DESC:Field of the invention
The present invention relates to 4-halo-2-alkoxy-5-nitroaniline, and more particularly to a process for preparation of 4-halo-2-methoxy-5-nitroaniline.

Background of the invention
4-halo-2-methoxy-5-nitroaniline of formula (I), is an important key intermediate used in the preparation of Osimertinib.

Osimertinib is third-generation epidermal growth factor receptor and is used in the treatment of metastatic non-small cell lung cancer. The key factor in the preparation of 4-halo-2-methoxy-5-nitroaniline is synthesis of 4-halo-2-methoxy nitrobenzene intermediate, which minimizes isomeric impurity formation. In addition, reduction of 4-halo-2-methoxy nitrobenzene requires avoiding impurity formation due to dehalogenation side reaction.

In general, synthesis of 4-halo-2-methoxy nitrobenzene by suspending 5-fluoro-2-nitrophenol, potassium carbonate and Iodomethane in DMF at 140°C is reported in WO2006071730. However the yield obtained is very low (26%).

It is known from the art that conversion of 4-halo-2-methoxy nitrobenzene to 4-halo-2-methoxy aniline is preferably either by reduction with iron-hydrochloric acid or by catalytic reduction with hydrogen over a noble metal catalyst. However it is observed that the catalytic reduction of 4-halo-2-methoxy nitrobenzene is difficult to achieve because of the occurrence of dehalogenation as a side reaction, which results in 4-dehalo impurities in the process.

Reduction with iron-hydrochloric acid is preferred, as reduction proceeds smoothly with high yield of 4-halo-2-methoxy aniline. However, it produces iron oxide sludge, and special separation techniques are required for separation of haloamine product from iron oxide sludge. In addition, environmental problems associated with disposing of the iron oxide sludge have led haloamine producers to seriously consider the catalytic reduction of 4-halo-2-methoxy nitrobenzene.

Hydrogenation of 4-halo-2-methoxy 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 dehalogenated impurities.
Accordingly, there is a need to provide a process for preparation of 4-halo-2-methoxy-5-nitroaniline of formula (I) from intermediate-1 i.e. 4-halo-2-methoxy nitrobenzene which minimizes isomeric impurities formation and from intermediate-2 i.e. 4-halo-2-methoxyaniline from intermediate-1 which selectively reduces nitro group of 4-halo-2-methoxy nitrobenzene and minimizes dehalogenation side reaction.

Objects of the invention
An object of the present invention is to provide process for preparation of intermediate-2 i.e. 4-halo-2-methoxyaniline (I-2) free from dehalogenated impurity.

An object of the present invention is to provide process for preparation of intermediate-2 i.e. 4-halo-2-methoxyaniline (I-2), to use the catalyst which can be recovered and reused in the hydrogenation.

An object of the present invention is to provide a process for preparation of 4-halo-2-methoxyaniline, which is cost effective and industrially feasible.

Another object of the present invention is to provide a process for preparation of intermediate-1 i.e. 4-halo-2-methoxy nitrobenzene (I-1) which minimizes the isomeric impurity formation.

Summary of the invention
In an aspect, a process for preparation of 4-halo-2-methoxy-5-nitroaniline of formula (I),

wherein X is a halo group selected from chloro (Cl), fluoro (F), bromo (Br) and iodo (I), comprises:
(a) conversion of a compound of formula (A) to a compound of formula (I-1);

(b) hydrogenation of the compound of formula (I-1) to form a compound of formula (I-2) in presence of a predefined bimetallic catalyst;

(c) conversion of the compound of formula (I-2) to form 4-halo-2-methoxy-5-nitroaniline of formula (I).

In this embodiment, compound of formula (A) is 4-halo-2-fluoro nitrobenzene, compound of formula (I-1) is 4-halo-2-methoxynitrobenzene and compound of formula (I-2) is 4-halo-2-methoxyaniline. 4-halo-2-methoxy-5-nitroaniline of formula (I) has 99.0% to 99.5% HPLC purity with 70% to 80% yield.

