DESC:FIELD OF THE INVENTION
The present invention relates to a novel process for the preparation of ethyl 2-[(2,6-difluoro-benzyl)-ethoxycarbonyl-amino]-4-methyl-5-(4-nitro-phenyl)-thiophene-3-carboxylate (1).

The compound of formula (1) is used as key intermediate for the manufacturing of Relugolix.
BACKGROUND OF THE INVENTION
The following discussion of the prior art is intended to present the invention in an appropriate technical context and allows its significance to be properly appreciated. Unless clearly indicated to the contrary, reference to any prior art in this specification should not be construed as an expressed or implied admission that such art is widely known or forms part of common general knowledge in the field.
Relugolix, is a once a daily selective antagonist of gonadotropin-releasing hormone receptor, which is used in the treatment of prostate cancer in men and uterine fibroids in women. Relugolix, sold under the brand names Orgovyx® and Relumina®. It was approved for use for the treatment of uterine fibroids in Japan in January 2019, and for the treatment of prostate cancer in the United States in December 2020. Relugolix is available in the form of 40 and 120 mg oral tablets.
Relugolix is a non-peptide, small-molecule compound, and is chemically termed as l-(4-(l-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxypyridazin-3-yl)-2,4-dioxo-l,2,3,4-tetrahydrothieno(2,3-d)pyrimidin-6-yl)phenyl)-3-methoxyurea, having the formula,

Relugolix
Synthesis of Relugolix involves a key intermediate of compound of formula (1). The preparation of compound of formula (1) is reported in J. Med. Chem. 2011, 54, 4998-5012, wherein it is synthesized by N-alkylation of compound (2) by using alkyl halide compound of formula (3) as shown in the scheme 1 below:

The process described in J. Med. Chem. 2011, 54, 4998-5012 poses the following limitations:
• requirement of excess amount of expensive alkyl halide;
• use of expensive potassium iodide as catalyst.
Hence, an object of the present invention is a new improved and commercially viable process for the manufacture of this compound of formula (1).
OBJECT OF THE INVENTION
An object of the present invention is to provide a method for preparation of ethyl 2-[(2,6-difluoro-benzyl)-ethoxycarbonyl-amino]-4-methyl-5-(4-nitro-phenyl)-thiophene-3-carboxylate of formula (1).

Another object of the invention is to provide a novel process for preparation of alkyl halide compound of formula (4), which is used in the preparation of intermediate compound of formula (1).

DETAILED DESCRIPTION OF THE INVENTION
Before the present invention is described, it is to be understood that this invention is not limited to particular methodologies and materials described, as these may vary as per the person skilled in the art. It is also to be understood that the terminology used in the description is for the purpose of describing the particular embodiments only and is not intended to limit the scope of the present invention.
Before the present invention is described, it is to be understood that unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Further, it is to be understood that the present invention is not limited to the methodologies and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, the preferred methods and materials are described, as these may vary within the specification indicated. Unless stated to the contrary, any use of the words such as "including," "containing," "comprising," "having" and the like, means "including without limitation" and shall not be construed to limit any general statement that it follows to the specific or similar items or matters immediately following it. Embodiments of the invention are not mutually exclusive but may be implemented in various combinations. The described embodiments of the invention and the disclosed examples are given for the purpose of illustration rather than limitation of the invention as set forth the appended claims. Further the terms disclosed embodiments are merely exemplary methods of the invention, which may be embodied in various forms.
The term “about,” as used herein, is intended to qualify the numerical values, which it modifies, denoting such a value as variable within a margin of error. When no particular margin of error, such as a standard deviation to a mean value given in a chart or table of data, is recited, the term “about” should be understood to mean that range which would encompass the recited value and the range which would be included by rounding up or down to that figure as well, considering significant figures.
The term “heating”, as used herein, is heating the solution gradually to a temperature in the range of 40°C - 150 °C.
According to one of the embodiments, the present invention provides a novel process for the preparation of ethyl 2-[(2,6-Difluoro-benzyl)-ethoxycarbonyl-amino]-4-methyl-5-(4-nitro-phenyl)-thiophene-3-carboxylate (1), comprising reacting a compound of (2) with a compound of formula (4) in a solvent and in presence of a base to provide ethyl 2-[(2,6-Difluoro-benzyl)-ethoxycarbonyl-amino]-4-methyl-5-(4-nitro-phenyl)-thiophene-3-carboxylate (1).

