Field of the Invention:
The present invention relates to an improved process for the preparation of 4-{3-[4-cyanoO-(trifluoromethyl)phenyl]-5,5-^^ fluoro-N-methylbenzamide compound of formula-1 represented by the following formula:
Background of the Invention:
Enzalutamide is chemically known as 4-{3-[4-cyano-3-(trifluoromethyl)phenyl]-5?5-dimethyl-4-oxo-2-sulfanylideneimidazolidin-l-yl}-2-fluoro-N-methylbenzamide.
Enzalutamide is marketed under the brand name Xtandi by Astellas. It is approved in United States as Enzalutamide on 31st Aug 2012. Xtandi is an androgen receptor inhibitor indicated for the treatment of patients with metastatic castration-resistant prostate cancer.
US 7709517B2 first disclosed the process for the preparation of 4-{3-[4-cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo-2-sulfanylideneimidazolidin-l-yl}-2-fluoro-N-methylbenzamide which involves reacting M-methyl-2-fluoro-4(l,l-dimethyl-cyanomethyl)-aminobenzamide with 4-isothiocyanato-2-trifluoromethylbenzonitrile in dimethylformamide followed by hydrolysis with hydrochloric acid in methanol to get the Ezalutamide with less yield. Further it was purified by column chromatography using dichloromethane and acetone which is a laborious and time consuming process and also it is not suitable for commercial scale purpose.
Hence, there is a need in the art to develop an improved, economically viable and efficient, simple process for the preparation of 4-{3-[4-cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo-2-sulfanylideneimidazolidin-l-yl}-2-fluoro-N-methylbenzamide with high yield and purity.

Brief description of the Invention:
The first aspect of the present invention is to provide an improved process for the preparation of 4-{3-[4-cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo-2-sulfanylidene imidazolidin-l-yl}-2-fluoro-N-methylbenzamide compound of formula-1.
The second aspect of the present invention is to provide an improved process for the preparation of 4-{3-[4-cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo-2-sulfanylidene imidazolidin-l-yl}-2-fluoro-N-methylbenzamide compound of formula-1 by using 4-(2-cyanopropane-2-ylamine)-2-fluoro-N-methylbenzamide compound of formula-5.
The third aspect of the present invention is to provide an improved process for the preparation of 4-{3-[4-cyano-3-(trifluoromethyl)phenyl]-535-dimethyl-4-oxo-2-sulfanylidene imidazolidin-l-yl}-2-fluoro-N-methylbenzamide compound of formula-1 by using 4-(2-cyanopropane-2-ylamine)-2-fluoro-N-methylbenzamide compound of formula-5.
The fourth aspect of the present invention is to provide a process for the purification of crystalline Form-A of 4-{3-[4-cyano-3-(trifluoromethyl)phenyl]-5?5-dimethyl-4-oxo-2-sulfanylideneimidazolidin-l-yl}-2-fluoro-N-methylbenzamide compound of formula-1.
Brief description of Drawings:
Figure 1: Illustrates the powder X-ray diffractogram of 4-{3-[4-cyano-3-(trifluoromethyl)
phenyl]-5,5-dimethyl-4-oxo-2-sulfanylideneimidazolidin-l-yl}-2-fluoro-N-methylbenzamide
compound of formula-1.
Figure 2: Illustrates the DSC thermogram of 4-{3-[4-cyano-3-(trifluoromethyl) phenyl]-5,5-
dimethyl-4-oxo-2-sulfanylideneimidazolidin-l-yl}-2-fluoro-N-methylbenzamide compound
of formula-1.
Detailed description of the Invention:
The term "suitable solvent" used in the present invention refers to "hydrocarbon solvents" such as n-pentane, n-hexane, n-heptane, cyclohexane, pet ether, benzene, toluene,

xylene and the like; "ether solvents" such as dimethyl ether, diethyl ether, diisqpropyl ether, methyl tert-butyl ether, 1,2-dimethoxyethane, tetrahydrofuran, 1,4-dioxane and the like; "ester solvents" such as methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, tert-butyl acetate and the like; "polar-aprotic solvents" such as dimethylacetamide, dimethylformamide, dimethylsulfoxide, N-methylpyrrolidone (NMP) and the like; "chloro solvents" such as dichloromethane, dichloroethane, chloroform, carbon tetrachloride and the like; "ketone solvents" such as acetone, methyl ethyl ketone, methyl isobutyl ketone and the like; "nitrile solvents" such as acetonitrile, propionitrile, isobutyronitrile and the like; "alcohol solvents" such as methanol, ethanol, n-propanol, iso-propanol, n-butanol, iso-butanol, t-butanol, ethane- 1,2-diol, propane-1,2-diol and the like; "polar solvents" such as water; formic acid, acetic acid or mixture of any of the aforementioned solvents.
The term "suitable base" used in the present invention refers to "inorganic bases" selected from "alkali metal carbonates" such as sodium carbonate, potassium carbonate, lithium carbonate, cesium carbonate and the like; "alkali metal bicarbonates" such as sodium bicarbonate, potassium bicarbonate, lithium bicarbonate, cesium bicarbonate and the like; "alkali metal hydroxides" such as sodium hydroxide, potassium hydroxide, lithium hydroxide and the like; "alkali metal alkoxides" such as sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, lithium methoxide, lithium ethoxide, sodium tert.butoxide, potassium tert.butoxide, lithium tert.butoxide and the like; "alkali metal hydrides" such as sodium hydride, potassium hydride, lithium hydride and the like; "alkali metal amides" such as sodium amide, potassium amide, lithium amide and the like; alkali metal and alkali earth metal salts of acetic acid such as sodium acetate, potassium acetate, magnesium acetate, calcium acetate and the like; ammonia; "organic bases" like dimethylamine, diethylamine, diisopropyl mine, diisopropylethylamine, diisobutylamine, triethylamine, triisopropyl amine, tributylamine, tert.butyl amine, pyridine, 4-dimethylaminopyridine (DMAP), imidazole, N-methylimidazole, l,8-diazabicyclo[5.4.0] undec-7-ene (DBU), l,5-diazabicyclo[4.3.0]non-5-ene(DBN), N-methylmorpholine (NMM), l,4-diazabicyclo[2.2.2]octane (DABCO), 2,6-lutidine and the like; "organolithium bases" such as methyl lithium, n-butyl lithium, lithium diisopropylamide (LDA) and the like; "organosilicon bases" such as lithium