In another aspect, a process for preparation of the compound of formula (I-1) in step (a):

wherein X is a halo group selected from chloro (Cl), fluoro (F), bromo (Br) and iodo (I), comprises:
(1) reacting the compound of formula (A)

with a predefined alkali in presence of a predefined alcoholic solvent at a predefined temperature in presence of a predefined emulsifier or a predefined phase transfer catalyst to form a compound of formula (B);

(2) methylation of the compound of formula (B) at a predefined temperature to form the compound of formula (I-1).

In this embodiment, the compound of formula (B) is 4-halo-2-hydroxynitrobenzene. The reaction in step (1) proceeds in presence of a predefined alkali selected from alkali hydroxide selected from sodium hydroxide, potassium hydroxide and lithium hydroxide in a suitable alcoholic solvent selected from methanol, ethanol, isopropanol and t-butanol, preferably t-butanol at a predefined reflux temperature from 65°C to 75°C. The predefined emulsifier used in step (1) is preferably selected from long chain alkyl sulfonates selected from sodium dodecylbenzene sulfonate and the predefined phase transfer catalyst used is quaternary ammonium salts selected from benzyltriethylammonium chloride, methyltricaprylammonium chloride, methyltributylammonium chloride, and methyltrioctylammonium chloride. The methylation in step (2) is preferably carried out using methylating agent selected from dimethyl sulfate or methyl iodide, at a predefined temperature from 10°C to 35°C, and preferably at 15°C to 25°C. Compound of formula (I-1) has 98% to 99% HPLC purity with 60% to 70% yield.

In another embodiment, an alternate process for preparation of the compound of formula (I-1) in step (a)

wherein X is a halo group selected from chloro (Cl), fluoro (F), bromo (Br) and iodo (I), comprises:
reacting the compound of formula (A)

with a predefined alkali in presence of a predefined solvent at a predefined temperature to form a compound of formula (I-1).

The reaction is carried out in a predefined alkali selected from sodium methoxide and in presence of predefined alcoholic solvent selected from methanol, ethanol, propanol, butanol and t-butanol, preferably t-butanol. Compound of formula (I-1) has 98% to 99% HPLC purity with 60% to 70% yield.

In another aspect, the process for preparation of the compound of formula (I-2) in step (b)

wherein X is a halo group selected from chloro (Cl), fluoro (F), bromo (Br) and iodo (I), comprises:
hydrogenation of compound of formula (I-1) in presence of a predefined bimetallic catalyst and a predefined solvent at a predefined temperature and a predefined hydrogen pressure to yield the compound of formula (I-2).

In this embodiment, the predefined bimetallic catalyst is composed of a platinum (Pt) catalyst alloyed with copper (Cu) and supported on Carbon. The catalyst is composed of 1% Pt and 0.1% to 0.5% Cu loaded on carbon. The catalyst is used in this embodiment is on wet basis, preferably 10% to 70% wet basis. The bimetallic catalyst is composed of 1% Pt and 0.1% Cu loaded on 98.9% carbon and is preferably used as 50% wet basis. The predefined solvent used is alcoholic solvent selected from methanol, ethanol, isopropanol, n-propanol, n-butanol, isobutanol and t-butanol, preferably t-butanol. Further the reaction proceeds at temperature less than 50°C, preferably at 40°C to 50°C. Compound of formula (I-2) has 98.0% to 99.5% HPLC purity with 90% to 95% yield.

In further embodiment, the process for the conversion of the compound of formula (I-2) to 4-halo-2-methoxy-5-nitroaniline of formula (I) in step (c)

wherein X is a halo group selected from chloro (Cl), fluoro (F), bromo (Br) and iodo (I), comprises:
(i) acetylation of compound of formula (I-2)

in presence of a predefined acetylating agent at a predefined temperature to yield a compound of formula (I-3);

(ii) nitration of the compound of formula (I-3) in presence of a predefined nitrating mixture without a solvent or with a predefined chlorinated solvent at a predefined temperature to form compound of formula (I-4); and

(iii) deacetylation of compound of formula (I-4) in presence of a predefined acid to form 4-halo-2-methoxy-5-nitroaniline of formula (I).