The solvent used in the preparation of formula (1) is an ether solvent selected from tetrahydrofuran, cyclopentyl methyl ether, 2-methyltetrahydrofuran, diethyl ether, 1,4-dioxane, 1,2-dioxane or 1,3-dioxane; a hydrocarbon solvent selected from toluene, hexane, heptane, pet ether, xylene, cyclohexane; an alcoholic solvent selected from methanol, ethanol, isopropanol (IPA), t-amyl alcohol, t-butyl alcohol or hexanol; a halogenated solvent selected from dichloromethane, 4-bromotoluene, diiodomethane, carbon tetrachloride, chlorobenzene or chloroform; a ketone solvent selected from acetone or methyl isobutyl ketone (MIBK); an aprotic solvent selected from acetonitrile, N,N-dimethyl formamide (DMF), N,N-dimethyl acetamide, dimethyl sulfoxide (DMSO) or N-methylpyrrolidone (NMP); an aromatic solvent selected from toluene, xylene or benzene; water; or a mixture thereof. The most preferred solvent used in the preparation of (1) is DMF.
The base used in in the preparation of formula (1) is selected from an alkali metal hydroxide such as lithium hydroxide, sodium hydroxide or potassium hydroxide; alkali metal and alkali earth metal salts of acetic acid such as sodium acetate, potassium acetate, magnesium acetate, calcium acetate; alkali metal carbonate such as lithium carbonate, sodium carbonate, potassium carbonate or caesium carbonate; alkali metal bicarbonate such as sodium bicarbonate or potassium bicarbonate; alkali metal alkoxide such as sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, potassium tert-butoxide, or organic amines such as diethylamine, triethylamine, di-n-propyl amine, di-isopropyl amine, tertbutylamine, morpholine, piperidine, diisopropylethylamine, pyridine, 4-dimethyl aminopyridine, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) or 1,5-diazabicyclo[4.3.0]non-5-ene (DBN). The most preferred base used in the preparation of (1) is potassium carbonate.
According to the present invention, the mole ratio of compound of formula (4) with respect to compound of formula (2) is selected from 1.0 to 3.0, preferably 1.4 equivalent.
The reaction for the preparation of compound of formula (1) is carried out at temperature ranging from 25° C to 90° C; preferably at temperature ranging from 60° C to 70° C.
In another aspect, the present invention relates to a novel process for preparation of compound of formula (4), comprising:
a) hydrolysing 2,6-difluorobenzonitrile (5) or 2,6-difluorobenzamide (5a) with an aqueous solution of hydrochloric acid or sulfuric acid to provide 2,6-difluorobenzoic acid (6);
b) esterification of 2,6-difluorobenzoic acid (6) by reacting it with an alcoholic solvent in presence of a suitable esterification catalyst to provide methyl 2,6-difluorobenzoate (7);
c) reducing methyl 2,6-difluorobenzoate (7) to provide (2,6-difluorophenyl) methanol (8); and
d) activating the hydroxyl group of (2,6-difluorophenyl) methanol (8) using an activating reagent, optionally in a solvent and optionally in presence of a base to provide compound of formula (4).
The suitable esterification catalyst used in step (b) is selected from thionyl chloride and concentrated sulfuric acid.
The alcoholic solvent used in step (b) is selected from methanol, ethanol, isopropanol (IPA), t-amyl alcohol, t-butyl alcohol or hexanol. Preferably, the solvent used is methanol.
The reduction of compound of formula (7) in step (c) is carried out using reducing agent selected from diborane, borane-dimethyl sulfide, borane-THF complex, sodium triacetoxyborohydride, sodium cyanoborohydride, Fe/CaCl2, FeSO4, Fe powder, Raney Nickel, Pd/C, NaBH4, Potassium Borohydride, SnCl2.2H2O, Zn dust, Sodium Borohydride with Pd/C, thiophenol/trifluoroacetic acid, sodium sulphite, sodium hyposulphite, Na2S, NaBH4, NaBH4/BF3-diethyl ether, NiCl2.6H2O, LiBH4, LiAlH4. Preferably, the reducing agent is NaBH4.