hexamethyldisilazide (LiHMDS), sodium hexamethyldisilazide (NaHMDS), potassium hexamethyldisilazide (KHMDS) and the like or their mixtures.
The term "acid" used in the present invention refers to inorganic acid selected from hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, sulfamic acid and the like; organic acid such as formic acid, acetic acid, trifluoro acetic acid, methane sulfonic acid, ethane sulfonic acid, benzene sulfonic acid, trifluoromethane sulfonic acid, p-toluene sulfonic acid, tartaric acid, mandelic acid, malic acid, maleic acid, succinic acid, malonic acid, oxalic acid, dibenzoyl tararic acid, lactic acid, cinnamic acid and the like.
The first aspect of the present invention provides a process for the preparation of 4-{3-[4-cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo-2-sulfanylideneimidazolidin-l-yl}-2-fluoro-N-methylbenzamide compound of formula-1, comprising of:
a) Reacting 2-fluoro-4-nitrobenzoic acid compound of formula-2 with thionyl chloride in a suitable solvent or mixture of solvents followed by treatment with methyl amine solution to provide 2-fluoro-N-methyl-4-nitrobenzamide compound of formula-3,
b) treating compound of formula-3 with iron powder in a suitable solvent or mixture of solvents in presence of acetic acid to provide 4-amino-2-fluoro-N-methylbenzamide compound of formula-4, which is optionally purifying from a suitable solvent to provide high pure 4-amino-2-fluoro-N-methylbenzamide compound of formula-4,
c) treating compound of formula-4 with sodium cyanide in a suitable solvent followed by treatment with acetic acid to provide 4-(2-cyanopropane-2-ylamine)-2-fluoro-N-methylbenzamide compound of formula-5, which is optionally purifying using a suitable solvent and followed by slurring in a suitable solvent to provide high pure 4-(2-cyanopropane-2-ylamine)-2-fluoro-N-methylbenzamide compound of formula-5,
d) reacting compound of formula-5 with 4-isothiocyanato-2-trifluoromethyl)benzonitrile compound of formula-7 in a suitable solvent or mixture of solvents followed by treatment with a suitable acid in a suitable solvent or mixture of solvents to provide 4-{3-[4-cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo-2-sulfanylidene imidazolidin-l-yl}-2-fluoro-N-methylbenzamide compound of formula-1,

e) optionally, purifying the compound of formula-1 with a suitable solvent or mixture of
solvents to provide high pure 4-{3-[4-cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-
4-oxo-2-sulfanylideneimidazolidin-l -yl}-2-fluoro-N-methylbenzamide compound of
formula-1. Wherein, in step-a) the suitable solvent is selected from hydrocarbon solvents and polar aprotic
solvents or mixtures thereof; in step-b) and c) the suitable solvent is selected from ester solvents, hydrocarbon solvents,
ketone solvents and polar solvents or mixtures thereof; in step-d) the suitable solvent is selected from ester solvents, polar aprotic solvents,
ether solvents, chloro solvents, hydrocarbon solvents, ketone solvents, alcohol
solvents and polar solvents or mixture thereof; and the suitable acid is selected from
inorganic acid or organic acid; in step-e) the suitable solvent is selected from ester solvents, ether solvents, chloro solvents,
hydrocarbon solvents, ketone solvents, polar aprotic solvents, alcohol solvents and
polar solvents or mixture thereof;
The preferred embodiment of the present invention provides a process for the preparation of 4-{3-[4-cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo-2-sulfanylidene imidazolidin-l-yl}-2-fluoro-N-methylbenzamide compound of formula-1, comprising of:
a) Reacting 2-fluoro-4-nitrobenzoic acid compound of formula-2 with thionyl chloride in toluene and dimethylformamide followed by treatment with methyl amine solution provides 2-fluoro-N-methyl-4-nitrobenzamide compound of formula-3,
b) treating compound of formula-3 with iron powder in ethyl acetate and water in presence of acetic acid to provide 4-amino-2-fluoro-N-methylbenzamide compound of formula-4, further purifying the obtained compound using cyclohexane to provide high pure 4-amino-2-fluoro-N-methylbenzamide compound of formula-4,
c) treating compound of formula-4 with sodium cyanide in acetone followed by treatment with acetic acid to provide 4-(2-cyanopropane-2-ylamine)-2-fluoro-N-methylbenzamide compound of formula-5, further purifying the obtained compound

