AN IMPROVED PROCESS FOR THE PREPARATION OF 2-(3-FLUORO-4-(METHYL-CARBAMOYL) PHENYL-AMINO)-2-METHYL-PROPIONIC ACID ETHYL ESTER

FIELD OF THE INVENTION

The present invention relates to an improved process for the preparation of 2-(3-fluoro-4-(methyl-carbamoyl) phenyl-amino)-2-methyl-propionic acid ethyl ester of formula I (an intermediate of Enzalutamide).

BACKGROUND OF THE INVENTION

Enzalutamide is chemically known as 4-{3-[4-cyano-3-(trifluoromethyI)phenyI]-515-dimethyl-4-oxo-2-sulfanyIideneimidazoIidin-I-yl}-2-fluoro-N-methylbenzamide. Enzalutamide is an androgen receptor inhibitor. Enzalutamide is indicated for the treatment of patients with metastatic castration-resistant -prostate cancer and it is marketed as under the brand name Xtandi®. 2-(3-Fluoro-4-(methyl-carbamoyl) phenyl-amino)-2-methyl-propionic acid ethyl ester of formula I is used as an intermediate in the preparation of Enzalutamide.

Enzalutamide first disclosed in US 7709517.

US '517 also disclosed a process for the preparation of Enzalutamide as follows in scheme-I:

Chinese, patent CN 103910679 A discloses a process for the preparation of Enzalutamide as follows in schenie-II

The reaction step (a), the substitution reaction temperature is 100-150°C, preferably at 120-130°C, the reaction time is 8-24 hours.

The major disadvantage associate with the above prior art process is that it is very time consuming- process and the use of acid binding agents like organic and inorganic bases alone leads to very lower yield.

SUMMARY OF THE INVENTION

In one aspect of the present invention provides an improved process for preparation of 2-(3-fluoro-4-(methyl-carbamoyl)phenyl-amino)-2-methyl-propionic acid ethyl ester (I),comprising the steps of;

a) 2-fluoro-4-nitrobenzoic acid (III) is reacted with methanol in presence of acid to produce methyl 2-fluoro-4-nitrobenzoate of formula (X).

b) methyl 2-fluoro-4-nitrobenzoate of (X) is reduced with a reducing agent to produce methyl 2-fluoro-4-amino benzoate (XI), .

c) methyl 2-fluoro-4-amino benzoate (XI) is condensed with ethyl 2-bromo-2-methylpropanoate in presence of a base and quaternary ammonium salt to produce 4-(l-ethoxycarbonyl-l-methyl-ethylamino)-2-fluoro benzoic acid methyl ester of formula (XII)

d) the compound of formula (XII) is reacted with aqueous methylamine in presence of methanol to produce 2-(3-fluoro-4-(methy]-carbamoy)) phenyl-amino)-2-methyl-propionic acid ethyl ester of formula (I). 'in another aspect tVie present 'invention provides an improved "pn^ess iurlVie -prepanfiiun xfi U- ethoxycarbonyI-l-methyl-ethylamino)-2-fluoro benzoic acid methyl ester of formula (XII) of formula (XII) comprising: the condensation of methyl 2-fluofo-4-amino benzoate (XI) with ethyl 2-bromo-2-methylpropanoate in presence of a base and quaternary ammonium salt to produce the compound of formula (XII)

The process is as follows shown below:

In another aspect the present invention provides an improved process for the preparation of 2-(3-fluoro-4-(methyl-carbamoyl)phenyl-amino)-2-methyl-propioiiic acid ethyl ester of formula (I) comprising: the amination of 4-(l-ethoxycarbonyl-l-methy|-ethylamino)-2-fluoro benzoic acid methyl ester of formula (XII) with methylamine in presence of methanol to produce 2-(3-fluoro-4-(methyl-carbamoyl)phenyl-amino)-2-methyl-propionic acid ethyl ester of formula (I)

The process is as follows shown below:

In yet another aspect of the present invention provides the use of 2-(3-fluoro-4-(methyl-carbamoyl) phenyl-amino)-2-methyl-propionic acid ethyl ester of formula I prepared by the present invention is used in the preparation of Enzalutamide.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides an improved process for the preparation, of 2-(3-fluoro-4-(methyl-carbamoyl)phenyl-amino)-2-methyl-propionic acid ethyl ester of formula (I), which is key raw material used for the preparation of Enzalutamide.