The solvent used for reducing compound of formula (7) in step (c) is an ether solvent selected from tetrahydrofuran, cyclopentyl methyl ether, 2-methyltetrahydrofuran, diethyl ether, 1,4-dioxane, 1,2-dioxane or 1,3-dioxane; a hydrocarbon solvent selected from toluene, hexane, heptane, pet ether, xylene, cyclohexane; an alcoholic solvent selected from methanol, ethanol, isopropanol (IPA), t-amyl alcohol, t-butyl alcohol or hexanol; a halogenated solvent selected from dichloromethane, 4-bromotoluene, diiodomethane, carbon tetrachloride, chlorobenzene or chloroform; a ketone solvent selected from acetone or methyl isobutyl ketone (MIBK); an aprotic solvent selected from acetonitrile, N,N-dimethyl formamide (DMF), N,N-dimethyl acetamide, dimethyl sulfoxide (DMSO) or N-methylpyrrolidone (NMP); an aromatic solvent selected from toluene, xylene or benzene; water; or a mixture thereof.
The solvent used in step (d) is an ether solvent selected from tetrahydrofuran, cyclopentyl methyl ether, 2-methyltetrahydrofuran, diethyl ether, 1,4-dioxane, 1,2-dioxane or 1,3-dioxane; a hydrocarbon solvent selected from toluene, hexane, heptane, pet ether, xylene, cyclohexane; an alcoholic solvent selected from methanol, ethanol, isopropanol (IPA), t-amyl alcohol, t-butyl alcohol or hexanol; a halogenated solvent selected from dichloromethane, 4-bromotoluene, diiodomethane, carbon tetrachloride, chlorobenzene or chloroform; a ketone solvent selected from acetone or methyl isobutyl ketone (MIBK); an aprotic solvent selected from acetonitrile, N,N-dimethyl formamide (DMF), N,N-dimethyl acetamide, dimethyl sulfoxide (DMSO) or N-methylpyrrolidone (NMP); an aromatic solvent selected from toluene, xylene or benzene; water; or a mixture thereof.
The base used in step (d) is selected from an alkali metal hydroxide such as lithium hydroxide, sodium hydroxide or potassium hydroxide; alkali metal and alkali earth metal salts of acetic acid such as sodium acetate, potassium acetate, magnesium acetate, calcium acetate; alkali metal carbonate such as lithium carbonate, sodium carbonate, potassium carbonate or caesium carbonate; alkali metal bicarbonate such as sodium bicarbonate or potassium bicarbonate; alkali metal alkoxide such as sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, potassium tert-butoxide, or organic amines such as diethylamine, triethylamine, di-n-propyl amine, di-isopropyl amine, tertbutylamine, morpholine, piperidine, diisopropylethylamine, pyridine, 4-dimethyl aminopyridine, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) or 1,5-diazabicyclo[4.3.0]non-5-ene (DBN). The most preferred base used in step (d) is a triethylamine.
The activating reagent used in step (d) for converting hydroxyl functionality into a good leaving group is selected from thionyl chloride, oxalyl chloride, thionyl bromide, methanesulfonyl chloride, methanesulfonic anhydride, trifluoromethanesulfonyl chloride, trifluoromethanesulfonic anhydride, p-toluenesulfonyl chloride, p-halobenzene sulfonyl chloride, p-nitrobenzenesulfonyl chloride, benzenesulfonyl chloride, halomethyl methyl ether (MOM), t-butyl chloride, t-butyl bromide, benzyl bromide, benzyl acetate, benzyl ethers, benzyl benzoate, benzyl chloride, p-methoxybenzyl chloride, halotrimethylsilanes, t-butyldimethylsilyl chloride, t-butyldiphenylsilyl chloride, triisopropylsilyl chloride, triphenylmethyl chloride, acyl chloride, acetic anhydride, t-butylacetyl chloride or t-butylacetic anhydride. Preferably, the activating reagent is methanesulfonyl chloride & thionyl chloride respectively.

