of skill in the art will be familiar with a variety of excipients and formulations that may be used to prepare desirable dosage forms with desired release characteristics and pharmacokinetic properties without undue experimentation.
Within the context of the present invention, dosage forms have about 40 mg of enzalutamide. When administered to human and non-human patients, formulations of enzalutamide may be adjusted to compensate for the age, weight, and physical condition of the patient. Enzalutamide may be administered over a wide dosage range from about 40 to about 160 milligrams per day.
When administered to patients, the enzalutamide of the present invention may be useful for treatment of patients with metastatic castration-resistant prostate cancer (CRPC).
Certain specific aspects and embodiments of the present application will be explained in greater detail with reference to the following examples, which are provided only for purposes of illustration and should not be construed as limiting the scope of the invention in any manner.

Example 1: Preparation of formula 2
2-fluro-4-nitrobenzoic acid [formula 1, 50 g] and dimethylformamide [500 ml] were charged in a clean and dried round bottom flask (RBF). The reaction mass was stirred to get a clear solution. If reaction mass was not clear, it was filtered and the filtrate was used to proceed forward. Carbonyldiimidazole [CDI, 52.7 g] was added as a single lot to the clear solution and the reaction mixture was flushed with dimethyl formamide. The reaction mass was stirred, methylamine [10 g] in dimethyl formamide solution was added and the solution was heated until the reaction was complete as verified by TLC. Next, the solvent was distilled from the reaction mixture under vacuum (680 ± 30 mm Hg) and the solid residue was cooled to room temperature. Water [200 ml] was charged to the solid residue and the mixture was stirred. The reaction mixture was then cooled to 5 to 10 °C and stirred to get a free-flowing solid. The solid was filtered and the product was washed with pre-chilled water (0 ± 5 °C). The filter cake was suck dried then dried in vacuum to result in formula 2.

Example 2: Preparation of formula 3
Methanol (450 ml) was combined with N-methyl-2-fluro-4-nitrobenzamide [formula 2, 50 g] in a clean and dried RBF. Pd/C [5 g] was then added as a single lot under nitrogen atmosphere and the reaction mixture was flushed with methanol [50 ml]. The reaction mixture was then purged with hydrogen gas while being stirred until the reaction was complete. Next, the reaction mass was flushed with nitrogen. The reaction mass was then filtered through a celite bed and washed with methanol [100 ml]. Next, the reaction mixture was distilled under vacuum (680 ± 30 mm Hg) to completely remove any solvent. The resulting solid residue was cooled to room temperature. Water [100 ml] was added while the reaction mass was stirred. The solid was filtered and washed with water. The solid was then dried under vacuum to result in formula 3.

Example 3: Preparation of formula 4
TMSCN [74 g] was combined with N-methyl-2-fluro-4-aminobenzamide [formula 3, 50 g] in a clean and dried RBF. Acetic acid [250 ml] was slowly added dropwise to create frothing. Next, acetone [250 ml] was added and the reaction mass was heated to about 85 °C. Heating continued until the reaction was complete. Next, the solvents were completely distilled off under vacuum (680 ± 30 mm Hg). The resultant solid residue was cooled to room temperature, water [1000 ml] was added to the residue, and the reaction mass was stirred to get a free-flowing solid. The solid was filtered and washed with water to form a slurry. The slurry was then washed with tert-butyl methyl ether (TBME). The filtered cake was suck dried and the product dried under vacuum to result in formula 4.

Example 4: Preparation of formula 6
Water [125 ml] and n-heptane [125 ml] were added to 4-amino-2-(trifluoromethyl) benzonitrile [formula 5, 50 g] in a clean and dried RBF. The reaction mass was then cooled to 5 to 10 °C. Thiophosgene [42 ml] was then added and the reaction mass was stirred. The reaction mass was then warmed to ambient temperature and stirred until the completion of the reaction as monitored by TLC. The reaction mass was allowed to settle and the organic and aqueous layers were separated. The aqueous layer was washed with n-heptane and the aqueous and organic layers were separated again. The organic n-heptane layers were then combined and washed with water. The aqueous and organic layers were again separated and the organic layer was distilled under vacuum. N-heptane (600 ml) was added to the reaction mass and the solution was distilled, cooled, and filtered under vacuum to result in formula 6.