One main embodiment of the present invention relates to an improved process for the preparation of 2-(3-fluoro-4-(rnethyl-carbamoyl) phenyl-amino)-2-methyl-propionic acid ethyl ester of formula (I), comprising steps of:

a) 2-fluoro-4-nitrobenzoic acid (III) is reacted with methanol in presence of an acid to produce methyl 2-fluoro-4-nitrobenzoate of formula (X),

b) methyl 2-fluoro-4-nitrobenzoate of (X) is reduced with a reducing agent to produce methyl 2-fIuoro-4-amino benzoate (XI),

c) methyl 2-fluoro-4-amino benzoate (XI) is condensed with ethyl 2-bromo-2-methylpropanoate in presence of a base and quaternary ammonium salt to produce 4-(l-ethoxycarbonyl-l-methyl-ethylamino)-2-fluoro benzoic acid methyl ester of formula (XII).

d) the compound of formula (XII) is reacted with aqueous methylamine in presence of methanol to produce 2-(3-fluoro-4-(methyl-carbamoyl) phenyl-amino)-2-methyl-propionic acid ethyl ester of formula (I).

According to the embodiment of the present invention, an acid is selected from the group comprising of p-toluene sulfonic acid, sulfuric acid or hydrochloric acid preferably p-toluene sulfonic acid; the reducing agent is selected from the group comprising of Palladium on carbon or Raney Nickel are under hydrogen pressure, preferably palladium; the base is selected from the group comprising of organic or inorganic bases wherein, the inorganic bases are selected form the group of alkali metal hydroxides such as NaOH, K.OH; alkali metal carbonates like sodum carbonate, potassium carbonate, lithium carbonate, sodium acetate, potassium acetate; the. organic base is selected from the group of pyridine, piperidine, aniline, mono methyl amine, dimethyl amine, trimethyl amine, diisopropyl ethyl amine; the aminating reagent is mono methyl amine, dimethyl amine, preferably mono methyl amine; the quaternary ammonium salt is selected from the group comprising of benzyftrimethylammonium chloride, benzyltrimethylammonium chloride, benzyltrimethylammonium bromide, n- octyltrimethylammonium bromide, stearyltrimethylammonium bromide, cetyldimethylammonium bromide, tetra butyl ammonium iodide, tetra butyl ammonium bromide, p-methylcholinium iodide, tetra butyl ammonium hydrogensulfate, phenyltrimethylammonium hydoxide, etc, preferably trimethyl benzyl ammonium chloride and triethyl benzyl ammonium hydrogen sulphate; A solvent is selected from the group comprising of methyl acetate, ethyl acetate, ethyl butyrate, ethyl hexanoate, isobutyl acetate, isobutyl butyrate, preferably ethyl acetate, methyl isobutyl ketone, methyl ketone, acetone.

According to the embodiment is step-a), the 2-fluoro-4-nitrobenzoic acid (III) is reacted with methanol in presence of p-tolunesulfonic acid stirring for 6-8 hours at reflux temperature to produce reaction mass, further cooled the reaction mass 0-5°C to produce methyl 2-fluoro-4-nitrobenzoate (X).