The whole synthetic scheme of preparation of compound of formula (1) according to the present invention can be represented as below in scheme 3:

According to the invention, the overall yield of compound of formula (1) as obtained by using the process of the present invention is at least about 91% yield with purity of at least about 98% by HPLC. Thereby, the practicability of the reaction is greatly enhanced at both the laboratory scale and the industrial scale.

The details of the present invention are described in the Examples given below which are provided to illustrate the invention and therefore should not be construed to limit the scope of the present invention.
Examples of the invention
Example 1:
Preparation of 2, 6-difluorobenzoic acid (6)
2, 6-difluorobenzonitrile (5) (30g, 0.215 mol) in (90ml) water was taken in a round bottom flask. To this reaction mixture sulfuric acid (72.6 ml) was added slowly. Heated the reaction mixture to 90-95° C for 5-7 hrs at same temperature. Cooled the reaction mixture to 10-20°C, added (150 ml water) and stirred for 1 hrs at 20-25°C temperature. Filtered the precipitated solid, washed with water and dried to at 55°C to provide the title compound. Yield: 31 g, Yield: 92%.
Example 2:
Preparation of 2, 6-difluorobenzoic acid (6)
2, 6-difluorobenzamide (5a) (30g, 0.215 mol) in (90ml) water was taken in a round bottom flask. To this reaction mixture sulfuric acid (72.6 ml) was added slowly. Heated the reaction mixture to 90-95° C for 5-7 hrs at same temperature. Cooled the reaction mixture to 10-20°C, added (150 ml water) and stirred for 1 hrs at 20-25°C temperature. Filtered the precipitated solid, washed with water and dried to at 55°C to provide the title compound. Yield: 31 g, Yield: 92%.
Example 3:
Preparation of methyl 2, 6-difluorobenzoate (7)
2, 6-difluorobenzoic acid of formula (6) (30g, 0.189mol) in (150ml) methanol was taken in a round bottom flask. To this reaction mixture thionyl chloride (33.84g, 0.284mol) was added slowly. Heated the reaction mixture to 60-65° C for 3-4 hrs at same temperature. Cooled the reaction mixture to room temperature. The reaction mixture was concentrated under vacuum. To this obtained residue (60 ml) water was added slowly. The compound was extracted using dichloromethane. Distilled off the solvent to get an oily product. Weight: 30.8 g, Yield: 96%
Example 4:
Preparation of (2, 6-difluorophenyl) methanol (8)
2, 6-difluorobenzoate (7) (30g, 0.174mol) in (200ml) tetrahydrofuran was taken in a round bottom flask. To this reaction mixture sodium borohydride (9.9g, 0.261mol) was added slowly and heated the reaction mixture to reflux temperature. To this reaction mixture (15ml) methanol was added slowly (effervescence was observed) and maintained at reflux temperature for 4 hrs. Cooled the reaction mixture to 5-10°C. Acidify the reaction mixture with hydrochloric acid. Added 150 ml water slowly to the reaction mixture. The compound was extracted using dichloromethane. Distilled off the solvent to get an oily product. Weight: 22.5 g, Yield: 90%.
Example 5:
Preparation of 2, 6-difluorobenzyl methanesulfonate (4)
(2,6-difluorophenyl) methanol (8) (20g, 0.138mol) in (500ml) dichloromethane was taken in a round bottom flask. To this reaction mixture methane sulfonyl chloride (19.07g, 0.166mol) was added slowly. The reaction mixture was cooled to 0-10° C and added triethyl amine (21.06g, 0.208mol) slowly to the reaction mixture over a period of 30 mins. The reaction mixture was stirred for 4 hrs at room temperature. Water (40 ml) was added to the obtained reaction mixture. Both the organic and aqueous layers were separated, and the organic layer was washed with sodium bicarbonate solution. Distilled off the solvent to get an oily product. Weight: 22 g, Yield: 71%.