In this embodiment, the compound of formula (I-3) is N-(4-halo-2-methoxyphenyl)acetamide and the compound of formula (I-4) is N-(4-halo-2-methoxy-5-nitrophenyl)acetamide. The predefined acetylating agent used in step (i) is selected from acetic anhydride, acetyl chloride and acetic acid, preferably selected from acetic anhydride and acetic acid. The reaction is carried out at a predefined temperature range from 70°C to 120°C. In this embodiment, nitration mixture used in step (ii) is preferably mixture of concentrated sulfuric acid and fuming nitric acid. The ratio of concentrated sulfuric acid to fuming nitric acid is 4.0:1 to 4.5:1. The nitration reaction in step (ii) is carried out without any solvent or in a predefined chlorinated solvent selected from methylene dichloride, chloroform and 1,2-dichloroethane. The reaction gives better yield at temperature at 10°C to 25°C, preferably at 15°C to 20°C. In this embodiment, the deacetylation reaction in step (iii) is carried out in presence of sulfuric acid preferably concentration of sulfuric acid in a range of 10% to 70%, preferably 20% to 40%.

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.

All materials used herein were commercially purchased as described herein or prepared from commercially purchased materials as described herein.

Although specific terms are used in the following description for sake of clarity, these terms are intended to refer only to particular structure of the invention selected for illustration in the drawings and are not intended to define or limit the scope of the invention.

References in the specification to “preferred embodiment” means that a particular feature, structure, characteristic, or function described in detail thereby omitting known constructions and functions for clear description of the present invention.

In a preferred embodiment, a process for preparation of 4-halo-2-methoxy-5-nitroaniline of formula (I),

wherein X is a halo group selected from chloro (Cl), fluoro (F), bromo (Br) and iodo (I), comprises:
(a) conversion of a compound of formula (A) to a compound of formula (I-1);

(b) hydrogenation of the compound of formula (I-1) to form a compound of formula (I-2) in presence of a predefined bimetallic catalyst;

(c) conversion of the compound of formula (I-2) to form 4-halo-2-methoxy-5-nitroaniline of formula (I).

In this embodiment, compound of formula (A) is 4-halo-2-fluoro nitrobenzene, compound of formula (I-1) is 4-halo-2-methoxynitrobenzene and compound of formula (I-2) is 4-halo-2-methoxyaniline.
In this embodiment, 4-halo-2-methoxy-5-nitroaniline of formula (I) has 99.0% to 99.5% HPLC purity with 70% to 80% yield.

In one embodiment, a process for preparation of the compound of formula (I-1) in step (a):

wherein X is a halo group selected from chloro (Cl), fluoro (F), bromo (Br) and iodo (I), comprises:
(1) reacting the compound of formula (A)

with a predefined alkali in presence of a predefined alcoholic solvent at a predefined temperature in presence of a predefined emulsifier or a predefined phase transfer catalyst to form a compound of formula (B);

(2) methylation of the compound of formula (B) at a predefined temperature to form the compound of formula (I-1).

In this embodiment, the compound of formula (B) is 4-halo-2-hydroxynitrobenzene.
In this embodiment, the reaction in step (1) proceeds in presence of a predefined alkali selected from alkali hydroxide selected from sodium hydroxide, potassium hydroxide and lithium hydroxide in a suitable alcoholic solvent selected from methanol, ethanol, isopropanol and t-butanol, preferably t-butanol at a predefined reflux temperature from 65°C to 75°C.
In this embodiment, the reaction of step (1) is carried out in presence of a predefined emulsifier or a predefined phase transfer catalyst and in a predefined solvent selected from t-butanol as it gives regioselectivity. Further use of t-butanol as a solvent minimizes the formation of 4-hydroxy impurity and specifically substitutes the fluorine in the ortho-position to form the compound of formula (B).

In this embodiment, the predefined emulsifier used in step (1) is preferably selected from long chain alkyl sulfonates is sodium dodecylbenzene sulfonate and the predefined phase transfer catalyst used is quaternary ammonium salts selected from benzyltriethylammonium chloride, methyltricaprylammonium chloride, methyltributylammonium chloride, and methyltrioctylammonium chloride.

