Description:Field of the Invention
The present invention generally relates to a field of process chemistry and, more particularly, to process for the preparation of 4-amino-2-fluoro-N-methylbenzamide an intermediate used in synthesizing enzalutamide and apalutamide.

Background of the Invention
4-amino-2-fluoro-N-methylbenzamide of formula (I),

(I)
is a key intermediate for the preparation of enzalutamide, a second-generation anti-androgen used in the treatment of metastatic castration-resistant prostate cancer. The compound of formula (I) is also an important key intermediate in the synthesis of apalutamide, a second-generation anti-androgen used in the treatment of a non-metastatic castration-resistant prostate cancer.
4-
US Patent No. 7,709,517 teaches process for preparation of compound of formula (I). The process comprises oxidation of 2-fluoro-4-nitrotoluene with chromium trioxide in presence of periodic acid in acetonitrile to yield 2-fluoro-4-nitrobenzoic acid. The acid obtained is treated with Thionyl chloride in DMF at -5°C followed by addition of excess methylamine to isolate N-Methyl-2-fluoro-4-nitrobenzamide. The amide isolated is hydrogenated in presence of iron in ethyl acetate and acetic acid to isolate N-methyl-2-fluoro-4-aminobenzamide (92% yield).

Scheme 1
Journal of Chemical Research, 37(10), 615-616; 2013 and CN 106478477 claims process for preparation of 4-amino-2-fluoro-N-methylbenzamide. The process comprises oxidation of 2-Fluoro-4-nitrotoluene using potassium permanganate in presence of phase transfer catalyst. After completion of the reaction, off-white solid of 2-fluoro-4-nitrobenzoic acid is isolated. The acid obtained is chlorinated in presence of thionyl chloride followed by reaction with methylamine gas. After completion of the reaction white solid 2-fluoro-4-nitro-N-methylbenzamide was isolated. The amide obtained is hydrogenated in presence of pd/C catalyst.

Scheme 2
Hydrogenation of halo-nitrobenzene in presence of noble metal catalyst such as palladium, platinum, ruthenium, rhodium is known in the art. However, the dehalogenation occurs simultaneously even in the controlled conditions, and gives rise to de-halogenated impurities.

Accordingly, there is a need to provide a process for preparation of 4-amino-2-halo-N-methylbenzamide which minimizes isomeric impurities formation. Further, there is need for a process for synthesis of 4-amino-2-halo-N-methylbenzamide, which selectively hydrogenates nitro group of 4-nitro-2-halo-N-methylbenzamide and minimizes dehalogenation side reaction and increases purity and yield of 4-amino-2-halo-N-methylbenzamide.

Summary of the invention
Accordingly, the present invention provides a process for the preparation of 4-amino-2-halo-N-methylbenzamide of Formula (I),

wherein X is halo selected from Chloro, Fluoro, bromo, iodo;
wherein the said process involves hydrogenation of 4-nitro-2-halo-N-methylbenz-amide of formula (II) in presence of bimetallic catalyst in a chemical reactor.

The present invention further provides process for the preparation 4-amino-2-halo-N-methylbenzamide which avoids formation of impurity formation due to dehalogenation occurring as a side reaction.
Detailed description of the invention
The foregoing objects of the present invention are accomplished, and the problems and shortcomings associated with the prior art, techniques and approaches are overcome by the present invention as described below in the preferred embodiments.

In one of the preferred embodiments, the present invention provides an improved process for preparation of 4-amino-2-halo-N-methylbenzamide of formula 1,

wherein the said process involves hydrogenation of 4-nitro-2-halo-N-methylbenza-mide of formula (II) in presence of bimetallic catalyst in a chemical reactor.

The bimetallic catalyst is composed of platinum catalyst alloyed with copper and supported on Carbon. The Pt and Cu alloy in a typical composition loaded on carbon. The catalyst is composed of 1% Pt and 0.1-0.5% copper loaded on carbon. The catalyst is used on wet basis, preferably 10-70% wet basis.

The hydrogenation is carried out in an alcoholic solvent preferably selected from methanol, ethanol, isopronaol, n-propanol, n-butanol, isobutanol and tert-butanol.

The chemical reactor used for the reaction is made up of material of construction selected from glass, stainless steel and Hastelloy. The higher yield and better purity of compound (I) is achieved by carrying out the hydrogenation in a glassline or Hastelloy reactor. This possible due to lesser interference of material of construction on reactivity of catalyst in case of glassline and Hastelloy reactors.

The compound of formula (II) is prepared by (a) reacting 2-halo-4-nitrobenzoic acid with thionyl chloride; and (b) reaction with monomethyl amine (40% solution) to yield 2-halo-4-nitro-N-methylbenzamide.

Step (a) is carried out in toluene and in presence of dimethyl formamide. Step (a) is carried out at 25-80°C, preferably at 60-80°C, more preferably at 70-75°C.
The reaction mass is added to N-mono methylamine chilled to 0-20°C in the reaction mass of step (a) is done at 0-15°C.

The following experimental examples are illustrative of the invention but not limited of the scope thereof. It will be apparent, however, that the disclosure can be practiced with other amounts and types of reactants and reaction conditions than those used in the examples, and the resulting devices various different properties and uses in accordance with the disclosure above and as pointed out hereinafter.