using cyclohexane and followed by slurring in water to provide high pure 4-(2-cyanopropane-2-ylamine)-2-fluoro-N-methylbenzamide compound of formula-5,
d) reacting compound of formula-5 with 4-isothiocyanato-2-trifluoromethyl)benzonitrile compound of formula-7 in dimethylsulfoxide and isopropyl * acetate followed by treatment with conc.HCl in water and methanol, further purifying the obtained compound using dimethyl sulfoxide, dichloromethane, acetone and isolating the compound using cyclohexane and methanol to provide 4- {3 - [4-cyano-3 -(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo-2-sulfanylideneimidazolidin-1 -yl} -2-fluoro-N-methylbenzamide compound of formula-1,
e) purifying the compound of formula-1 with isopropyl alcohol, isopropyl acetate and dimethylsulfoxide followed by slurring in cyclohexane and methanol to provide high pure 4-{3-[4-cyano-3-(trifluoromethyl)phenyl]r5,5-dimethyl-4-oxo-2-sulfanylidene imidazolidin-l-yl}-2-fluoro-N-methylbenzamide compound of formula-1.
The 4-isothiocyanato-2-trifluoromethyl)benzonitrile compound of formula-7 used in the above aspect can be prepared by the process comprising of, reacting 4-amino-2-(trifluoromethyl)benzonitrile compound of formula-6 with thiophosgene in water followed by crystallization using n-heptane provides pure 4~isothiocyanato-2-trifluoromethyl)benzonitrile compound of formula-7.
The second aspect of the present invention provides a process for the preparation of 4-{3-[4-cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo-2-sulfanylideneimidazolidin-l-yl}-2-fluoro-N-methylbenzamide compound of formula-1, comprising of
a) Reacting 4-(2-cyanopropane-2-ylamine)-2-fluoro-N-methylbenzamide compound of formula-5 with lot-wise addition of 4-isothiocyanato-2-trifluoromethyl)benzonitrile compound of formula-7 in a suitable solvent selected from polar-aprotic solvents and ester solvents or their mixture and heating to form a reaction mixture,
b) adding a suitable solvent selected from alcohol solvents and polar solvents or their mixtures and a suitable acid to the reaction mixture,
c) heating the reaction mixture,
d) stirring the reaction mixture,

e) cooling the reaction mixture,
f) adding a suitable polar aprotic solvent to the obtained reaction mixture and stirring the reaction mixture at a suitable temperature,
g) filtering the reaction mixture to provide crude compound of formula-1,
h) purifying the solid obtained in step-g) to provide pure compound of formula-1.
Wherein, the suitable solvents and suitable acid used are same as defined in step-d) of the first aspect of the present invention.
Further, the purification of compound of formula-1 described in above step-(h) comprising of the following steps:
i) Dissolving the crude compound of formula-1 in a suitable first solvent,
ii) optionally, filtering the reaction mixture,
iii) washing the filtrate with a suitable aqueous base solution followed by with water,
iv) adding a suitable second solvent,
v) distilling off the reaction mixture,
vi) adding a suitable third solvent/mixture of solvents to the obtained compound,
vii) heating the reaction mixture,
viii) cooling the reaction mixture,
ix) filtering the reaction mixture and drying the material to provide pure compound of formula-1.
Wherein, the suitable first, second and third solvents used are same as defined in step-d) of the first aspect of the present invention.
The preferred embodiment of present invention provides a process for the preparation
Of 4-{3-[4-cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo-2-sulfanylidene
imidazolidin-l-yl}-2-fluoro-N-methylbenzamide compound of formula-1, comprising of
a) Reacting 4-(2-cyanopropane-2-ylamine)-2-fluoro-N-methylbenzamide compound of formula-5 with lot-wise addition of 4-isothiocyanato-2-trifluoromethyl)benzonitrile compound of formula-7 in dimethylsulfoxide and isopropyl acetate and heating to form a reaction mixture,
b) adding methanol, water and conc.HCl to the reaction mixture,
c) heating the reaction mixture to 70-75°C,
d) stirring the reaction mixture,
e) cooling the reaction mixture,
f) adding dimethylsulfoxide to the obtained reaction mixture and stirring the reaction mixture at 25-30°C,
g) filtering the reaction mixture to provide crude compound of formula-1,
h) purifying the solid obtained in step-g) using cyclohexane and methanol to provide pure compound of formula-1.
Further, the purification of compound of formula-1 described in above step-(h) comprising of the following steps:
i) Dissolving the crude compound of formula-1 in dichloromethane,
ii) filtering the reaction mixture,
iii) washing the filtrate with sodium bicarbonate solution followed by with water,
iv) adding acetone to the obtained filtrate,
v) distilling off the reaction mixture,
vi) adding cyclohexane and methanol to the obtained compound,
vii) heating the reaction mixture 55-60°C,
viii) cooling the reaction mixture,
ix) filtering the reaction mixture and drying the material to provide pure compound of
formula-1.
The third aspect of the present invention provides a process for the preparation of 4-{3-[4-cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo-2-sulfanylideneimidazolidin-l-yl}-2-fluoro-N-methylbenzamide compound of formula-1, comprising of
a) Reacting 4-(2-cyanopropane-2-ylamine)-2-fluoro-N-methylbenzamide compound of formula-5 with lot-wise addition of 4-isothiocyanato-2-trifluoromethyl)benzonitrile compound of formula-7 in a suitable solvent selected from polar-aprotic solvents and ester solvents or their mixture and heating to form a reaction mixture,
b) adding a suitable solvent selected from ketone solvents and polar solvents or their mixtures and a suitable acid to the reaction mixture,
c) heating the reaction mixture,
d) stirring the reaction mixture,
e) cooling the reaction mixture,
f) extracting the organic layer by using a suitable organic solvent,
g) distilling off the solvent completely from the organic layer,
h) adding a suitable solvent/mixture of solvents to the obtained compound,
i) heating the reaction mixture,
j) cooling the reaction mixture,
k) filtering the reaction mixture and drying the material to provide pure compound of
formula-1.
Wherein, the suitable solvents and suitable acid used are same as defined in step-d) of the first aspect of the present invention.
The preferred embodiment of the present invention provides a process for the preparation of 4-{3-[4-cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo-2-sulfanylidene imidazolidin-l-yl}-2-fluoro-N-methylbenzamide compound of formula-1, comprising of
a) Reacting 4-(2-cyanopropane-2-ylamine)-2-fluoro-N-methylbenzamide compound of j
formula-5 with lot-wise addition of 4-isothiocyanato-2-trifluoromethyl)benzonitrile ;
compound of formula-7 in dimethylsulfoxide and isopropyl acetate and heating to
form a reaction mixture,
b) adding acetone, water and conc.HCl to the reaction mixture,
c) heating the reaction mixture to 70-75°C,
d) stirring the reaction mixture,
e) cooling the reaction mixture,
f) extracting the organic layer by using dichloromethane,
g) distilling off the solvent completely from the organic layer,
h) adding cyclohexane and methanol to the obtained compound,
i) heating the reaction mixture to 55-60°C,
j) cooling the reaction mixture to 25-30°C,
k) filtering the obtained compound and drying to provide pure compound of formula-1.