Example 6:
Preparation of 2, 6-difluorobenzyl chloride (3a)
(2, 6-difluorophenyl) methanol (8) (20g, 0.138 mol) in (500ml) dichloromethane, N,N-dimethyl formamide (DMF) were taken in a round bottom flask. To this reaction mixture thionyl chloride (22.82g, 0.191mol) was added slowly at 25-35°C. The reaction mixture was stirred under reflux temperature till completion of reaction. Water (40ml) was added to the reaction mixture at 10-20°C. Both the organic and aqueous layers were separated, and the organic layer was washed with sodium bicarbonate solution. Distilled off the solvent to get an oily product 2, 6-difluorobenzyl chloride. Weight: 18.8 g, Yield: 94%.
Example 7:
Preparation of ethyl 3-(ethoxycarbonyl)-4-methyl-5-(4-nitrophenyl) thiophen-2-ylcarbamate (2)
Ethyl 2-amino-4-methyl-5-(4-nitrophenyl) thiophene-3-carboxylate (35g, 0.114 mol) in (105ml) toluene was taken in a round bottom flask. The reaction mixture was heated to 80-90° C and ethyl chloroformate (24.79g, 0.228mol) was added slowly over a period of 30 mins. The temperature of the reaction mixture was raised to 100-105° C and maintain the same temperature for 3 hrs. The reaction mixture was cooled to 55-60°C and ethanol slowly added at same temperature. The reaction mixture was stirred for 30 minutes at 55 to 60°C. Further cooled the reaction mixture to 15-20° C and stirred for 1 hrs at the same temperature. Filtered the precipitated solid and then dried the material to get the title compound. Weight: 40g, Yield: 93%, HPLC purity >98%.

Example 8:
Preparation of ethyl 2-[(2,6-difluoro-benzyl)-ethoxycarbonyl-amino]-4-methyl-5-(4-nitro-phenyl)-thiophene-3-carboxylate (1)
Ethyl 3-(ethoxycarbonyl)-4-methyl-5-(4-nitrophenyl) thiophen-2-ylcarbamate (2) (10g, 0.026 mol) in (50ml) dimethyl formamide (DMF) was taken in a round bottom flask at room temperature. Potassium carbonate (5.5g, 0.039mol) was added and stirred for 30 mins at room temperature. 2,6-difluorobenzyl methanesulfonate (4) (8.22g, 0.037mol) was added to the reaction mixture and stirred for 45 minutes and heated to 65-70°C for 6-8 hrs. The reaction mixture was cooled to room temperature and slowly added (100ml) water. The reaction mixture was stirred for 1 hr at room temperature. Filtered the solid, washed with water and then dried to get the title compound. Further the obtained solid recrystallized from ethyl acetate-cyclohexane. Weight: 12g, Yield: 91%. HPLC purity >98%.
Example 9:
Preparation of ethyl 2-[(2,6-difluoro-benzyl)-ethoxycarbonyl-amino]-4-methyl-5-(4-nitro-phenyl)-thiophene-3-carboxylate (1)
Ethyl 3-(ethoxycarbonyl)-4-methyl-5-(4-nitrophenyl) thiophen-2-ylcarbamate (2) (10g, 0.026 mol) in (50ml) dimethyl formamide (DMF) was taken in a round bottom flask at room temperature. Potassium carbonate (5.5g, 0.039mol) was added and stirred for 30 mins at room temperature. 2,6-difluorobenzyl chloride (4) (6.44g, 0.039mol) was added to the reaction mixture in a sequential manner and (0.44g) potassium iodide was added into it. The reaction mixture was heated to 65-70°C for 6-8 hrs. The reaction mixture was cooled to room temperature and slowly added (100 ml) water. The reaction mixture was stirred for 1 hr at room temperature. Filtered the solid, washed with water and then dried to get the title compound. Further the obtained solid recrystallized from ethyl acetate-cyclohexane. Weight: 12g, Yield: 91%. HPLC purity >98%.

,CLAIMS:1. A novel process for the preparation of Ethyl 2-[(2,6-Difluoro-benzyl)-ethoxycarbonyl-amino]-4-methyl-5-(4-nitro-phenyl)-thiophene-3-carboxylate (1), comprising reacting a compound of (2) with a compound of formula (4) in a solvent and in presence of a base to provide Ethyl 2-[(2,6-Difluoro-benzyl)-ethoxycarbonyl-amino]-4-methyl-5-(4-nitro-phenyl)-thiophene-3-carboxylate (1).

2. The process as claimed in claim 1, wherein the solvent used in the preparation of formula (1) is an ether solvent selected from tetrahydrofuran, cyclopentyl methyl ether, 2-methyltetrahydrofuran, diethyl ether, 1,4-dioxane, 1,2-dioxane or 1,3-dioxane; a hydrocarbon solvent selected from toluene, hexane, heptane, pet ether, xylene, cyclohexane; an alcoholic solvent selected from methanol, ethanol, isopropanol (IPA), t-amyl alcohol, t-butyl alcohol or hexanol; a halogenated solvent selected from dichloromethane, 4-bromotoluene, diiodomethane, carbon tetrachloride, chlorobenzene or chloroform; a ketone solvent selected from acetone or methyl isobutyl ketone (MIBK); an aprotic solvent selected from acetonitrile, N,N-dimethyl formamide (DMF), N,N-dimethyl acetamide, dimethyl sulfoxide (DMSO) or N-methylpyrrolidone (NMP); an aromatic solvent selected from toluene, xylene or benzene; water; or a mixture thereof.

