DESC:Title of the Invention
An improved process for the preparation of Edoxaban Tosylate Monohydrate.

Field of the Invention
The present invention relates to an improved process for the preparation of Edoxaban Tosylate Monohydrate compound of Formula-I.

Background of the Invention
Edoxaban Tosylate monohydrate (also known as Savaysa) is chemically known as N-(5-Chloropyridin-2-yl)-N'-[(1S,2R,4S)-4-(N,N-dimethyl carbamoyl)-2-(5-methyl-4,5, 6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridine-2-carbox amido)cyclohexyl]oxamide mono (4-methylbenzenesulfonate) monohydrate. The molecular formula is C24H30ClN7O4S• C7H8O3S•H2O and the molecular weight is 738.27 grams per mole. The structural Formula-I is:

Savaysa is a factor Xa inhibitor, indicated to reduce the risk of stroke and systemic embolism (SE) in patients with nonvalvular atrial fibrillation (NVAF). Savaysa is available as 15 mg, 30 mg and 60 mg oral tablets.

US 7,365,205 B2 (WO 2003000657 A1, Daiichi Pharmaceutical Co., Ltd) discloses Edoxaban Tosylate Monohydrate. This patent discloses process for the preparation of Edoxaban Tosylate Monohydrate compound of Formula-I, which is schematically shown below in Scheme-I:

Scheme-I
IN 290088 B (Daiichi Pharmaceutical Co., Ltd) reported process for the preparation of Edoxaban Tosylate Monohydrate compound of Formula-I, which is schematically shown below in Scheme-II:

Scheme-II

Further, several routes to the synthesis of Edoxaban Tosylate Monohydrate compound of Formula-I are disclosed in which are JP 2014051492 A, US 9,175,012 B2, US 2015/0353577 A1, US 9,447,118 B2, US 9,920,071 B2, WO 2019158550 A1 and US 9,809,546 B2.

The synthesis disclosed in this prior art are difficult to operate, reaction longer time generally needed, and the reagents are expensive, finally the product was purified by repeated purification procedures.

Therefore, it would be desirable and of paramount importance to have a process for the preparation of Edoxaban Tosylate compound of Formula-I, by employing inexpensive, readily available, easy to handle reagents. It would also be desirable to have a process that can be readily scaled up and which does not require a special purification step and workup procedures, thereby making it more suitable for industrial scale preparation.

Summary of the Invention

The present invention provides a cost effective, an efficient process for the preparation of Edoxaban Tosylate Monohydrate compound of Formula-I with higher yields and purity.

In one aspect, the present invention provides an improved process for the preparation of Edoxaban Tosylate Monohydrate compound of Formula-I.


which comprises:
i) condensation of 2-Amino-5-chloro pyridine compound of Formula-2

with Ethyl oxalyl chloride of Formula-3 in presence of dimethylformamide and water to obtain Ethyl 2-((5-chloropyridin-2-yl) amino)-2-oxoacetate compound of Formula-4;

ii) condensation of Ethyl 2-((5-chloropyridin-2-yl) amino)-2-oxoacetate compound of Formula-4;

with compound of tert-Butyl ((1R,2S,5S)-2-amino-5-(dimethyl carbamoyl) cyclohexyl) carbamate oxalate compound of Formula-5 in the presence of Dimethyl sulfoxide, Diisopropylamine and water to obtain Tert-butyl((1R,2S,5S)-2-(2-((5-chloropyridin-2-yl)amino)-2-oxoacetamido)-5 (dimethyl carbamoyl)-cyclohexyl) carbamate compound of Formula-6;

iii) deprotection of Tert-butyl((1R,2S,5S)-2-(2-((5-chloropyridin-2-yl)amino)-2-oxoacetamido)-5-(dimethylcarbamoyl)-cyclohexyl)carbamate compound of Formula-6 in the presence of acid, base and solvent to obtain N1-((1S,2R,4S)-2-amino-4-(dimethyl carbamoyl) cyclohexyl)-N2-(5-chloropyridin-2-yl)oxalamide compound of Formula-7 (in-situ);

