DESC:The following specification particularly describes the nature of this invention and the manner in which it is to be performed.
PROCESS FOR THE PREPARATION OF ENZALUTAMIDE AND ITS INTERMEDIATES

Aspects of the present application relate to process for the preparation of enzalutamide and its intermediates.
The drug compound having the adopted name enzalutamide, has a chemical name 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)-2-fluoro-N-methylbenzamide, and is represented by structure of formula I.

Formula I
Enzalutamide is an oral, once-daily investigational agent that is an androgen receptor signaling inhibitor used for the potential treatment of men with castration-resistant prostate cancer previously treated with docetaxel-based chemotherapy. Enzalutamide inhibits androgen receptor signaling in three distinct ways: it inhibits 1) testosterone binding to androgen receptors; 2) nuclear translocation of androgen receptors; and 3) DNA binding and activation by androgen receptors. U.S. Patent No. 7,709,517 discloses enzalutamide, method of use and its pharmaceutical composition.

US patent 7709517 discloses a process for the preparation of enzalutamide by reacting N-Methyl-2-fluoro-4-(1,1-dimethyl-cyanomethyl)-aminobenzamide with 4-Isothiocyanato-2 –trifluoromethylbenzonitrile under microwave irradiation.

The international application WO 2011106570A1 discloses process for the preparation of enzalutamide by reacting methyl 2-(3-fluoro-4-(methylcarbamoyl)phenylamino) propanoate with 4-Isothiocyanato-2–trifluoromethyl benzonitrile. The application also discloses process for the preparation of enzalutamide by reacting 2-((3-fluoro-4-(methylcarbamoyl)phenyl)amino)-2-methylpropanoic acid with 4-amino-2-(trifluoromethyl) benzonitrile in presence of EDCI to give 4-((1-((4-cyano-3-(trifluoromethyl)phenyl)amino)-2-methyl-1-oxopropan-2-yl)amino)-2-fluoro-N-methylbenzamide, which on reaction with thiophosgene gives enzalutamide.

WO 2014/041487 discloses crystalline enzalutamide Form R1, Form R2 and amorphous form and the process for preparation thereof.

Despite the existence of processes for the preparation of enzalutamide and its intermediates, there is an unmet need in the field for the provision of a simple, controlled procedure for the preparation of enzalutamide and its intermediates. The inventors of the present application developed an improved route for the preparation of enzalutamide and its intermediates.

SUMMARY OF THE INVENTION
In an aspect, the present application provides a process for the preparation of enzalutamide, which comprises; reacting the compound of formula II,

Formula II
wherein R is selected from H, trimethylsilane, Boc or a labile protecting group.
with compound of formula III,

Formula III
in presence of cyanide reagent and solvent comprising dimethyl sulfoxide, toluene, isopropyl acetate or mixtures thereof.
In an aspect, the present application provides a process for the preparation of enzalutamide, which comprises; reacting the compound of formula V,

Formula V
with compound of formula III,

Formula III
in a solvent comprising dimethyl sulfoxide, toluene, isopropyl acetate or mixtures thereof.
In an another aspect, the present application provides a process for purification of enzalutamide, which comprises;
a) dissolving crude enzalutamide in an alcohol solvent,
b) adding cyclohexane to the solution obtained in step (a) and
c) isolation
In an aspect, the present application provides a process for preparation of crystalline enzalutamide form R1, which comprises drying the R2 crystalline polymorphic form of enzalutamide.