Example 1
Preparation of 2-fluoro-4-nitro-N-methylbenzamide
Under nitrogen atmosphere, 2-fluoro-4-nitro-benzoic acid (500 gm) was charged to Toluene (1 L) at 25-30°C. Dimethylformamide (5 ml) was charged to the reaction mixture at 25-30°C. The reaction mass was heated to 60-65°C and thionyl chloride (367 ml) was slowly added to the reaction mass at 60-65°C. The reaction was maintained at 60-65°C for 2 hours. The mass was chilled to 5-10°C.

The reaction mass was added drop wise to the previously cooled solution of 40% solution of Monomethyl amine (1883 ml) at 5-15°C under nitrogen for 2-3 hours. The temperature of the mass was raised to 25-30°C and stirred for 1 hour. The mass was filtered and washed with toluene to isolate 2-Fluoro-4-nitro-N-methylbenzamide (Wet wt. 610 gm).

The wet material was slurried in water (1.5 L) and stirred for 1 hour at 25-30°C. The product was filtered and suck dried to get wet 2-fluoro-4-nitro-N-methylbenzamide (600 gm). The compound was dried at 55-60°C in oven to get 2-Fluoro-4-nitro-N-methylbenzamide (506 gm) (Purity 99.93%).

Example 2
Preparation of 2-fluoro-4-amino-N-methylbenzamide in SS autoclave
In an autoclave 2-Fluoro-4-nitro-N-methylbenzamide (500 gm) was charged to methanol (8 L) at 25-30°C in a stainless-steel reactor. 1% Pt/Cu on carbon (50% wet) (50 gm) was charged to the reaction mixture. The autoclave was closed and flushed with N2 gas and hydrogen gas. 8-8.5 kg/cm2 pressure of hydrogen was applied and maintained at 25-30°C for 20-25 hours. The reaction mass was filtered under hyflow bed under nitrogen atmosphere and bed was washed with methanol (250 ml). Methanol was distilled out under vacuum at 45-50°C and degassed.
wt. = 410 gm, HPLC purity = 98.86 %

Example 3
Purification of 2-fluoro-4-amino-N-methylbenzamide
Degassed mass from example 2 was charged to methanol (800 ml) and heated to 60-65°C for 30 minutes. The mass was cooled to 55-60°C and filtered. Toluene (1.6 L) and the filtrate was charged to flask and the mixture was heated to 60-65°C and stirred for 30 minutes.

Methanol was distilled out at 75-80°C, the mass was cooled to 25-30°C and stirred for 1 hour. The reaction mass was chilled to 5-10°C and stirred for 1 hour. The product was filtered and washed with toluene (200 ml). The precipitate was suck dried at 25-30°C and further dried under vacuum at 55-60°C for 5-6 hours to yield 2-fluoro-4-amino-N-methylbenzamide (Wt = 370 gm). HPLC purity: 99.67%.

Example 4
Preparation of 2-fluoro-4-amino-N-methylbenzamide in Hastealloy autoclave
In an autoclave 2-fluoro-4-nitro-N-methylbenzamide (500 gm) was charged to methanol (8 L) at 25-30°C in a Hastelloy reactor. 1% Pt/Cu on carbon (50% wet) (50 gm) was charged to the reaction mixture. The autoclave was closed and flushed with N2 gas and hydrogen gas. 8-8.5 kg/cm2 pressure of hydrogen was applied and maintained at 25-30°C for 20-25 hours. The reaction mass was filtered under hyflow bed under nitrogen atmosphere and bed was washed with methanol (250 ml). Methanol was distilled out under vacuum at 45-50°C and degassed.
wt. = 420 gm HPLC purity = 99.91%

Example 5
Purification of 2-fluoro-4-amino-N-methylbenzamide
Degassed mass from example 4 was charged to methanol (800 ml) and heated to 60-65°C for 30 minutes. The mass was cooled to 55-60°C and filtered. Toluene (1.6 L) was charged to filtrate and the mixture was heated to 60-65°C and stirred for 30 minutes.

Methanol was distilled out at 75-80°C, the mass was cooled to 25-30°C and stirred for 1 hour. The reaction mass was chilled to 5-10°C and stirred for 1 hour. The product was filtered and washed with toluene (200 ml). The precipitate was suck dried at 25-30°C and further dried under vacuum at 55-60°C for 5-6 hours to yield 2-fluoro-4-amino-N-methylbenzamide (Wt = 370 gm). HPLC purity: 99.99%.
, Claims:1. A process for the preparation of 4-amino-2-fluoro-N-methylbenzamide of formula (I)

comprising step of hydrogenation of 4-nitro-2-halo-N-methylbenzamide of formula (II)

in the presence of a bimetallic catalyst.
wherein X is halo selected from chloro, fluoro, bromo and iodo.
2. The process as claimed in claim 1, wherein the bimetallic catalyst is platinum alloyed with copper.
3. The process as claimed in claim 2, wherein 1% platinum is alloyed with 0.5% copper.
4. The process as claimed in claim 1, wherein the bimetallic catalyst is supported on carbon.
5. The process as claimed in claim 1, wherein the bimetallic catalyst is used on 10-70% wt. basis.
6. The process as claimed in claim 1, wherein hydrogenation is carried out in an alcoholic solvent.
7. The process as claimed in claim 6, wherein the solvent is selected from the group of methanol, ethanol, isopropanol, b-propanol, isobutanol and tert-butanol.
8. The process as claimed in claim 1, wherein the reacted is made of glass, stainless-steel or Hastelloy material.