In this embodiment, the methylation in step (2) is preferably carried in presence of methylating agents selected from dimethyl sulfate and methyl iodide, at predefined temperature from 10°C to 35°C, and preferably at 15°C to 25°C.

In this embodiment, compound of formula (I-1) has 98% to 99% HPLC purity with 60% to 70% yield.

In another embodiment, an alternate process for preparation of the compound of formula (I-1) in step (a)

wherein X is a halo group selected from chloro (Cl), fluoro (F), bromo (Br) and iodo (I), comprises:
reacting the compound of formula (A)

with a predefined alkali in presence of a predefined solvent at a predefined temperature to form a compound of formula (I-1).

In this another embodiment, the reaction is carried out in a predefined alkali selected from sodium methoxide and in presence of predefined alcoholic solvent selected from methanol, ethanol, propanol, butanol and t-butanol, preferably t-butanol.

In this another embodiment, the reaction is carried out in t-butanol as it give regioselectivity. Further use of t-butanol as a solvent, minimizes the formation of 4-methoxy impurity and specifically substitutes the fluoro group in the ortho-position to yield compound of formula (I-1). Further, the process of this another embodiment of the present invention for preparation of compound of formula (I-1) minimizes 4-methoxy impurity formation between 0 to 0.5%, preferably 0 to 0.3%.

In this another embodiment, compound of formula (I-1) has 98% to 99% HPLC purity with 60% to 70% yield.

In yet another embodiment, the process for preparation of the compound of formula (I-2) in step (b)

wherein X is a halo group selected from chloro (Cl), fluoro (F), bromo (Br) and iodo (I), comprises:
hydrogenation of compound of formula (I-1) in presence of a predefined bimetallic catalyst and a predefined solvent at a predefined temperature and a predefined hydrogen pressure to yield the compound of formula (I-2).

In this embodiment, the bimetallic catalyst is composed of a platinum (Pt) catalyst alloyed with copper (Cu) and supported on Carbon wherein the Pt and Cu alloy in a typical composition are loaded on carbon. The catalyst is composed of 1% Pt and 0.1% to 0.5% Cu loaded on carbon. The catalyst is used in this embodiment is on wet basis, preferably 10% to 70% wet basis. The composition of the alloy plays an important role in the reaction and it broadly depends on substrate. The bimetallic catalyst is composed of 1% Pt and 0.1% Cu loaded on 98.9% carbon and is preferably used as 50% wet basis.

In this embodiment, the predefined solvent used is alcoholic solvent selected from methanol, ethanol, isopropanol, n-propanol, n-butanol, isobutanol and t-butanol, preferably t-butanol. Further the reaction proceeds at temperature less than 50°C, preferably at 40°C to 50°C and the predefined hydrogen pressure applied in the reaction is 4 kg to 10 kg pressure, preferably at 5 kg to 7 kg pressure, and particularly at 6 kg pressure.

In this embodiment, compound of formula (I-2) has 98.0% to 99.5% HPLC purity with 90% to 95% yield.

In further embodiment, the process for the conversion of the compound of formula (I-2) to 4-halo-2-methoxy-5-nitroaniline of formula (I) in step (c)

wherein X is a halo group selected from chloro (Cl), fluoro (F), bromo (Br) and iodo (I), comprises:
(i) acetylation of compound of formula (I-2)

in presence of a predefined acetylating agent at a predefined temperature to yield a compound of formula (I-3);

(ii) nitration of the compound of formula (I-3) in presence of a predefined nitrating mixture without a solvent or with a predefined chlorinated solvent at a predefined temperature to form compound of formula (I-4); and

(iii) deacetylation of compound of formula (I-4) in presence of a predefined acid to form 4-halo-2-methoxy-5-nitroaniline of formula (I).

In this embodiment, the compound of formula (I-3) is N-(4-halo-2-methoxyphenyl)acetamide and the compound of formula (I-4) is N-(4-halo-2-methoxy-5-nitrophenyl)acetamide.

In this embodiment, the predefined acetylating agent used in step (i) is selected from acetic anhydride, acetyl chloride and acetic acid, preferably selected from acetic anhydride and acetic acid. The reaction is carried out at a predefined temperature range from 70°C to 120°C.