3. The process as claimed in claim 1, wherein the base used in in the preparation of formula (1) is selected from an alkali metal hydroxide such as lithium hydroxide, sodium hydroxide or potassium hydroxide; alkali metal and alkali earth metal salts of acetic acid such as sodium acetate, potassium acetate, magnesium acetate, calcium acetate; alkali metal carbonate such as lithium carbonate, sodium carbonate, potassium carbonate or caesium carbonate; alkali metal bicarbonate such as sodium bicarbonate or potassium bicarbonate; alkali metal alkoxide such as sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, potassium tert-butoxide, or organic amines such as diethylamine, triethylamine, di-n-propyl amine, di-isopropyl amine, tertbutylamine, morpholine, piperidine, diisopropylethylamine, pyridine, 4-dimethyl aminopyridine, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) or 1,5-diazabicyclo[4.3.0]non-5-ene (DBN).

4. The process as claimed in claim 1, wherein the mole ratio of compound of formula (4) with respect to compound of formula (2) is selected from 1.0 to 3.0.

5. The process as claimed in claim 1, wherein the reaction for the preparation of compound of formula (1) is carried out at temperature ranging from 60° C to 70° C.

6. The process as claimed in claim 1, wherein the novel process for preparation of compound of formula (4), comprising:
a) hydrolysing 2,6-difluorobenzonitrile (5) or 2,6-difluorobenzamide (5”) with an aqueous solution of hydrochloric acid or sulfuric acid to provide 2,6-difluorobenzoic acid (6);
b) esterification of 2,6-difluorobenzoic acid (6) by reacting it with an alcoholic solvent in presence of a suitable esterification catalyst to provide methyl 2,6-difluorobenzoate (7);
c) reducing methyl 2,6-difluorobenzoate (7) to provide (2,6-difluorophenyl) methanol (8); and
d) activating the hydroxyl group of (2,6-difluorophenyl) methanol (8) using an activating reagent, optionally in a solvent and optionally in presence of a base to provide compound of formula (4).

7. The process as claimed in claim 1, wherein,
in step (b) the esterification catalyst is selected from thionyl chloride and concentrated sulfuric acid;

in step (b) the alcoholic solvent is selected from methanol, ethanol, isopropanol (IPA), t-amyl alcohol, t-butyl alcohol or hexanol;

in step (c) the reduction of compound of formula (7) is carried out using reducing agent selected from diborane, borane-dimethyl sulfide, borane-THF complex, sodium triacetoxyborohydride, sodium cyanoborohydride, Fe/CaCl2, FeSO4, Fe powder, Raney Nickel, Pd/C, NaBH4, Potassium Borohydride, SnCl2.2H2O, Zn dust, Sodium Borohydride with Pd/C, thiophenol/trifluoroacetic acid, sodium sulphite, sodium hyposulphite, Na2S, NaBH4, NaBH4/BF3-diethyl ether, NiCl2.6H2O, LiBH4, LiAlH4;