The fourth aspect of the present invention provides a process for the purification of crystalline Form-A of 4-{3-[4-cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo-2-sulfanylideneimidazolidin-1 -yl} -2-fluoro-N-methylbenzamide compound pf formula-1, comprising of:
a) Dissolving the compound of formula-1 in a suitable solvent or mixture of solvents,
b) heating the reaction mixture,
c) stirring the reaction mixture,
d) treating the reaction mixture with charcoal,
e) adding a suitable solvent to the reaction mixture at a suitable temperature,
f) cooling the reaction mixture,
g) stirring the reaction mixture, h) filtering the reaction mixture,
i) optionally, slurrying the obtained solid from a suitable solvent to get pure crystalline Form-A of compound of formula-1.
Wherein, the suitable solvent used is same as defined in step-e) of the first aspect of the present invention.
The preferred embodiment of the present invention provides a process for the purification of crystalline Form-A of 4-{3-[4-cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo-2-sulfanylideneimidazolidin-l-yl}-2-fluoro-N-methylbenzamide compound of formula-1, comprising of:
a) Dissolving the compound of formula-1 in a mixture of isopropyl alcohol, isopropyl acetate and dimethylsulfoxide,
b) heating the reaction mixture to 55-60°C,
c) stirring the reaction mixture,
d) treating the reaction mixture with charcoal,
e) adding acetone to the reaction mixture at 45-50°C,
f) cooling the reaction mixture to 0-5 °C,
g) stirring the reaction mixture,
h) filtering the reaction mixture, r

i) slurrying the obtained solid from cyclohexane and methanol to get pure crystalline Form-A of compound of formula-1.
The crystalline Form-A of 4-{3-[4-cyano-3-(trifluoromethyl)phenyl]-535-dimethyl-4-oxo-2-sulfanylideneimidazolidin-l-yl}-2-fluoro-N-methylbenzamide compound of formula-1 is useful in the preparation of pharmaceutical composition.
HPLC Method of Analysis:
4-{3-[4-cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo-2-sulfanylidene imidazoIidin-l-yI}-2-fluoro-N-methylbenzamide:
Apparatus: A liquid chromatographic system is to be equipped with variable wavelength UV-detector; Column: Symmetry shield RP18, 250 x 4.6 mm, 5 \im (or) equivalent; Flow rate: 1.0 ml/min; Wavelength: 210 nm; Column Temperature: 25°C; Injection volume: 10 JIL; Run time: 48 mins; Diluent: Acetonitrile; Needle wash: Diluent; Elution: Gradient; Mobile phase-A: Buffer (100%); Mobile phase-B: Acetonitrile : Water (95 : 5) v/v. Transfer accurately 1.5 mL of Perchloric acid into a lOOOmL of Milli-Q water and filter this solution through 0.45 ^m nylon membrane filter paper,
PXRD analysis of the 4-{3-[4-cyano-3-(trifluoromethyl)phenyl]-535-dimethyl-4-oxo-2-sulfanylideneimidazolidin-l-yl}-2-fluoro-N-methylbenzamide compound of formula-1 of the present invention was carried out by using BRUKER/AXS X-Ray diffractometer using Cu Ka radiation of wavelength 1.5406 A° and at continuous scan speed of 0.03°/min.
Differential scanning calorimetric (DSC) analysis of the 4-{3-[4-cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo-2-sulfanylideneimidazolidin-l-yl}-2-fluoro-N-methylbenzamide compound of formula-1 of the present invention was performed with TA Instruments. Samples of about 2 to 3 milligrams were analyzed.
The 4-{3-[4-cyano-3-(trifluoromethyl)phenyl]-5J5-dimethyl-4-oxo-2-sulfanylidene imidazolidin-l-yl}-2-fluoro-N-methylbenzamide compound of formula-1 which is obtained by the present invention can be further micronized or milled to get the desired particle size to achieve desired solubility profile based on different forms of pharmaceutical composition requirements. Techniques that may be used for particle size reduction include, but not limited

to ball, roller and hammer mills, and jet mills. Milling or micronization may be performed before drying, or after the completion of drying of the product.
The present invention is schematically represented as below:

The process described in the present invention was demonstrated in examples illustrated below. These examples are provided as illustration only and therefore should not be construed as limitation of the scope of the invention.
Examples:
Example-1: Preparation of 2-fluoro-N-methyl-4-nitrobenzamide (FormuIa-3)
Thionyl chloride (57-9 gm) was added to a mixture of 2-fluoro-4-nitrobenzoic acid compound of formula-2 (50 gm), toluene (200 ml) and N,N-dimethylformamide (1 ml) at 25-30°C and stirred for 45 minutes at the same temperature. Heated the reaction mixture to 75-80°C and stirred for 5 hrs at the same temperature. Distilled off the solvent from the reaction mixture under reduced pressure. Cooled the reaction mixture to 25-30°C. The above obtained reaction mixture was slowly added to methyl amine solution (100 ml) at 2-3°C and stirred for 3 hrs at the same temperature. Water was added to the reaction mixture. Raised the temperature of the reaction mixture to 25-30°C and stirred for 60 minutes at the same temperature. The solid formed was filtered, washed with water and dried to get the title compound. Yield: 50 gm. MR: 150-155°C; Purity by HPLC: 99.74%.
Example-2: Preparation of 4-amino-2-fluoro-N-methyIbenzamide (Formula-4)
A mixture of 2-fluoro-N-methyl-4-nitrobenzamide compound of formula-3 (50 gm), water (250 ml) and ethyl acetate (500 ml) was stirred for 15 minutes. Iron powder (49 gm) was added to the reaction mixture. Heated the reaction mixture to 55-60°C. Acetic acid (71 ml) was slowly added to the reaction mixture at 55-60°C and stirred for 60 minutes at the same temperature. Heated the temperature of the reaction mixture to 70-75°C and stirred for 3 hrs at the same temperature. Cooled the reaction mixture to 25-30°C and stirred for 20 minutes at the same temperature. Filtered the reaction mixture and washed with water and ethyl acetate. Both the organic and aqueous layers from the filtrate were separated. The aqueous layer was extracted with ethyl acetate. Combined the organic layers and washed with aqueous sodium bicarbonate solution. Distilled off the solvent completely from the organic layer under reduced pressure. Cyclohexane was added to the reaction mixture and

distilled off the solvent completely under reduced pressure. Cyclohexane was added to the reaction mixture. Cooled the reaction mixture to 25-30°C and stirred for 60 minutes at the same temperature. The solid formed was filtered, washed with cyclohexane and dried to get the title compound. Yield: 32 gm; MR: 150-155°C.
Example-3: Preparation of 4-(2-cyanopropane-2-ylamine)-2-fluoro-N-methylbenzamide (Formula-5)
Sodium cyanide (51 gm) was added to a mixture of 4-amino-2-fluoro-Nr methylbenzamide compound of formula-4 (50 gm) and acetone (100 ml). Acetic acid (188 ml) was slowly added to the reaction mixture at 25-30°C and stirred for 20 hrs at the same temperature. Water (500 ml) was added to the reaction mixture at 25-30°C and stirred for 15 minutes at the same temperature. The solid formed was filtered and washed with water and cyclohexane. Water (250 ml) was added to the obtained wet compound and stirred for 15 minutes at 25-30°C. Filtered the solid, washed with water and dried to get the title compound. Yield: 50 gm; MR: 160-165°C; Purity by HPLC: 99.50%.
ExampIe-4: Preparation of 4-isothiocyanato-2-trifluoromethyI)benzonitrile (Formula-7)
4-Amino-2-(trifluoromethyl)benzonitrile compound of formula-6 (50 gm) was added to a mixture of water (250 ml) and thiophosgene (41 ml) at 25-30°C and stirred for 3 hrs at the same temperature. Dichloromethane (250 ml) was added to the reaction mixture. Both the organic and aqueous layers were separated. The aqueous layer was extracted with dichloromethane. Combined the organic layers and washed with water. Distilled off the solvent completely from the organic layer and co-distilled with n-heptane. n-Heptane was added to the reaction mixture. Cooled the reaction mixture to 25-30°C and stirred for 1.3 hrs at the same temperature. Filtered the solid, washed with n-heptane and dried to get the title compound. Yield: 55 gm; MR: 40-45°C; Purity by HPLC: 99.86%.

Example-5: Preparation of 4-{3-[4-cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-0XQ-2-suIfanylideneimidazolidin-l-yl}-2-fluoro-N-methylbenzamide (Formula-1)
4-(2-cyanopropane-2-ylamine)-2-fluoro-N-methylbenzamide compound of formula-5 (50 gm) was added to a mixture of dimethyl sulfoxide (50 ml) and isopropyl acetate (100 ml). Added first lot of 4-isothiocyanato-2-trifluoromethyl)benzonitrile compound pf formula-7 (26.75 gm) to the reaction mixture. Heated the reaction mixture to 60-65°C and stirred for 7 hrs at the same temperature. Cooled the reaction mixture to 25-30°C. Added second lot of 4-isothiocyanato-2-trifluoromethyl)benzonitrile compound of formula-7 (26.75 gm) to the reaction mixture. Heated the reaction mixture to 60-65 °C and stirred for 7 hrs at the same temperature. Cooled the reaction mixture to 25-30°C. Added third lot of 4-isothiocyanatQ-2-trifluoromethyl)benzonitrile compound of formula-7 (26.75 gm) to the reaction mixture. Heated the reaction mixture to 60-65°C and stirred for 7 hrs at the same temperature. Added fourth lot of 4-isothiocyanato-2-trifluoromethyl)benzonitrile compound of formula-7 (26.75 gm) to the reaction mixture. Heated the reaction mixture to 60-65°C and stirred for 18 hrs at the same temperature. Cooled the reaction mixture to 25-30°C. Water (500 ml), conc.HCl (50 ml) and methanol (500 ml) were added to the reaction mixture. Heated the reaction mixture to 70-75°C and stirred for 6 hrs at the same temperature. Cooled the reaction mixture to 25-30°C. Dimethylsulfoxide (50 ml) was added to the reaction mixture at 25-30°C and stirred for 60 minutes at the same temperature. Filtered the reaction mixture and washed with cyclohexane. Dichloromethane (200 ml) was added to the above obtained reaction mixture and stirred for 20 minutes. Filtered the reaction mixture through high flow bed and washed with dichloromethane. The filtrate was washed with sodium bicarbonate solution followed by water. Acetone (50 ml) was added to the reaction mixture. Distilled off the solvent completely from the organic layer and co-distilled with cyclohexane. Cooled the reaction mixture to 25-30°C. Cyclohexane and methanol were added to the reaction mixture. Heated the reaction mixture to 55-60°C and stirred for 30 minutes at the same temperature. Cooled the reaction mixture to 25-30°C and stirred for 2 hrs at the same temperature. The solid formed was filtered, washed with cyclohexane and dried to get the title compound. Yield: 58 gm; MR: 200-201°C; Purity by HPLC: 99.49%. The P-XRD pattern of the obtained compound is depicted in figure-1.