In step-b) methyl 2-fluoro-4-nitrobenzoate (X), in methanol solvent is reduced with reducing agent under hydrogen pressure to produce methyl 2-fluoro-4-amino benzoate (XI),

In step-c) methyl 2-fluoro-4-amino benzoate (XI) is condensed with ethyl l,2-bromo-2-methylpropanoate in presence of base and quaternary ammonium salt to produce 4-(l-ethoxycarbohyl-l-methyl-ethylamino)-2-fluoro benzoic acid methyl ester of formula (XII).
In step-d) 4-(l-ethoxycarbonyI-l-methyl-ethylamino)-2-fluoro benzoic acid methyl ester of formula (XII) is reacted with methyl amine in presence of methanol to produce 2-(3-fluoro-4-(methyl-carbamoyl) phenyl-amino)-2-methyl-propionic acid ethyl ester of formula (I).

In another embodiment of the present invention provides an improved process for the preparation of 4-(l-ethoxycarbonyl-I-methyl-ethyIamino)-2-fIuoro benzoic acid methyl ester of formula (XII) by reacting of methyl 2-fluoro-4-amino benzoate (XI) in presence of sodium carbonate and trimethyl benzyl ammonium chloride stirring for 12 hours at I35-150°C.

The above condensation reaction in presence of base and quaternary ammonium salt catalyst is carried out to reduce the reaction time periods to achieve the desired'product with" more yield and purity.

After the completion of reaction, the product may be isolated by filtration followed by washing with water (or) any organic solvent from the reaction may be removed using any suitable methods such as evaporation, atmospheric distillation or distillation under vacuum.

The following examples illustrate the nature of the invention and are provided for illustrative purpose only and should not be construed to the limit the scope of the invention.

EXAMPLES

Example 1: Preparation of methyl-2-fluoro-4-nitro benzoate.

To a clean and dry four necked R B flask fitted with mechanical stirrer, thermo pocket and reflux condenser, charged methanol (200 ml) and 2-fluoro-4-nitro benzoic acid (100 gm, 0.54 moles) at ambient temperature. Stirred the reaction mass for 5-10 minutes andp-toluene sulphonic acid (50 gm, 0.29 moles) was charged. The reaction mass was heated to reflux temperature and maintained under stirring for 6-8 hours. The progress of reaction was monitored by TLC. After completion of reaction gradually cooled reaction mass 25-30°C and stirred at 25-30°C for 30 minutes. Further cooled reaction mass to 0-5°C and maintained 0-5°C for one hour. The solid was collected by filtration and washed with cold methanol to get desired product. Weight of the product: 90-95 gms.

Example 2: Preparation of methyI-2-fluoro-4-nitro benzoate.

To a clean and dry four necked R B flask fitted with mechanical stirrer, thermo pocket and reflux condenser, charged methanol (200 ml) and 2-fluoro-4-nitro benzoic acid (100 gm, 0.54 moles) at ambient temperature. Stirred the reaction mass for 5-10 minutes and sulfuric acid (25 ml) was charged. The reaction mass was heated to reflux temperature f»"d maintained under stirring for 6-8 hours. The progress of reaction was monitored by TLC. After completion of reaction gradually cooled ceacUoa ixiass 25-3G°C a.ad stitted at 15-1Q°C fat id minutes... Fujihfit cooled reaction mass to 0-5°C and maintained 0-5°C for one hour. The solid was collected by filtration and washed with cold methanol to get desired product.

Weight of the product: 90-95 gms.

Example 3: Preparation of methyl-2-fluoro-4-amino benzole.
To a clean and dried autoclave vessel charged methanol (1000 ml) and methyJ-2-fluoro-4-nitro benzoate (100 gm, 0.502 moles), Raney nickel (10 gm, already washed with water followed by methanol) was charged to autoclave and reaction mass w#s stirred under 5.0 kg hydrogen pressure till TLC shows absence of starting material. After completion of reaction, the hydrogen pressure was release and reaction mass was filtered to remove Raney nickel. The filtrate was charged to R B flask and methanol was distill out completely under reduced pressure below 50° C. Ethyl acetate (150 ml) was charged to the residue below 50° C and stirred reaction mass for 10-15 minutes. Gradually cool reaction mass 0-5°C and the slurry were maintained at 0-5° C for one hour. Filtered the solid and washed wet cake with 25 ml chilled ethyl acetate. Dried in.hot air oven at 65-70° C to get title compound.