iv) condensation N1-((1S,2R,4S)-2-amino-4-(dimethylcarbamoyl) cyclohexyl)-N2-(5-chloropyridin-2-yl)oxalamide compound of Formula-7 (in-situ);

with 5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxylic acid hydrochloride compound of Formula-8 in the presence of EDC.HCl, HOBt.H2O, base and solvent to obtain N1-(5-chloropyridin-2-yl)-N2-((1S,2R,4S)-4-(dimethyl carbamoyl)-2-(5-methyl-4,5,6, 7-tetrahydrothiazolo[5,4-c]pyridine-2-carbox amido) cyclohexyl) oxal amide (Edoxaban free base) compound of Formula-9;

v) salt formation of N1-(5-chloropyridin-2-yl)-N2-((1S,2R,4S)-4-(dimethyl carbamoyl)-2-(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carbox amido) cyclohexyl) oxalamide (Edoxaban free base) compound of Formula-9 in the presence of PTSA.H2O, methylene chloride, ethanol and water to obtain N1-(5-chloropyridin-2-yl)-N2-((1S,2R,4S)-4-(di-methylcarbamoyl)-2-(5-methyl-4,5,6,7-tetrahydrothiazolo-[5,4,-c]-pyridine-2-carboxamido) cyclohexyl) oxalamide; 4-methyl benzenesulfonate hydrate compound of Formula-I.

In another aspect, the present invention provides an improved process for the preparation of Ethyl 2-((5-chloropyridin-2-yl) amino)-2-oxoacetate compound of Formula-4.

which comprises:
i) condensation of 2-Amino-5-chloro pyridine compound of Formula-2

with Ethyl oxalyl chloride of Formula-3 in presence of dimethylformamide and water to obtain Ethyl 2-((5-chloropyridin-2-yl) amino)-2-oxoacetate compound of Formula-4.

In further aspect, the present invention provides an improved process for the preparation of Tert-butyl((1R,2S,5S)-2-(2-((5-chloropyridin-2-yl) amino)-2-oxoacetamido)-5 (dimethylcarbamoyl)-cyclohexyl) carbamate compound of Formula-6.

which comprises:
i) condensation of Ethyl 2-((5-chloropyridin-2-yl) amino)-2-oxoacetate compound of Formula-4;

with compound of Tert-butyl ((1R,2S,5S)-2-amino-5-(dimethyl carbamoyl) cyclohexyl) carbamate oxalate compound of Formula-5 in the presence of Dimethyl sulfoxide, Diisopropylamine and water to obtain Tert-butyl((1R,2S,5S)-2-(2-((5-chloropyridin-2-yl) amino)-2-oxoacetamido)-5 (dimethyl carbamoyl)-cyclohexyl) carbamate compound of Formula-6.

Detailed Description of the Invention

Unless otherwise stated, the following terms used in the specification have the meanings given below:
Base used throughout the invention is selected from organic base or inorganic base.

Organic base is selected from the group consisting of pyridine, triethyl amine, diisopropylamine, methylamine, imidazole, benzimidazole, histidine, guanidine or quaternary ammonium cations.

Inorganic base is selected from the group consisting of sodium carbonate, potassium carbonate, cesium carbonate, potassium hydroxide, sodium hydroxide or sodium hydride.

Acids used throughout the invention is selected from the group consisting of mineral acids such as methanesulfonic acid, ethanolic hydrochloride, hydrochloric acid, oxalyl chloride, sulphuric acid, sulphurous acid, nitric acid, nitrous acid, hydrobromic acid, acetic acid, sulfonic acid or phosphoric acid.