in step (c) the solvent used for reducing compound of formula (7) is an ether solvent selected from tetrahydrofuran, cyclopentyl methyl ether, 2-methyltetrahydrofuran, diethyl ether, 1,4-dioxane, 1,2-dioxane or 1,3-dioxane; a hydrocarbon solvent selected from toluene, hexane, heptane, pet ether, xylene, cyclohexane; an alcoholic solvent selected from methanol, ethanol, isopropanol (IPA), t-amyl alcohol, t-butyl alcohol or hexanol; a halogenated solvent selected from dichloromethane, 4-bromotoluene, diiodomethane, carbon tetrachloride, chlorobenzene or chloroform; a ketone solvent selected from acetone or methyl isobutyl ketone (MIBK); an aprotic solvent selected from acetonitrile, N,N-dimethyl formamide (DMF), N,N-dimethyl acetamide, dimethyl sulfoxide (DMSO) or N-methylpyrrolidone (NMP); an aromatic solvent selected from toluene, xylene or benzene; water; or a mixture thereof;
in step (d) the solvent used is an ether solvent selected from tetrahydrofuran, cyclopentyl methyl ether, 2-methyltetrahydrofuran, diethyl ether, 1,4-dioxane, 1,2-dioxane or 1,3-dioxane; a hydrocarbon solvent selected from toluene, hexane, heptane, pet ether, xylene, cyclohexane; an alcoholic solvent selected from methanol, ethanol, isopropanol (IPA), t-amyl alcohol, t-butyl alcohol or hexanol; a halogenated solvent selected from dichloromethane, 4-bromotoluene, diiodomethane, carbon tetrachloride, chlorobenzene or chloroform; a ketone solvent selected from acetone or methyl isobutyl ketone (MIBK); an aprotic solvent selected from acetonitrile, N,N-dimethyl formamide (DMF), N,N-dimethyl acetamide, dimethyl sulfoxide (DMSO) or N-methylpyrrolidone (NMP); an aromatic solvent selected from toluene, xylene or benzene; water; or a mixture thereof;

in step (d) the base used is selected from an alkali metal hydroxide such as lithium hydroxide, sodium hydroxide or potassium hydroxide; alkali metal and alkali earth metal salts of acetic acid such as sodium acetate, potassium acetate, magnesium acetate, calcium acetate; alkali metal carbonate such as lithium carbonate, sodium carbonate, potassium carbonate or caesium carbonate; alkali metal bicarbonate such as sodium bicarbonate or potassium bicarbonate; alkali metal alkoxide such as sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, potassium tert-butoxide, or organic amines such as diethylamine, triethylamine, di-n-propyl amine, di-isopropyl amine, tertbutylamine, morpholine, piperidine, diisopropylethylamine, pyridine, 4-dimethyl aminopyridine, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) or 1,5-diazabicyclo[4.3.0]non-5-ene (DBN); and

in step (d) the activating reagent used for converting hydroxyl functionality into a good leaving group is selected from methanesulfonyl chloride, methanesulfonic anhydride, trifluoromethanesulfonyl chloride, trifluoromethanesulfonic anhydride, p-toluenesulfonyl chloride, p-halobenzene sulfonyl chloride, p-nitrobenzenesulfonyl chloride, benzenesulfonyl chloride, halomethyl methyl ether (MOM), t-butyl chloride, t-butyl bromide, benzyl bromide, benzyl acetate, benzyl ethers, benzyl benzoate, benzyl chloride, p-methoxybenzyl chloride, halotrimethylsilanes, t-butyldimethylsilyl chloride, t-butyldiphenylsilyl chloride, triisopropylsilyl chloride, triphenylmethyl chloride, acyl chloride, acetic anhydride, t-butylacetyl chloride or t-butylacetic anhydride.

8. The process as claimed in claim 1, wherein, the preparation of ethyl 2-[(2,6-difluoro-benzyl)-ethoxycarbonyl-amino]-4-methyl-5-(4-nitro-phenyl)thiophe- ne-3-carboxylate (1), comprising reacting a compound of (2) with a compound of formula (4) in DMF and in presence of potassium carbonate to provide ethyl 2-[(2,6-difluoro-benzyl)-ethoxycarbonyl-amino]-4-methyl-5-(4-nitro-phenyl)-thiophene-3-carboxylate (1).

9. The process as claimed in claim 1, wherein, the process for preparation of compound of formula (4), comprising:
a) hydrolysing 2,6-difluorobenzonitrile (5) or 2,6-difluorobenzamide (5”) with an aqueous solution of hydrochloric acid or sulfuric acid to provide 2,6-difluorobenzoic acid (6);
b) esterification of 2,6-difluorobenzoic acid (6) by reacting it with methanol in presence of thionyl chloride to provide methyl 2,6-difluorobenzoate (7);
c) reducing methyl 2,6-difluorobenzoate (7) by using NaBH4 in THF to provide (2,6-difluorophenyl) methanol (8); and
d) activating the hydroxyl group of (2,6-difluorophenyl) methanol (8) using methanesulfonyl chloride in DCM and in presence of triethylamine to provide compound of formula (4).

10. The process as claimed in claim 1, wherein the compound of formula (1) obtained has a purity greater than 99% by HPLC.