DETAILED DESCRIPTION
In an aspect, the present application provides a process for the preparation of enzalutamide, which comprises:
(a) reacting the compound of formula II,

Formula II
wherein R is selected from H, trimethylsilane, BoC or a labile protecting group.
with compound of formula III,

Formula III
in presence of cyanide reagent and solvent comprising dimethyl sulfoxide, toluene, isopropyl acetate or mixtures thereof.
The cyanide reagents that may be used include but not limited to metal cyanide such as sodium cyanide, potassium cyanide, copper (I) cyanide and the like, cyanohydrin, trimethylsilyl cyanide, potassium ferrocyanide or the like.
The reaction may be carried out in presence of suitable lewis acid. Suitable lewis acids include but not limited to transition metal halides, transition metal triflates, transition metal acetate, alkyl halides, boron containing reagents, aluminium containing reagent but, are not limited to BF3: TBME (t-butyl methyl ether); BF3:OEt2; BF3: O(CH2CH2CH2CH3)2; BF3:THF; and the like; alkyl aluminum halides, dialkyl aluminum halides, trialkyl aluminum, and (e.g., AlCl3 and AlBr3); trimethylsilyl halides, trimethylsilyl triflates or the like.
The above reaction may be carried out at a suitable temperature. The suitable temperature may be less than about 150°C, less than about 100°C, less than about 80°C, less than about 60°C, less than about 40°C, less than about 30°C, less than about 20°C, less than about 10°C, less than about 0°C, less than about -10°C, less than about -20°C, less than about -30°C, less than about -40°C or any other suitable temperatures.

The mineral acid used for hydrolysis may include hydrochloric acid, sulphuric acid, phosphoric acid, nitric acid, boric acid, hydrofluoric acid, hydrobromic acid, perchloric acid or the like; preferably hydrochloric acid.

The recovered solid may be optionally further dried. Drying may be carried out in a tray dryer, vacuum oven, air oven, fluidized bed dryer, spin flash dryer, flash dryer, or the like. The drying may be carried out at temperatures less than about 150°C, less than about 120°C, less than about 100°C, less than about 80°C, less than about 60°C, less than about 40°C or any other suitable temperatures as long as the compound is not degraded in quality, at atmospheric pressure or under a reduced pressure. The drying may be carried out for any desired times until the required purity is achieved. For example, it may vary from about 1 hour to about 10 hours, or longer.
In an aspect, the present application provides a process for the preparation of enzalutamide, which comprises:
(a) reacting the compound of formula V,

Formula V
with compound of formula III,

Formula III
in a solvent comprising dimethyl sulfoxide, toluene, isopropyl acetate or mixtures thereof to obtain a compound of formula (IV) and

Formula IV
b) hydrolyzing the compound of formula (IV) with mineral acid.

The solvent is selected from dimethyl sulfoxide, toluene, isopropyl acetate or mixtures thereof; preferably a mixture of dimethyl sulfoxide and isopropyl acetate.
The above reaction may be carried out at a suitable temperature. The suitable temperature may be less than about 150°C, less than about 100°C, less than about 80°C, less than about 60°C, less than about 40°C, less than about 30°C, less than about 20°C, less than about 10°C, less than about 0°C, less than about -10°C, less than about -20°C, less than about -30°C, less than about -40°C or any other suitable temperatures.
The mineral acid used for hydrolysis may include hydrochloric acid, sulphuric acid, phosphoric acid, nitric acid, boric acid, hydrofluoric acid, hydrobromic acid, perchloric acid or the like; preferably hydrochloric acid.

The recovered solid may be optionally further dried. Drying may be carried out in a tray dryer, vacuum oven, air oven, fluidized bed dryer, spin flash dryer, flash dryer, or the like. The drying may be carried out at temperatures less than about 150°C, less than about 120°C, less than about 100°C, less than about 80°C, less than about 60°C, less than about 40°C or any other suitable temperatures as long as the compound is not degraded in quality, at atmospheric pressure or under a reduced pressure. The drying may be carried out for any desired times until the required purity is achieved. For example, it may vary from about 1 hour to about 10 hours, or longer.