In this embodiment, nitration mixture used in step (ii) is preferably mixture of concentrated sulfuric acid and fuming nitric acid. The ratio of concentrated sulfuric acid to fuming nitric acid is 4.0:1 to 4.5:1.

In this embodiment, the nitration reaction is step (ii) is carried out without any solvent or in a predefined chlorinated solvent selected from methylene dichloride, chloroform and 1,2-dichloroethane. The reaction gives better yield at temperature at 10°C to 25°C, preferably at 15°C to 20°C.

In this embodiment, the deacetylation reaction in step (iii) is carried out in presence of sulfuric acid preferably concentration of sulfuric acid in a range of 10% to 70%, preferably 20% to 40%.

EXAMPLES
Only a few examples and implementations are disclosed. Variations, modifications, and enhancements to the described examples and implementations and other implementations can be made based on what is disclosed.

Examples are set forth herein below and are illustrative of different amounts and types of reactants and reaction conditions that can be utilized in practicing the disclosure. 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 4-Fluoro-2-methoxynitrobenzene
t-butanol (2000 ml) was charged 2,4-difluronitorbenzene (500 gm) at room temperature. Sodium methoxide (178.30 gm) was charged to the resulted reaction mass at 30°C. The reaction mass was stirred at 30-35°C for 2 hours. pH of the reaction mass was adjusted to 6-6.5 using acetic acid. Reaction mixture was heated and t-butanol was distilled at 90-95°C. The reaction mixture was degassed under vacuum for 30 min. The reaction mass was cooled at 30°C. Water (3000 ml) and chloroform (2000 ml) was added to reaction mass and resulted mixture was stirred for 30 min. The organic layer was separated. The aqueous layer was washed with chloroform (500 ml) and combined chloroform layer was distilled out. The reaction mass was degassed under vacuum for 30 minutes and the mass was cooled at 30°C.
Crude sample was analyzed and showed GC purity 87.5% and regioisomer formed is 1.45%.
The crude 4-Fluoro-2-methoxynitrobenzene was purified using isopropyl alcohol. Isopropyl alcohol (250 ml) was charged to the oily product obtained and stirred for 30 minutes at 30°C. The mass was cooled to 15-20°C and stirred for 30 minutes. The mass was filtered and washed with isopropyl alcohol (200 ml) to get 4-Fluoro-2-methoxynitrobenzene (365 gm, Yield: 68%) as off white crystalline solid.
GC purity observed was 99.3% and the regioisomer: 0.07%

Example 2
Preparation of 4-Fluoro-2-methoxyaniline
In an autoclave isopropyl alcohol (1280 ml) was charged to 4-Fluoro-2-methoxynitrobenzene (320 gm). Modified platinum catalyst (6.6 gm) was added to the reaction mixture at room temperature. The autoclave was flushed with nitrogen two times.
Nitrogen was flushed out by applying 2 kg hydrogen pressure 3 times. Finally 6 kg hydrogen pressure was applied and temperature was raised to 50°C. After completion, the reaction mass was cooled to RT and filtered on hyflo bed under nitrogen. The hyflo bed was washed with IPA (250 ml) under nitrogen and catalyst was recovered. The IPA layer was distilled at 80-850C to get crude oil. The crude oil was then subjected to high vacuum distillation at 125°C to get 4-Fluoro-2-methoxyaniline as colorless oil (240 gm, Yield: 90%) and GC purity observed was 99.1%.

Example 3
Preparation of N-(4-Fluoro-2-methoxyphenyl)acetamide
At room temperature, acetic acid (200 ml) was charged to 4-Fluoro-2-methoxyaniline (50 gm). The reaction mixture was heated to 120°C and stirred for 3-4 hours. After completion of reaction, the mass was cooled to 65-70°C. Acetic acid was distilled at 65-70°C under vacuum. The reaction mass was cooled to room temperature. Water (400 ml) was charged to the reaction mass and stirred for 30 minutes. The suspension was filtered and washed with water (200 ml). The product was dried under vacuum to get N-(4-Fluoro-2-methoxyphenyl)acetamide (58 gm, Yield: 89%) as light violet color solid. GC purity: observed was 99.9%