The DSC thermogram of the obtained compound is depicted in figure-2.
Example-6: Preparation of 4-{3-[4-cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo-2-sulfanylideneimidazoIidin-l-yl}-2-fluoro-N-methyIbenzamide (Formula-l)
4-(2-cyanopropane-2-ylamine)-2-fluoro-N-methylbenzamide compound of formula-5 (2 gm) was added to a mixture of dimethyl sulfoxide (2 ml) and isopropyl acetate (4 ml). Added first lot of 4-isothiocyanato-2-trifluoromethyl)benzonitrile compound of formula-7 (1 gm) to the reaction mixture. Heated the reaction mixture to 60-65 °C and stirred for 1 hrs at the same temperature. Cooled the reaction mixture to 25-30°C. Added second lot of 4-isothiocyanato-2-trifluoromethyl)benzonitrile compound of formula-7 (1 gm) to the reaction mixture. Heated the reaction mixture to 60-65 °C and stirred for 7 hrs at the same temperature. Cooled the reaction mixture to 25-30°C. Added third lot of 4-isothiocyanato-2-trifluoromethyl)benzonitrile compound of formula-7 (1 gm) to the reaction mixture. Heated the reaction mixture to 60-65°C and stirred for 7 hrs at the same temperature. Added fourth lot of 4-isothiocyanato-2-trifluoromethyl)benzonitrile compound of formula-7 (1 gm) to the reaction mixture. Heated the reaction mixture to 60-65°C and stirred for 18 hrs at the same temperature. Cooled the reaction mixture to 25-30°C. Water (20 ml), conc.HCl (2 ml) and acetone (6 ml) were added to the reaction mixture. Heated the reaction mixture to 70-75°C and stirred for 6 hrs at the same temperature. Cooled the reaction mixture to 25-30°C. Dichloromethane (20 ml) was added to the above reaction mixture and stirred for 10 minutes. Separated both the organic and aqueous layers and washed the organic layer with sodium bicarbonate solution followed by water. Distilled off the solvent completely from the organic layer and co-distilled with cyclohexane. Cooled the reaction mixture to 25-30°C. Cyclohexane and methanol were added to the obtained compound at 25-30°C. Heated the reaction mixture to 55-60°C and stirred for 30 minutes at the same temperature. Cooled the reaction mixture to 25-30°C and stirred for 2 hrs at the same temperature. The solid formed was filtered, washed with cyclohexane and dried to:get the title compound. Yield: 1.5 gm; MR: 200-201°C; Purity by HPLC: 90.72 %. The P-XRD pattern of the obtained compound is depicted in figure-1. The DSC thermogram of the obtained compound is depicted in figure-2.

Example-7: Purification of crystalline Form-A of 4-{3-[4-cyano-3-(trifluoromethyl) phenyl]-5,5-dimethyl-4-oxo-2-suIfanyIideneimidazolidin-l-yl}-2-fluoro-N-methyl benzamide (Formula-l)
4-{3-[4-cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo-2-sulfanylidene imidazolidin-l-yl}-2-fluoro-N-methylbenzamide compound of formula-l (50 gm) was added, to a mixture of isopropyl alcohol (100 ml), isopropyl acetate (100 ml) and dimethyl sulfoxide (25 ml). Heated the reaction mixture to 55-60°C and stirred for 30 minutes at the same temperature. Carbon (5 gm) was added to the reaction mixture and stirred for 20 minutes at 55-60°C. Filtered the reaction mixture through high flow and washed with isopropyl alcohol. Acetone (25 ml) was added to the filtrate at 45-50°C. Cooled the reaction mixture to 0-5°C and stirred for 2 hrs at the same temperature. Filtered the reaction mixture and washed with isopropyl alcohol. The above obtained solid was added to a mixture of cyclohexane (500 ml) and methanol (25 ml). Heated the reaction mixture to 55-60°C and stirred for 30 minutes at the same temperature. Cooled the reaction mixture to 25-30°C. The solid formed was filtered, washed with cyclohexane and dried to get the title compound. The P-XRD pattern of the obtained compound is depicted in figure-1.
Yield: 37 gm; MR: 200-201°C; Purity by HPLC: 99.89%. Amine amide impurity: Not detected; Trifluoromethyl impurity: Not detected; Dioxoimidazolidine impurity: 0.02%; Desfluoro impurity: Not detected.
Particle size distribution before micronization: Dio ' 3.34 (am; D50: 24.4 jam; D90: 72.4 jam; and D[4,3]: 32.1 urn.
Particle size distribution after micronization: Dio : 0.910 (am; D50: 3.38 jam; D90: 6.67 jam; and D[4,3]: 3.59 nm.