Weight of the product: 70-80 gms.

Example 4: Preparation of methyl-2-fluoro-4-amino benzoate.

Methanol(1000 ml) and methyl-2-fluoro-4-nitro benzoate (100 gm, 0.502 moles) charged into a clean and dried autoclave vessel, charged 5% 10 gm Palladium on carbon (50% wet) to autoclave and reaction mass was stirred under 5.0 kg hydrogen pressure till TLC shows absence of starting material. After completion of reaction, the hydrogen pressure was release and reaction mass was filtered to remove Palladium. The filtrate was charged to R B flask and methanol was distill out completely under reduced pressure below 50° C. Ethyl acetate (150 ml) was added to the residue below 50° C and stirred for 10-15 minutes. Gradually cooled the reaction mass 0-5°C and the slurry were maintained at 0-5° C for one hour. Filtered the solid and washed with 25 ml chilled ethyl acetate. Dried in hot air oven at 65-70° C to get title compound.

Weight of the product: 70-80 gms.

Example 5: Preparation of 4-(l-ethoxycarbonyl-l-methyl-ethylamino)-2-fluoro benzoic acid methyl ester.

To a clean and dry four necked R B flask fitted with mechanical stirrer, thermo-pocket and reflux condenser, charged ethyl-2-bromo-isobutyrate (200 gm), methyl-2-fluoro-4-amino benzoate (50 gm), sodium carbonate (100 gm) and trimethyl benzyl ammonium chloride (10 gm) at ambient temperature. Reaction mass was heated to 135°-150° C and maintained under stirring at 135°-150° C for 12 hours. Reaction mass cooled to 80-90° C and slowly added 2nd lot of ethyl-2-bromo isobutyrate (50 gm). Temperature was raised to 135-150° C and maintained for 10-12 hours. After completion of reaction cooled the reaction mixture to 25-30° C. Charged purified water (100 ml), and dichloromethane (600 ml) and the product was extracted in dichloromethane. The dichloromethane layer was washed with purified water, stir for 10 min and settle for 20 minutes. Separate two layers take MDG layer in a flask wash the layer with purified water dichloromethane was distilled out completely under reduced pressure at below 50° C. Residue was cooled to 25-30° C ethyl acetate (150 ml) was charged and stirred for 30 min at 25-30° C. Reaction mass further cooled to 0-5° C and maintained at same temperature for one hour.

The solid was collected by filtration and washed with chilled ethyl acetate (25 ml) to get desired compound.

Weight of the product: 40-45 gms.

Example 6: Preparation of. 4-(l-ethoxycarbonyl-l-methyI-ethyIamino)-2-fluoro benzoic acid methyl ester.

To a clean and dry four necked R B flask fitted with mechanical stirrer, thermo-pocket and reflux condenser, charged ethyl-2-bromo-isobutyrate (200 gm), methyl-2-fluoro-4-amino benzoate (50 gm), sodium carbonate (100 gm) and triethyl benzyl ammonium, chloride (10 gm) at ambient temperature. Reaction mass was heated to 135°-150° C and maintained under stirring at 135°-150° C for 12 hours. Reaction mass cooled to 80-90° C and slowly added 2nd lot of ethyl-2-bromo isobutyrate (50 gm). Temperature was raised to 135-150° C and maintained for 10-12 hours. After completion of reaction cooled the reaction mixture to 25-30° C. Charged purified water (100 ml), and dichloromethane (600 ml) and the product was extracted in dichloromethane. The dichloromethane layer was washed with purified water, stir for 10 min and settle for 20 minutes. Separate two layers take MDC layer in a flask wash the layer with purified water dichloromethane was distilled out completely under reduced pressure at below 50° C. Residue was cooled to 25-30° C ethyl acetate (150 ml) was charged and stirred for 30 min at 25-.30° C. Reaction mass further cooled to 0-5° C and maintained at same temperature for one hour. The solid was collected by filtration and washed with chilled ethyl acetate (25 ml) to get desired compound.