In an another aspect, the present application provides a process for purification of enzalutamide, which comprises;
a) dissolving crude enzalutamide in an alcoholic solvent,
b) adding cyclohexane to the solution obtained in step (a) and
c) isolation.
The alcohol solvent is selected from methanol, ethanol, isopropanol, n-butanol and the like; preferably isopropanol.
Crude enzalutamide is dissolved in an alcoholic solvent by heating the reaction mass to the reflux temperature of the solvent used.
Cyclohexane may be added to the solution obtained in step (a) in the temperature range of 10-40°C; preferably 15-25°C.
Crude enzalutamide may also be purified by dissolving it in an alcoholic solvent, cooling and filtration of the solid. The solid washed with cyclohexane and dried to obtain pure enzalutamide.
The solution of crude enzalutamide in alcohol cooled to -10 to 30 °C; preferably 0-20°C.
The product thus obtained may be isolated using conventional methods including decantation, centrifugation, gravity filtration, suction filtration, or other techniques known in the art.
In an aspect, the present application provides a process for preparation of crystalline enzalutamide form R1, which comprises drying the R2 crystalline polymorphic form of enzalutamide. The crystalline enzalutamide form R2 may be dried under vacuum in an oven. Drying temperature may be in the range of 80-150°C; preferably 110°C.

Enzalutamide obtained may have purity greater than or equal to 99% (by HPLC). More preferably, may have purity greater than 99.7% (by HPLC).

In another embodiment the present invention provides enzalutamide having the following one or more impurities less than 1.0% or less than 0.7% or less than 0.5% or less than 0.3% or less than 0.2% or less than 0.1% or less than 0.05% or not detectable.
Impurity A: 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)-N-methylbenzamide,
Impurity B: 1,3-bis(4-cyano-3-(trifluoromethyl)phenyl)thiourea,
Impurity C: Isopropyl (4-cyano-3- (trifluoromethyl)phenyl)carbamothioate,
Impurity D: Isopropyl (4-cyano-3-(trifluoromethyl)phenyl)carbamate and
Impurity E: Sulphur.
Impurity F: 1,3-bis(4-cyano-3-(trifluoromethyl)phenyl)urea

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 application in any manner. Reasonable variations of the described procedures are intended to be within the scope of the present invention. While particular aspects of the present invention have been illustrated and described, it would be obvious to those skilled in the art that various other changes and modifications can be made without departing from the spirit and scope of the invention. It is therefore intended to cover in the appended claims all such changes and modifications that are within the scope of this invention.
Analytical Methods:
Apparatus:
A liquid chromatograph equipped with variable wavelength detector or equivalent analytical balance.
Typical chromatographic conditions:
Column YMC-Pack ODS-A 150*4.6 mm, 3.0µm
Flow Rate 1.0mL/min
Column Temperature 40°C
Wave Length 260nm by UV
Injection volume 10 µL
Run Time 60 min
Elution Gradient
Sample Concentration 1.0mg/mL
Diluent Acetonitrile
Gradient Programme Time (Min) % Mobile Phase-A % Mobile Phase-B
0 95 5
5 95 5
35 50 50
40 15 85
50 15 85
51 95 5
60 95 5

Examples
Example 1:
Preparation of 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimida zolidin-1-yl)-2-fluoro-N-methylbenzamide (Formula I)
0.5 g of 4-((2-cyanopropan-2-yl)amino)-2-fluoro-N-methylbenzamide and 0.97 g of 4-isothiocyanato-2-(trifluoromethyl)benzonitrile were charged into bottom flask along with toluene (2 mL) and DMSO (2 mL) at 22 0C. 0.97 g of trimethylsilalyl cyanide and 0.5 mL acetone were added. 10 mg of ZnCl2 dissolved in THF (1M solution) was added to the above flask. The contents were heated to 80-85 0C and maintained at 82 0C for 12 hours. 20 mL of water solution was added and the aqueous layer was extracted with ethylacetate (2 x 20mL). The organic layers were combined and concentrated under reduced pressure at 50 0C. The concentrated material was purified by column chromatography using 40% acetone in n-hexane. The purified compound was charged into a fresh round bottom flask and 10 mL of isopropyl alchol was added and heated to 70-75 0C. The reaction was maintained at 70-75 0C for 40 minutes and then cooled to 25-35 0C over a period of 2 hours. The contents of the reaction were filtered and washed with 3 mL of IPA. The material was dried under reduced pressure at 48 0C for 6 hours to afford the title material. Yield: 0.35 g

