Claims:We claim;

1. A process for selective preparation of highly pure 4 -fluoro-2-methoxy-5-nitroaniline, with less than 0.5% of 2-fluoro-4-methoxy-5-nitrobenzenamine and 2,4-dimethoxy-5-nitrobenzenamine comprising;
(i) Nitrating 2,4-difluoro-aniline with the nitrating agent at -5 to 0°C to obtain 2,4-difluoro-5-nitrobenzenamine;
(ii) Methylating 2,4-difluoro-5-nitrobenzenamine dissolved in methanol using methanolic sodium hydroxide to obtain crude 4-fluoro-2-methoxy-5-nitroaniline; and
(iii) Purifying the crude product by slurrying in a mixture of acetone and water as anti-solvent.

2. The process according to claim 1, wherein the sulphuric acid in step (i) is used in an amount of 8-10 volumes.

3. The process according to claim 1, wherein the sodium hydroxide in step (i) is used in the molar ratio of 2-2.5 moles and pH range up to 9-9.5.

4. The process according to claim 1, wherein the solvent in step (i) is selected from DCM, MTBE, EtOAc alone or mixtures thereof.

5. The process according to claim 1, wherein the sodium hydroxide in step (ii) is used in the molar ratio of 1-2 moles.

6. The process according to claim 1, wherein pH of the reaction mixture was adjusted to 6-6.5 using 6N HCl.

7. The process according to claim 1, wherein acetone in step (iii) is used in an amount of 2 to 4 volumes and water as anti-solvent in an amount of 5 to 15 volumes.
8. The process according to claim 1, wherein the temperature of step (iii) is in the range of 40-80°C.
, Description:FIELD OF INVENTION:
The present invention relates to a process for selective preparation of highly pure 4-fluoro-2-methoxy-5-nitroaniline with less than 0.5% of 2-fluoro-4-methoxy-5-nitrobenzenamine and 2,4-dimethoxy-5-nitrobenzenamine impurities.

BACKGROUND OF THE INVENTION:
Chemical synthesis of API should meet acceptable standards of quality including limits of impurities and residual solvents. During commercial synthesis of API various factors such as starting materials, intermediates formed, reaction conditions, amount of reagents/solvents used, purification and reprocessing methods used, the enantiomeric or isomeric nature of the API, humidity and pressure levels and others are found to influence the yield and purity of the desired product.

4-fluoro-2-methoxy-5-nitroaniline is a useful intermediate in the manufacture of a variety of chemical products and in the preparation of intermediates for third-generation epidermal growth factor receptor inhibitor, Osimertinib.

US8946235 discloses an intermediate 4-fluoro-2-methoxy-5-nitroaniline (intermediate 23) for synthesis of intermediates of pyrimidine compounds of general formula I, which broadly covers Osimertinib.

(I)
The said intermediate 23 is prepared by nitration of 4-Fluoro-2-methoxyaniline using concentrated H2SO4 and KNO3 at a temperature below 10° C, the mixture was basified with NH4OH, filtered washed and purified by FCC.

Selectivity can be a challenge during nitration of aniline or substituted aniline and there is a possibility of formation of more than one compound which can act as contaminants and impact the yield and purity of the desired product. Further, since the rate and selectivity in electrophilic aromatic substitution depend upon the substituents on the aromatic ring it is necessary to design a process which can control the selectivity of the desired compound.

Thus, it is desirable to provide a process for selective preparation of 4-fluoro-2-methoxy-5-nitroaniline which is highly pure and contain less than 0.5% of the undesired impurities.

SUMMARY OF THE INVENTION:
To meet the objectives, the present invention provide a process for synthesis of highly pure compound, 4 -fluoro-2-methoxy-5-nitroaniline, which contain less than 0.5% of 2-fluoro-4-methoxy-5-nitrobenzenamine and 2,4-dimethoxy-5-nitrobenzenamine impurities.

Accordingly, the process step comprises:
(i) Nitrating 2,4-difluoro-aniline with the nitrating agent at -5 to 0°C, to obtain 2,4-difluoro-5-nitrobenzenamine;
(ii) Methylating 2,4-difluoro-5-nitrobenzenamine dissolved in methanol using methanolic sodium hydroxide to obtain crude 4 -fluoro-2-methoxy-5-nitroaniline; and
(iii) Purifying the crude product by slurrying in a mixture of acetone and water to obtain pure 4 -fluoro-2-methoxy-5-nitroaniline with less than 0.5% of 2-fluoro-4-methoxy-5-nitrobenzenamine and 2,4-dimethoxy-5-nitrobenzenamine.

DETAILED DESCRIPTION OF THE INVENTION:
The present invention relates to cost effective process for selective preparation of highly pure 4-fluoro-2-methoxy-5-nitroaniline which contain less than 0.5% of 2-fluoro-4-methoxy-5-nitrobenzenamine and 2,4-dimethoxy-5-nitrobenzenamine.