Weight of the product: 40-45 gms.

Example 7: Preparation of 4-(l-ethoxycarbonyI-l-methyI-ethyIamino)-2-fluoro benzoic acid methyl ester.
To a clean and dry four necked R B flask fitted with mechanical stirrer, thermo-pocket and reflux condenser, charged ethyl-2-bromo-isobutyrate (200 gm), methyl-2-fluoro-4-amino benzoate (50 gm), sodium carbonate (100 gm) and trimethyl benzyl ammonium hydrogen sulphate (10 gm) at ambient temperature. Reaction mass was heated to 135°-150° C and maintained under stirring at 135°-150° C for 12 hours. Reaction mass cooled to 80-90° C and slowly added 2nd lot of ethyl-2-bromo isobutyrate (50 gm). Temperature was raised to 135-150° C and maintained for 10-12 hours. After completion of reaction cooled the reaction mixture to 25-30° C. Charged purified water (100 ml), and dichloromethane (600 ml) and the product was extracted in dichloromethane. The dichloromethane layer was washed with purified water, stir for 10 min and settle for 20 minutes. Separate two layers take MDC layer in a flask wash the layer with purified water dichloromethane was distilled out completely under reduced pressure at below 50° C. Residue was cooled to 25-30° C ethyl acetate (150 ml) was charged and stirred for 30 min at 25-30° C. Reaction mass further cooled to 0-5° C and maintained at same temperature for one hour. The solid was collected by filtration and washed with chilled ethyl acetate (25 ml) to get desired compound.

Weight of the product: 40-45 gms.

Examplc-8: Preparation of 4-(l-ethoxycarbonyl-l-methyl-ethylamino)-2-fluoro benzoic acid methyl ester

To a clean and dry four neck R B flask fitted with mechanical stirrer, thermo-pocket and reflux condenser, charged EthyI-2-bromo-isobutyrate (200 g), methyl 2-fluoro-4-amino benzoate (50 g), sodium carbonate (100 g ) and tetra butyl ammonium hydrogen sulphate (lOgm ) at ambient temperature. Reaction mass was heated to 135-150°C and maintained under stirring at 135-I50°C for 12 hours. Reaction mass cooled to 80-90° and slowly added 2nd lot of methyl-2-bromo isobutyrate (50gm). Temperature was raised to 135-150°C and maintained for 10-12hrs. After completion of reaction cooled the reaction mixtureto 25-30°C. Charged purified water (100 ml), and Dichloromethane (600ml) and the product was extracted in Dichloromethane. The Dichloromethane layer was washed with purified water, stir for lOmin and settle for 20min.separate two layers take MDC layer in a flask wash the layer with purified water(lOOml), Dichloromethane was distilled out'completely under reduced pressure at below 50°C. Residue was cooled to 25-30°C ethyl acetate (150ml) was charged and stirred for 30 min at 25-30. Reaction mass further cooled to 0-5°C and maintained at same temperature for one hour. The solid was collected by filtration and washed with chilled ethyl acetate (25 ml) to get 40-45 g ethyl-(4- isobutyl)-2-yl amino-2-fluoro methyl benzoate .

Example-9: Preparation of 4-(l-ethoxycarbonyl-l-methyl-ethylamino)-2-fluoro benzoic acid methyl ester