Example 2:
Preparation of 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimida zolidin-1-yl)-2-fluoro-N-methylbenzamide (Formula I)
4-((2-cyanopropan-2-yl)amino)-2-fluoro-N-methylbenzamide (15 g) and 4-isothiocyanato-2-(trifluoromethyl)benzonitrile (43.6 g) were charged into bottom flask along with isopropyl acetate (126 ml) and DMSO (24 ml) at 20.5 °C, heated to 61.5°C and stirred 16 hours. Isopropyl alcohol (150 ml) was added, heated to 79.6°C and stirred for 5 hours. The reaction mixture was cooled to 55°C and isopropyl alcohol (10 volume) was added. Conc. HCl (45 ml) and water (78.75 ml) were added, heated to 44-45°C and stirred at 43.8°C for 6 hours. The reaction mixture was cooled to 15-20°C, the solid was filtered, washed with isopropyl alcohol (2 volume) and dried. Yield: 30 g; Purity: 57.6% (by HPLC); Impurities: D=37.22%, C=1.93% & E=2.43% (by HPLC)

Example-3:
Purification of 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimida zolidin-1-yl)-2-fluoro-N-methylbenzamide.
Enzalutamide (30 g) and isopropyl alcohol (360 ml) were charged into bottom flask at 24.3°C and heated to 79.7°C. 10% of activated charcoal (3 g) was added, filtered the reaction mass through hyflow and washed with isopropyl alcohol (60 ml). Cyclohexane (195 ml) was added to the filtrate at 18-19.5°C, filter the solid and dried. Yield: 10.6 g; Purity: 99.21% (by HPLC) Impurities: A=0.04%, C=0.10%, D=0.22% & E=0.01% (by HPLC).

Example-4:
Preparation of 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)-2-fluoro-N-methylbenzamide (R1 Form)
Enzalutamide (8 g) was added to methanol (80 ml) at 22.3°C then the temperature raised to 65°C and cooled to 5°C in 74 minutes. The solid was filtered, washed with isopropyl alcohol (32 ml) and dried under suction at 10.5°C to obtain Form R2 which was dried at 110°C under vacuum in an oven for 2 hours 20 minutes to obtain crystalline enzalutamide Form R1. Yield: 5.8g; Purity: 99.7% (by HPLC)
,CLAIMS:We Claim,
1. A process for preparation of enzalutamide (I), which comprises; reacting the compound of formula V,

Formula V
with compound of formula III,

Formula III
in a solvent comprising dimethyl sulfoxide, toluene, isopropyl acetate or mixtures thereof to obtain a compound of formula (IV) and

Formula IV
b) hydrolyzing the compound of formula (IV) with mineral acid.

2. The process according to claim 1, wherein the solvent is a mixture of dimethyl sulfoxide and isopropyl acetate.

3. The process according to claim 1, wherein the reaction is carried out at 20-100 °C; preferably 40-90°C.

4. The process according to claim 1, wherein the mineral acid is selected from hydrochloric acid, sulphuric acid, phosphoric acid, nitric acid, boric acid, hydrofluoric acid, hydrobromic acid, perchloric acid or the like; preferably hydrochloric acid.

5. A process for purification of enzalutamide (I), comprising;
a) dissolving crude enzalutamide in an alcoholic solvent,
b) adding cyclohexane to the solution obtained in step (a) and
c) isolation.

6. The process according to claim 5, wherein the alcoholic solvent is selected from methanol, ethanol, isopropanol, n-butanol and the like; preferably isopropanol.

7. A process for preparation of crystalline enzalutamide Form R1 comprises drying crystalline enzalutamide Form R2 in the temperature range of 80-150 °C.

8. The process according to claim 7, wherein the crystalline enzalutamide Form R2 is dried at 110°C.