Example 4
Preparation of N-(4-Fluoro-2-methoxy-5-nitrophenyl)acetamide
N-(4-Fluoro-2-methoxyphenyl)acetamide (150 gm) was added in small portions to Sulfuric acid (109 ml) at 30-35°C. The reaction mass was stirred for 30 minutes at 30-35°C and cooled to 15°C. Nitric acid (54 gm) and sulfuric acid (22 gm) was added to the reaction mass at 15°C. During addition the temperature was maintained to 15°C. The mass was stirred for 1 hour. After completion of the reaction, the mass was quenched in crush ice and water (900 ml). The mixture was stirred for 30 minutes, filtered and washed with water (150 ml). The crude product obtained was slurried in water (300 ml) and stirred for 15 minutes. 25% of aqueous ammonia (365 ml) was added drop wise to the suspension to adjust the pH to 7-7.5. The mass was cooled, filtered and washed with water (150 ml). The product was dried under vacuum to obtain N-(4-Fluoro-2-methoxy-5-nitrophenyl)acetamide (180 gm, Yield: 96%) as light pink to off white solid. HPLC purity observed was 98.2%

Example 5
Preparation of N-(4-Fluoro-2-methoxy-5-nitrophenyl)acetamide
Concentrated sulfuric acid (172 gm) was added drop wise to water (260 ml) and mass was heated to 90-95°C. N-(4-Fluoro-2-methoxy-5-nitrophenyl)acetamide (100 g) was added lot wise to the resulted reaction mass at 90-95°C over a period of 45-60 minutes. After addition completion, the reaction mass was heated to 90-95°C for 1 hour. After completion of the reaction, the mass was cooled to 75-80°C and charcoal (8.5 g) was added. The mixture was stirred for 1 hour at 80°C. The mass was cooled to room temperature and filtered on hyflo bed. The hyflo bed was washed with water (200 ml) and aqueous layer was extracted with chloroform (200 ml). The layers were separated and pH of aqueous layer was adjusted ~7.0 by adding 25% aqueous ammonia (330 ml). The mixture was stirred for 30 minutes, filtered and washed with water (200 ml). The solid was dried under vacuum to get N-(4-Fluoro-2-methoxy-5-nitrophenyl)acetamide (63 gm, Yield: 77%) as brownish yellow solid. HPLC purity observed was 99.2%.

Example 6: Comparative Data
Preparation of 4-fluoro-2-methoxy-1-nitrobenzene using methanol as a solvent
Methanol (1000 ml) was charged to 2,4-difluoronitrobenzene (1000 g) and stirred. The mixture was heated to 50°C for 15 -20 minutes. Sodium methoxide solution was prepared separately by dissolving sodium methoxide (339 gm) in methanol (3000 ml). Sodium methoxide solution was added dropwise to the above reaction mixture over 7 hours. The reaction mass was maintained for 20-24 hours. pH of the reaction mass was adjusted to 7.5-8 using acetic acid. Methanol was distilled under vacuum and water (2000 ml) was charged to the mass. Chloroform (2000 ml) was charged and the mixture was stirred and the layers were separated. The aqueous layer was extracted again with chloroform (500 ml x 2). The organic layer was combined and dried over sodium sulfate. The organic layer was distilled and the oily mass of 4-fluoro-2-methoxy-1-nitrobenzene was isolated.
The 4-fluoro-2-methoxy-1-nitrobenzene was analyzed for regioisomer formed.
4-fluoro-2-methoxy-1-nitrobenzene formed in the reaction was 44% and 4-methoxy-2-fluoro-1-nitrobenzene (regeoisomer formed) was 43%.

In the context of the present invention, the process of the present invention is an eco-friendly and a cost effective process. The process of the present invention for the preparation of 4-halo-2-methoxy nitrobenzene (I-1) minimizes isomeric impurities formation. Further, a process for preparation of 4-halo-2-methoxy aniline (I-2) selectively reduces nitro group of 4-halo-2-methoxy nitrobenzene and minimizes dehalogenation side reaction and is free from dehalogenated impurity. The process for preparation of 4-halo-2-methoxyaniline (I-2), wherein use of the catalyst can be recovered and reused in the hydrogenation and further the process is cost effective and industrially feasible.