To a clean and dry four neck R B flask fitted with mechanical stirrer, thermo-pocket and reflux ' condenser, charged EthyI-2-bromo-isobutyfate (200 .g), methyl 2-fluoro-4-amino benzoate (50 g), sodium carbonate (100 g ) and tetra butyl ammonium bromide (lOgm ) at ambient temperature. Reaction mass was heated to 135-150°C and maintained under stirring at 135-150°C for 12 hours. Reaction mass cooled to 80-90° and slowly added 2nd lot of methyl-2-bromo isobutyrate (50gm). Temperature was raised to 135-150°C and maintained for 10-12hrs. After completion of reaction cooled the reaction mixture to 25-30°C. Charged purified water (100 ml), and Dichloromethane (600ml) and the 'product was extracted in DichJoromethane. The Dichloromethane layer was washed with purified water, stir for lOmin and settle for 20min.separate two layers take MDC layer in a flask wash the layer with purified water(lOOml), Dichloromethane was distilled out completely under reduced pressure at below 50°C. Residue was cooled to 25-30°C ethyl acetate (150ml) was charged and stirred for 30 min at 25-30. Reaction mass further cooled to 0-5°C and maintained at same temperature for one hour. The solid was collected by filtration and washed with chilled ethyl acetate (25 ml) to get 40-45 g ethyl-(4- isobutyl)-2-yl amino-2-fluoro methyl benzoate .

Example-10: Preparation of 4-(l-ethoxycarbonyl-l-methyl-ethylamino)-2-fluoro benzoic acid methyl ester To a clean and dry four neck R B flask fitted with mechanical stirrer, thermo-pocket and reflux condenser, charged Ethyl-2-bromo-isobutyrate (200 g), methyl 2-fluoro-4-amino benzoate (50 g), sodium carbonate (100 g ) and tetra butyl ammonium iodide (5gm ) at ambient temperature. Reaction mass was heated to 135-150°C and maintained under stirring at 135-150°C for 12 hours. Reaction mass cooled to 80-90° and slowly added 2nd lot of methyl-2-bromo isobutyrate (50gm). Temperature was raised to I35-150°C and maintained for 10-12hrs. After completion of reaction cooled the reaction mixture to 25-30°C. Charged purified water (100 ml), and Dichloromethane (600ml) and the product was extracted in Dichloromethane. The Dichloromethane layer was washed with purified water, stir for lOmin and settle for 20min.separate two layers take MDC layer in a flask wash the layer with purified water(IOOml), Dichloromethane was distilled out completely under reduced pressure at below 50°C. Residue was cooled to 25-30°C ethyl acetate (150ml) was charged and stirred for 30 min at 25-30. Reaction mass further cooled to 0-5°C and maintained at same temperature for one hour. The solid was collected by filtration and washed with chilled ethyl acetate (25 ml) to get 45-50 g ethyl-(4- isobutyl)-2-yl amino-2-fluoro methyl behzoate .

Example 11: Process for the preparation of 2-(3-fluoro-4-(methyl-carbamoyl) phenyl-amino)^-methyl-propionic acid ethyl este Methanol (250 ml) was charged into a cleaned flask and 4-(l-ethoxycarbonyl-l-methyl-ethylamino)-2-fluoro benzoic acid methyl ester (50gm) added at 25-30° C and cooled to 0-5° C. Methyl amine gas was slowly passed for 2-4 hours at 0-5° C, and maintain for 1-2 hours at 0-5° C. Check completion of the reaction. Purified water (750 ml) was slowly added at 0-10° C and maintain for 30 minutes at 0-10° C. Filtered the solid, acetone (150 ml) was added and heat the reaction mixture to 50-55°C for 30 minutes. Cooled to 25-30° C and maintained for 30 minutes, further cooled to 0-5° C and maintained for 30 minutes at 0-5° C, filtered the solid, washed with chilled ethyl acetate ( 25 ml). Suck dried for 30 minutes and unload the wet material in a poly cover, dry the. material at 60-65° C for 10-12 hours .

Weight of the product: 55 gms.