The presence of the halogen atom (i.e. fluorine atom), in the starting compound 2,4-difluoro-aniline, substituted at ortho and para to amino group deactivate the meta position and ensures electrophilic substitution of the nitro group at the desired location under the nitrating conditions employed. Further, the negative inductive effect of the nitro group (at 5th position) para to fluorine atom (ortho to aniline), in the intermediate 2,4-difluoro-5-nitrobenzenamine, assist in substitution of said fluorine group by the methoxy group during methylation and reduces the formation of undesired impurities such as 2-fluoro-4-methoxy-5-nitrobenzenamine and 2,4-dimethoxy-5-nitrobenzenamine resulting in preparation of highly pure 4-fluoro-2-methoxy-5-nitroaniline.

In an embodiment of the present process, to the solution of the starting reagent 2,4-difluoro-aniline is added nitrating mixture of nitric acid (conc. 65%) and sulphuric acid (conc.) at -5 to 0°C. The reaction mixture is stirred for about an hour, filtered and the filtrate is basified using 50% sodium hydroxide solution. The aqueous layer is extracted in a suitable organic solvent, the organic layer is washed and concentrated to yield 2,4-difluoro-5-nitrobenzenamine in high purity.

The concentrated sulphuric acid is used in an amount ranging from 8 to 10 volumes; the sodium hydroxide for basification of the mixture is used in the molar ratio of 2-2.5 moles. The pH of the mixture is maintained in the range of 9 to 9.5 and the aqueous layer is extracted using polar solvents such as DCM, MTBE or EtOAc alone or mixtures thereof.

Further, to the methanolic suspension of 2,4-difluoro-5-nitrobenzenamine is added drop wise methanolic sodium hydroxide at 0 to 5°C and the reaction mixture is stirred for 7-8 hrs in the temperature range 25- 65°C; preferably at room temperature. The base is used in 1-2 molar ratio; preferably 1.7 mole ratio. The pH of the mixture is adjusted to 6-6.5 using 6N HCl. The solid obtained is collected by filtration and washed to isolate the crude 4 -fluoro-2-methoxy-5-nitroaniline.

The purification of the crude product comprises slurrying crude 4 -fluoro-2-methoxy-5-nitroaniline using 2 to 4 volumes of acetone; preferably 3 volumes of acetone and 5 to 15 volumes of water; preferably 10 volumes at a temperature of 40-80°C preferably at 60-65°C for about 2-3 hours followed by cooling the mixture to room temperature and filtering. The purification is repeated three or four times to yield highly pure 4-fluoro-2-methoxy-5-nitroaniline with 99.71% purity.

Experimental:
Example 1: Preparation of 2, 4-difluoro-5-nitrobenzenamine
Nitric acid (65%, 75mL) was added to the solution of 2,4-Fluoroaniline (100g, 0.774moles) in sulfuric acid (1L) at -5 to 0°C. Reaction mixture was stirred for 1hr before pouring into cold water (4L). The solution was filtered and the filtrate was basified using 50% Sodium hydroxide solution (2L). The aqueous layer was extracted with dichloromethane. The organic layer was washed with water and concentrated to obtain 115g of 2,4-difluoro-5-nitrobenzenamine with 85% yield and 99.52% purity.

Example 2: Preparation of 4-fluoro-2-methoxy-5-nitroaniline
Sodium hydroxide (43.7g, 1.092moles) dissolved in Methanol (560mL) was added drop wise to a suspension of 2,4-difluoro-5-nitrobenzenamine (112 g, 0.643moles) of example 1 in Methanol (560mL) at 0 to 5°C. The reaction mixture was further stirred for 7 hrs at room temperature. pH of the reaction mixture was adjusted to 6-6.5 using 6N HCl (100mL). Obtained solid was collected by filtration and washed with water. 78 g of the crude product was isolated with 65% yield and 94.8% purity with 3.6% of 2,4-dimethoxy-5-nitrobenzenamine and 0.14% of 2-fluoro-4-methoxy-5-nitrobenzenamine.

Example 3: Purification of crude 4-fluoro-2-methoxy-5-nitroaniline
The crude product (73gm) of example 2 was dissolved in acetone (219mL), and water (730 mL) as anti-solvent was added slowly. The obtained slurry was heated to 60 to 65°C for 3h. It was cooled to room temperature and filtered. The process of purification was repeated thrice to get 48g of the product in 40% yield and 99.6% purity with 0.4% of 2-fluoro-4-methoxy-5-nitrobenzenamine and 2,4-dimethoxy-5-nitrobenzenamine.

The examples described in are by way of illustration and therefore, should not be construed to limit the scope of the invention. Certain modifications and equivalents will be apparent to those skilled in the art and are included within the scope of the invention.