The foregoing description of specific embodiments of the present invention has been presented for purposes of illustration and description. They are not intended to be exhaustive or to limit the present invention to the precise forms disclosed, and obviously many modifications and variations are possible in light of the above teaching.

The embodiments were chosen and described in order to best explain the principles of the present invention and its practical application, to thereby enable others, skilled in the art to best utilize the present invention and various embodiments with various modifications as are suited to the particular use contemplated.

It is understood that various omission and substitutions of equivalents are contemplated as circumstance may suggest or render expedient, but such are intended to cover the application or implementation without departing from the spirit or scope of the present invention.
,CLAIMS:
1. A process for preparation of 4-halo-2-methoxy-5-nitroaniline of formula (I),

wherein X is a halo group selected from chloro (Cl), fluoro (F), bromo (Br) and iodo (I), comprising:
(a) conversion of a compound of formula (A) to a compound of formula (I-1);

(b) hydrogenation of the compound of formula (I-1) to form a compound of formula (I-2) in presence of a predefined bimetallic catalyst;

(c) conversion of the compound of formula (I-2) to form 4-halo-2-methoxy-5-nitroaniline of formula (I).

2. The process as claimed in claim 1, wherein a process for preparation of the compound of formula (I-1) in step (a):

wherein X is a halo group selected from chloro (Cl), fluoro (F), bromo (Br) and iodo (I), comprising:
(1) reacting the compound of formula (A)

with a predefined alkali in presence of a predefined alcoholic solvent at a predefined temperature in presence of a predefined emulsifier or a predefined phase transfer catalyst to form a compound of formula (B);

(2) methylation of the compound of formula (B) at a predefined temperature to form the compound of formula (I-1).

3. The process as claimed in claim 2, wherein the predefined alkali in step (1) is selected from alkali hydroxide selected from sodium hydroxide, potassium hydroxide and lithium hydroxide.

4. The process as claimed in claim 2, wherein the predefined alcoholic solvent in step (1) is selected from methanol, ethanol, isopropanol and t-butanol.
5. The process as claimed in claim 2 and 4, wherein the predefined alcoholic solvent is preferably t-butanol.

6. The process as claimed in claim 2, wherein the predefined reflux temperature is 25°C to 30°C.

7. The process as claimed in claim 2, wherein the predefined emulsifier is selected from long chain alkyl sulfonates selected from sodium dodecylbenzene sulfonate.

8. The process as claimed in claim 2, wherein the predefined phase transfer catalyst used is quaternary ammonium salts selected from benzyltriethylammonium chloride, methyltricaprylammonium chloride, methyltributylammonium chloride, and methyltrioctylammonium chloride.

9. The process as claimed in claim 2, wherein the methylation in step (2) is preferably carried out using a predefined methylating agent selected from dimethyl sulfate and methyl iodide.

10. The process as claimed in claim 2, wherein the methylation in step (2) is carried out at a predefined temperature from 10°C to 35°C.

11. The process as claimed in claim 2, wherein the temperature is preferably at 15°C to 25°C.

12. The process as claimed in claim 2, wherein the compound of formula (I-1) has purity of 98% to 99% HPLC purity with 60 % to 70% yield.

13. The process as claimed in claim 1, wherein an alternate process for preparation of the compound of formula (I-1) in step (a)

wherein X is a halo group selected from chloro (Cl), fluoro (F), bromo (Br) and iodo (I), comprising:
reacting the compound of formula (A)

with a predefined alkali in presence of a predefined alcoholic solvent at a predefined temperature to form a compound of formula (I-1).
14. The process as claimed in claim 13, wherein the predefined alkali is selected from sodium methoxide.

15. The process as claimed in claim 13, wherein the predefined alcoholic solvent is selected from methanol, ethanol, propanol, butanol and t-butanol.