Example 12: Process for the preparation of 2-(3-fluoro-4-(methyl-carbamoyl) phenyl-amino)-2-methyl-propionic acid ethyl ester Methanol (250 ml) was charged into a cleaned flask and 4-(l-ethoxycarbonyl-l-methyl-ethylamino)-2-fluoro benzoic acid methyl ester (50gm) added at 25-30° C and cooled to 0-5° C. Methyl amine solution in methanol (200 ml, 33%) was slowly added to it over a period of 1-2 hours at 0-5° C, and maintain for 4-5 hours at 0-5° C. Check completion of the reaction. Purified water (750 ml) was slowly added at 0-10° C and maintain for 30 minutes at 0-10° C. Filtered the solid, wash with purified water (100 ml), suck dry the solid for 30 minutes , take wet solid in a flask and ethyl acetate (150 ml) was added while heat to reflux with stirring for 30 minutes, cool to 25-30° C and maintain for 30 minutes, further cool to 0-5° C and maintain for 30 minutes at 0-5° C, filtered and washed the solid with chilled ethyl acetate ( 25 ml). Suck dried for 30 minutes and unload the wet material in a poly cover, dry the material at 60-65° C for 10-12 hours . Weight of the product: 55 gms.

We Claim:

An improved process for the preparation of 2-(3-fluoro-4-(methyl-carbamoyl) phenyl-amino)-2-methyI-propionic acid ethyl ester (I), comprising steps of;

a) 2-fluoro-4-nitrobenzoic acid (III) is reacted with methanol in presence of an acid to produce methyl 2-fluoro-4-nitrobenzoate of formula (X).

b) methyl 2-fluoro-4-nitrobenzoate of (X) is reduced with a reducing agent to produce methyl 2-fluoro-4-amino benzoate (XI),

c) methyl 2-fluoro-4-amino benzoate (XI) is condensed with ethyl 2-bromo-2-methylpropanoate in presence of a base and quaternary ammonium salt to produce 4-(l-ethoxycarbonyl-l-methyl-ethylamino)-2-fluoro benzoic acid methyl ester of formula (XII)

d) the compound of formula (XII) is reacted with aqueous methylamine in presence of methanol to produce 2-(3-fluoro-4-(methyl-carbamoyl) phenyl-amino)-2-methyl-propionic acid ethyl ester of formula (I).

2. The process according to claim I, in step-a) an acid is selected form/?-toluenesulphonic acid, sulfuric acid, hydrochloric acid, preferably p-toluene sulphonic acid.

3. The process according to claim 1, in step-b) reducing agent is selected from Palladium on carbon or Raney Nickel is under hydrogen pressure, preferably palladium, and the base is selected from sodium hydroxide, potassium hydroxide, preferably sodium hydroxide.

4. An improved process for the preparation of 4-(l-ethoxycarbonyM-methyl-ethylamino)-2-fluoro benzoic acid methyl ester of formula (XII) comprising: the condensation of methyl 2-fluoro-4-amino benzoate (XI) with ethyl 2-bromo-2-methylpropanoate in presence of a base and quaternary ammonium salt to produce the compound of formula (XII).

wherein, the base is selected from alkaline carbonate, such as sodium carbonate, potassium carbonate, lithium carbonate, sodium acetate, potassium acetate; the quaternary ammonium salt is selected from trimethyl benzyl ammonium chloride, trimethyl benzyl ammonium bromide, trimethyl n-octyl ammonium bromide, trimethyl stearyl ammonium bromide, tetra butyl ammonium iodide, tetra butyl ammonium bromide, p-methylcholinium iodide, tetra butyl ammonium hydrogensulfate, phenyltrimethylammonium hydoxide.

5. An improved process for the preparation of 2-(3-fluoro-4-(methyl-carbamoyl)phenyl-amino)-2-methyl-propionic acid ethyl ester of formula (I) comprising: the amination of 4-(l-ethoxycarbonyl-l-methyl-ethylamino)-2-fluoro benzoic acid methyl ester of formula (XII) with methylamine in presence of methanol to produce 2-(3-fluoro-4-(methyl-carbamoyl)phenyl-amino)-2-methyl-propionic acid ethyl ester of formula (1)

6. The process according to claim 1, the compound of formula I used in the preparation of Enzalutamide.