We Claim:
1. A process for the preparation of 4-{3-[4-cyanp-3-(trifluoromethyl)phenyl]-5,5-dimethyl-
4-oxo-2-sulfanylideneimidazolidin-1 -yl} -2-fluoro-N-methylbenzamide compound of
formula-1, comprising of:
a) Reacting 2-fluoro-4-nitrobenzoic acid compound of formula-2 with thionyl chloride in a suitable solvent or mixture of solvents followed by treatment with methyl amine solution to provide 2-fluoro-N-methyl-4-nitrobenzamide compound of formula-3,
b) treating compound of formula-3 with iron powder in a suitable solvent or mixture of solvents in presence of acetic acid to provide 4-amino-2-fluoro-N-methylbenzamide compound of formula-4, which is optionally purifying from a suitable solvent to provide high pure 4-amino-2-fluoro-N-methylbenzamide compound of formula-4,
c) treating compound of formula-4 with sodium cyanide in a suitable solvent followed by treatment with acetic acid to provide 4-(2-cyanopropane-2-ylamine)-2-fluoro-N-methylbenzamide compound of formula-5, which is optionally purifying using a suitable solvent and followed by slurring in a suitable solvent to provide pure 4-(2-cyanopropane-2-ylamine)-2-fluoro-N-methylbenzamide compound of formula-5,
d) reacting compound of formula-5 with 4-isothiocyanato-2-trifluoromethyl)benzonitrile compound of formula-7 in a suitable solvent or mixture of solvents followed by treatment with a suitable acid in a suitable solvent or mixture of solvents to provide 4-{3-[4-cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo-2-sulfanylidene imidazolidin-1-yl}-2-fluoro-N-methylbenzamide compound of formula-1,
e) optionally, purifying the compound of formula-1 with a suitable solvent or mixture of solvents to provide high pure 4-{3-[4-cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo-2-sulfanylideneimidazolidin-1 -yl} -2-fluoro-N-methylbenzamide compound of formula-1.
2. The process according to claim-1, wherein,
in step-a) the suitable solvent is selected from hydrocarbon solvents and polar aprotic
solvents or mixtures thereof; in step-b) and c) the suitable solvent is selected from ester solvents, hydrocarbon solvents,
ketone solvents and polar solvents or mixtures thereof;

in step-d) the suitable solvent is selected from ester solvents, polar aprotic solvents,
ether solvents, chloro solvents, hydrocarbon solvents, ketone solvents, alcohol solvents and polar solvents or mixture thereof; and the suitable acid is selected from inorganic acid or organic acid;
in step-e) the suitable solvent is selected from ester, solvents, ether solvents, chloro solvents, hydrocarbon solvents, ketone solvents, polar aprotic solvents, alcohol solvents and polar solvents or mixture thereof;
3. A process for the preparation of 4-{3-[4-cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo-2-sulfanylideneimidazolidin-l-yl}-2-fluoro-N-methylbenzamide compound of formula-1, comprising of:
a) Reacting 2-fluoro-4-nitrobenzoic acid compound of formula-2 with thionyl chloride in toluene and dimethylformamide followed by treatment with methyl amine solution provides 2-fluoro-N-methyl-4-nitrobenzamide compound of formula-3,
b) treating compound of formula-3 with iron powder in ethyl acetate and water in presence of acetic acid to provide 4-amino-2-fluoro-N-methylbenzamide compound of formula-4, further purifying the obtained compound using cyclohexane to provide high pure 4-amino-2-fluoro-N-methylbenzamide compound of formula-4,
c) treating compound of formula-4 with sodium cyanide in acetone followed by treatment with acetic acid to provide 4-(2-cyanopropane-2-ylamine)-2-fluoro-N-methylbenzamide compound of formula-5, further purifying the obtained compound using cyclohexane and followed by slurring in water to provide high pure 4-(2-cyanopropane-2-ylamine)-2-fluoro-N-methylbenzamide compound of formula-5,
d) reacting compound of formula-5 with 4-isothiocyanato-2-trifluoromethyl)benzonitrile compound of formula-7 in dimethylsulfoxide and isopropyl acetate followed by treatment with conc.HCl in water and methanol, further purifying the obtained compound using dimethyl sulfoxide, dichloromethane, acetone and isolating the compound using cyclohexane and methanol to provide 4-{3-[4-cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo-2-sulfanylidene imidazolidin-l-yl}-2-fluoro-N-methylbenzamide compound of formula-1,

e) purifying the compound of formula-1 with a mixture of isopropyl alcohol, isopropyl acetate and dimethylsulfoxide followed by slurring in cyclohexane and methanol to provide high pure 4-{3-[4-cyano-3-(trifluoromethyl)phenyl]-535-dimethyl-4-oxo-2-sulfanylidene imidazolidin-1 -yl} -2-fluoro-N-methylbenzamide compound of formula-1.
4. An improved process for the preparation of 4-{3-[4-cyano-3-(trifluoromethyl)phenyl]-
5,5-dimethyl-4-oxo-2-sulfanylideneimidazolidin-l-yl}-2-fluoro-N-methylbenzamide
compound of formula-1, comprising of
a) Reacting 4-(2-cyanopropane-2-ylamine)-2-fluoro-N-methylbenzamide compound of formula-5 with lot-wise addition of 4-isothiocyanato-2-trifluoromethyl)benzonitrile compound of formula-7 in a suitable solvent selected from polar-aprotic solvents and ester solvents or their mixture and heating to form a reaction mixture,
b) adding a suitable solvent selected from alcohol solvents and polar solvents or their mixtures and a suitable acid to the reaction mixture,
c) heating the reaction mixture,
d) stirring the reaction mixture,
e) cooling the reaction mixture,
f) adding a suitable polar aprotic solvent to the obtained reaction mixture and stirring the reaction mixture at a suitable temperature,
g) filtering the reaction mixture to provide crude compound of formula-1,
h) purifying the solid obtained in step-g) to provide pure compound of formula-1.
5. The process according to claim-4, wherein in step-(h), the purification of compound of
formula-1, comprising of:
i) Dissolving the crude compound of formula-1 in a suitable first solvent,
ii) optionally, filtering the reaction mixture,
iii) washing the filtrate with a suitable aqueous base solution followed by with water,
iv) adding a suitable second solvent,
v) distilling off the reaction mixture, v
vi) adding a suitable third solvent/mixture of solvents to the obtained compound,