16. The process as claimed in claim 13 and 15, wherein the predefined alcoholic solvent is preferably t-butanol.

17. The process as claimed in claim 13, wherein the predefined temperature is preferably 25°C to 35°C.

18. The process as claimed in claim 13, wherein the compound of formula (I-1) has purity of 98% to 99% HPLC purity with 60% to 70% yield.

19. The process as claimed in claim 1, wherein a process for preparation of the compound of formula (I-2) in step (b)

wherein X is a halo group selected from chloro (Cl), fluoro (F), bromo (Br) and iodo (I), comprising:
hydrogenation of compound of formula (I-1) in presence of a predefined bimetallic catalyst and a predefined solvent at a predefined temperature and a predefined hydrogen pressure to yield the compound of formula (I-2).

20. The process as claimed in claim 19, wherein the bimetallic catalyst is composed of a platinum (Pt) catalyst with a copper (Cu) alloy loaded on a carbon (C).

21. The process as claimed in claim 19 and 20, wherein the bimetallic catalyst is composed of 1% Pt and 0.1% to 0.5% Cu loaded on carbon.

22. The process as claimed in claim 19 to 21, wherein the bimetallic catalyst is preferably composed of 1% Pt and 0.1% Cu loaded on 98.9% carbon.

23. The process as claimed in claim 19 to 22, wherein the bimetallic catalysts used is preferably 40% to 60% wet basis.

24. The process as claimed in claim 19 to 23, wherein the bimetallic catalyst used is preferably 50% wet basis.

25. The process as claimed in claim 19, wherein the predefined solvent used is alcoholic solvent selected from methanol, ethanol, isopropanol, n-propanol, n-butanol, isobutanol and t-butanol.

26. The process as claimed in claim 19 and 25, wherein the predefined solvent is preferably t-butanol.

27. The process as claimed in claim 19, wherein the predefined temperature is 40°C to 50°C.

28. The process as claimed in claim 19, wherein the compound of formula (I-2) has purity of 98% to 99.5% HPLC purity with 90% to 95% yield.

29. The process as claimed in claim 1, wherein a process for the conversion of the compound of formula (I-2) to 4-halo-2-methoxy-5-nitroaniline of formula (I) in step (c)

wherein X is a halo group selected from chloro (Cl), fluoro (F), bromo (Br) and iodo (I), comprising:
(i) acetylation of compound of formula (I-2)

in presence of a predefined acetylating agent at a predefined temperature to yield a compound of formula (I-3);

(ii) nitration of the compound of formula (I-3) in presence of a predefined nitrating mixture without a solvent or with a predefined chlorinated solvent at a predefined temperature to form compound of formula (I-4); and

(iii) deacetylation of compound of formula (I-4) in presence of a predefined acid to form 4-halo-2-methoxy-5-nitroaniline of formula (I).

30. The process as claimed in claim 29, wherein the predefined acetylating agent used in step (i) is selected from acetic anhydride, acetyl chloride and acetic acid.

31. The process as claimed in claim 29, wherein the predefined temperature in step (i) is 70°C to 120°C.

32. The process as claimed in claim 29, wherein the nitrating mixture used in step (ii) is preferably a mixture of concentrated sulfuric acid and fuming nitric acid.

33. The process as claimed in claim 32, wherein the ratio of concentrated sulfuric acid to fuming nitric acid is 4.0:1 to 4.5:1.

34. The process as claimed in claim 29, wherein the nitration reaction is step (ii) is carried out without any solvent or in a predefined chlorinated solvent selected from methylene dichloride, chloroform and 1,2-dichloroethane.

35. The process as claimed in claim 29, wherein the predefined temperature is at temperature is 10°C to 25°C.

36. The process as claimed in claim 29, wherein the predefined temperature is preferably 15°C to 20°C.

37. The process as claimed in claim 29, wherein the predefined acid used in the deacetylation reaction of step (iii) is sulfuric acid.

38. The process as claimed in claim 37, wherein sulfuric acid used is in range of 10% to 70%, and preferably 20% to 40%.

39. The process as claimed in claim 1, wherein 4-halo-2-methoxy-5-nitroaniline of formula (I) has purity of 99.0% to 99.95% HPLC purity with 70% to 80% yield.