Example 5: Preparation of crude enzalutamide
N-methyl-2-fluro-4-(1,1 dimethyl-cynomethyl)aminobenzamide [formula 4, 2 g] was combined with pyridine [10 ml] in a clean and dried RBF. 4-isothiocyanato-2-(trifluoromethyl) benzonitrile [formula 6, 5.82 g] was then added and the reaction mass was stirred and heated to about 60 °C. Next, the temperature of the reaction mass was raised to about 90 °C and maintained at that temperature until the reaction was complete, as monitored by TLC. The pyridine was distilled off completely with toluene. Next, the residue was dissolved in ethanol [40 ml] and 1N HCl [20 ml] was added. The reaction mass was heated while stirring. Ethanol was distilled off and ethyl acetate was added to the residual mass three times. The combined ethyl acetate layers were washed with water , followed by brine solution, and the ethyl acetate and aqueous layers were separated. The ethyl acetate layer was dried over sodium sulphate and concentrated under vacuum. The residual thick solid was degassed under vacuum then dissolved in isopropanol [20 ml]. Diisopropyl ether [20 ml] was then added and the mixture was stirred. The reaction mass was cooled and stirred, then filtered and washed with 50 ml 10% isopropanol in diisopropyl ether. The solid was then dried under vacuum to result in crude enzalutamide.

Example 6: Preparation of crude enzalutamide
Dimethylacetamide [10 ml] [or pyridine and dimethylacetamide (10 ml)] were combined in a clean and dried RBF. N-methyl-2-fluro-4-(1,1 dimethyl-cyanomethyl) aminobenzamide [formula 4, 2 g] was then added, followed by 4-isothiocyanato-2-(trifluoromethyl) benzonitrile [formula 6, 5.82 g]. The reaction mass was heated to about 60 ºC while stirring for 24 hours. After 24 hours of stirring, the reaction mass was cooled to 25-30 ºC. Water (100 ml) and ethyl acetate (50 ml) were then added. The aqueous and organic layers were separated. The aqueous layer was further extracted with 50 ml ethyl acetate and the combined ethyl acetate layers were washed twice with 50 ml water. The organic layer was dried over sodium sulfate and concentrated to get an oily residue. To the oily residue, 20 ml isopropanol was added and the solid obtained was filtered. The solids were washed with 20 ml of diisopropyl ether. The filtrate was concentrated and the residue was dissolved in 40 ml isopropanol and 60 ml toluene. The clear solution was refluxed at 90 - 95 ºC for 3 hours. After 3 hours, the solvent was distilled off completely and the residue was dissolved in 60 ml ethanol. 20 ml 1.0 N hydrochloric acid was added and the reaction mass was stirred for 1 hour at 90 ºC. After completion of the reaction, ethanol was distilled out and water was added to the reaction mass at 25 - 30 ºC. The product was then extracted in ethyl acetate (50 ml). The ethyl acetate layer was washed with water and brine solution. The organic layer was distilled completely to get an oily residue. The oily residue was dissolved in 12 ml of isopropanol and heated to 80 ºC to get a clear solution. The reaction mass was then cooled to 25 - 30 ºC and 12 ml of diisopropyl ether was added. The reaction mass was stirred at 25 - 30 ºC for 4 hours. The product was filtered and washed with diisopropyl ether. The solid was dried under vacuum to result in crude enzalutamide.
,CLAIMS:1. A process for the preparation of Enzalutamide comprising the steps of:
reacting compound of formula 4

with compound of formula 6

in presence of an alcohol or an aromatic organic solvent, or N,N-dialkyl acetamide or mixtures thereof.
2. The process according to claim 1, wherein the alcohol is selected from methanol, ethanol, isopropanol, aromatic organic solvent is selected from xylene, toluene or pyridine, and N,N-dialkyl acetamide is selected from N,N-dimethyl acetamide or N,N-diethyl acetamide or their mixtures thereof.

3. A process for the preparation of Enzalutamide comprising the steps of:

a) converting the acid of formula 1 to amide of formula 2

b) reducing the amide of compound of formula 2 to give amine of compound of formula 3

c) treating the amine of compound of formula 3 with trimethylsilyl cyanide to give compound of formula 4

d) treating the compound of formula 5 with thiophosgene to give compound of formula 6

e) reacting the compound of formula 4 with compound of formula 6 gives crude Enzalutamide, and

f) optionally purifying the obtained crude Enzalutamide to given pure Enzalutamide.

4. The process according to claim 3, wherein conversion of formula 1 to formula 2 is carried using alkyl amine selected from methyl amine, ethyl amine, n-propyl amine, iso-propyl amine or butyl amine.

5. The process according to claim 3, wherein the reduction in step b is carried using palladium/carbon in presence of organic solvent such as alcohols selected from methanol, ethanol, isopropyl alcohol.

6. The process according to claim 3, wherein the reaction of trimethylsilyl cyanide is carried in presence of an acid selected from acetic acid and organic solvent selected from ketones.

7. The process according to claim 3, wherein compound of formula 4 may be reacted with compound of formula 6 in presence of N,N-dimethylacetamide, Pyridine, Isopropanol, N,N-dimethylacetamide in combination with Pyridine or Isopropanol in combination with Toluene.

8. The process according to claim 1 or 3, wherein the crude Enzalutamide may be purified in an alcoholic solvent.

9. The process according to claim 8, wherein the crude Enzalutamide may be purified using isopropanol.