vii) heating the reaction mixture, viii) cooling the reaction mixture,
ix) filtering the reaction mixture and drying the material to provide pure compound of formula-1.
6. An improved process for the preparation of 4-{3-[4-cyano-3-(trifluoromethyl)phenyl]-
5,5-dimethyl-4-oxo-2-sulfanylideneimidazolidin-l-yl}-2-fluoro-N-methylbenzamide
compound of formula-!, comprising of
a) Reacting 4-(2-cyanopropane-2-ylamine)-2-fluoro-N-methylbenzamide compound of formula-5 with lot-wise addition of 4-isothiocyanato-2-trifluoromethyl)benzonitrile compound of formula-7 in dimethylsulfoxide and isopropyl acetate and heating to form a reaction mixture,
b) adding methanol, water and conc.HCl to the reaction mixture,
c) heating the reaction mixture to 70-75 °C,
d) stirring the reaction mixture,
e) cooling the reaction mixture,-
f) adding dimethylsulfoxide to the obtained reaction mixture and stirring the reaction mixture at 25r30°C,
g) filtering the reaction mixture to provide crude compound of formula-1,
h) purifying the solid obtained in step-g) using cyclohexane and methanol to provide pure compound of formula-1.
7. The process according to claim-6, wherein in step-(h), the purification of compound of
formula-1, comprising of:
i) Dissolving the crude compound of formula-1 in dichloromethane,
ii) filtering the reaction mixture,
iii) washing the filtrate with sodium bicarbonate solution followed by with water,
iv) adding acetone to the obtained filtrate,
v) distilling off the reaction mixture,
vi) adding cyclohexane and methanol to the obtained compound,
vii) heating the reaction mixture 55-60°C,

viii) cooling the reaction mixture,
ix) filtering the reaction mixture and drying the material to provide pure compound of formula-1.
8. A process for the preparation of 4-{3-[4-cyano-3-(trifluorpmethyl)phenyl]-5,5-dimethyl-
4-oxo-2-sulfanylideneimidazolidin-l-yl}-2-fluoro-N-methylbenzamide compound of
formula-1, comprising of
a) Reacting 4-(2-cyanopropane-2-ylamine)-2-fluoro-N-methylbenzamide compound of formula-5 with lot-wise addition of 4-isothiocyanato-2-trifluoromethyl)benzonitrile compound of formula-7 in a suitable solvent selected from polar-aprotic solvents and ester solvents or their mixture and heating to form a reaction mixture,
b) adding a suitable solvent selected from ketone solvents and polar solvents or their mixtures and a suitable acid to the reaction mixture,
c) heating the reaction mixture,
d) stirring the reaction mixture,
e) cooling the reaction mixture,
f) extracting the organic layer by using a suitable organic solvent,
g) distilling off the solvent completely from the organic layer,
h) adding a suitable solvent/mixture of solvents to the obtained compound, i) heating the reaction mixture, j) cooling the reaction mixture,
k) filtering the reaction mixture and drying the material to provide pure compound of formula-1.
9. A process for the preparation of 4-{3-[4-cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-
4-oxo-2-sulfanylidene imidazolidin-l-yl}-2-fluoro-N-methylbenzamide compound of
formula-1, comprising of
a) Reacting 4-(2-cyanopropane-2-ylamine)-2-fluoro-N-methylbenzamide compound of formula-5 with lot-wise addition of 4-isothiocyanato-2-trifluoromethyl)benzonitrile compound of formula-7 in dimethylsulfoxide and isopropyl acetate and heating to form a reaction mixture.

b) adding acetone, water and conc.HCl to the reaction mixture,
c) heating the reaction mixture to 70-75°C,
d) stirring the reaction mixture,
e) cooling the reaction mixture,
f) extracting the organic layer by using dichloromethane,
g) distilling off the solvent completely from the organic layer,
h) adding cyclohexane and methanol to the obtained compound,
i) heating the reaction mixture to 55-60°C,
j) cooling the reaction mixture to 25-30°C,
k) filtering the obtained compound and drying to provide pure compound of formula-1.
10. A process for the purification of 4-{3-[4-cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo-2-sulfanylideneimidazolidin-l-yl}-2-fluoro-N-methylbenzamide compound of formula-1, comprising of:
a) Dissolving the compound of formula-1 in a mixture of isopropyl alcohol, isopropyl acetate and dimethylsulfoxide,
b) heating the reaction mixture to 55-60°C,
c) stirring the reaction mixture,
d) treating the reaction mixture with charcoal,
e) adding acetone to the reaction mixture at 45-50°C,
f) cooling the reaction mixture to 0-5°C,
g) stirring the reaction mixture,
h) filtering the reaction mixture,
i) slurrying the obtained solid from cyclohexane and methanol to get pure compound of formula-1.