Solvents used throughout the invention is selected from the group consisting of hydrocarbon solvents such as pentane, hexane, heptane, xylene or toluene; nitril solvents such as acetonitrile; alcohol solvents such as isopropyl alcohol or methanol, ethanol, ester solvent such as ethyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate or methyl acetate; ether solvent such as diethyl ether, tetrahydrofuran, methyl tert-butyl ether or ethyl-tert-butyl ether; ketone solvents such as acetone or methyl ethyl ketone, chloro solvents such as dichloromethane, chloroform, ethylene chloride or carbon tetrachloride, polar aprotic solvents such as dimethyl sulfoxide or dimethyl formamide and water.

Accordingly, the present invention provides an improved process for the preparation of Edoxaban Tosylate Monohydrate compound of Formula-I.

The main embodiment of the present invention provides an improved process for the preparation of Edoxaban Tosylate Monohydrate compound of Formula-I, which is outlined below in Scheme-III:
Scheme-III
In stage-i), condensation of 2-Amino-5-chloro pyridine compound of Formula-2 with Ethyl oxalyl chloride of Formula-3 in presence of dimethylformamide and water to obtain Ethyl 2-((5-chloropyridin-2-yl) amino)-2-oxoacetate compound of Formula-4;

The reaction temperature may range from 15-40 °C and preferably at a temperature in the range from 25-30 °C. The duration of the reaction may range from 1-5 hours, preferably for a period of 4 hours.

In stage-ii), condensation of Ethyl 2-((5-chloropyridin-2-yl) amino)-2-oxoacetate compound of Formula-4 with compound of tert-Butyl ((1R,2S,5S)-2-amino-5-(dimethyl carbamoyl) cyclohexyl) carbamate oxalate compound of Formula-5 in the presence of Dimethyl sulfoxide, Diisopropylamine and water to obtain Tert-butyl ((1R,2S,5S)-2-(2-((5-chloropyridin-2-yl)amino)-2-oxoacetamido)-5 (dimethyl carbamoyl)-cyclohexyl)carbamate compound of Formula-6;

The reaction temperature may range from 45-90 °C and preferably at a temperature in the range from 65-75 °C. The duration of the reaction may range from 5-8 hours, preferably for a period of 7 hours.

In stage-iii), deprotection of Tert-butyl((1R,2S,5S)-2-(2-((5-chloropyridin-2-yl) amino)-2-oxoacetamido)-5-(dimethylcarbamoyl)-cyclohexyl) carbamate compound of Formula-6 in the presence of acid, base, solvent, purified water and n-heptane to obtain N1-((1S,2R,4S)-2-amino-4-(dimethyl carbamoyl)cyclohexyl)-N2-(5-chloropyridin-2-yl)oxalamide compound of Formula-7 (in-situ);

The reaction temperature may range from 15-45 °C and preferably at a temperature in the range from 25-35 °C. The duration of the reaction may range from 2-4 hours, preferably for a period of 3 hours.

In stage-iv), condensation N1-((1S,2R,4S)-2-amino-4-(dimethyl carbamoyl) cyclo hexyl)-N2-(5-chloropyridin-2-yl)oxalamide compound of Formula-7 (in-situ) with 5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxylic acid hydrochloride compound of Formula-8 in the presence of EDC.HCl, HOBt.H2O, base and solvent to obtain N1-(5-chloropyridin-2-yl)-N2-((1S,2R,4S)-4-(dimethyl carbamoyl)-2-(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carbox amido) cyclohexyl) oxalamide free base (Edoxaban) compound of Formula-9;

The reaction temperature may range from 15-45 °C and preferably at a temperature in the range from 25-30 °C. The duration of the reaction may range from 20-35 hours, preferably for a period of 25-30 hours.

In stage-v), salt formation of N1-(5-chloropyridin-2-yl)-N2-((1S,2R,4S)-4-(dimethyl carbamoyl)-2-(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carbox amido) cyclohexyl) oxalamide (Edoxaban free base) compound of Formula-9 in the presence of PTSA.H2O, methylene chloride, ethanol and water to obtain N1-(5-chloropyridin-2- yl)-N2-((1S,2R,4S)-4-(di-methylcarbamoyl)-2-(5-methyl-4,5,6,7-tetrahydrothiazolo-[5,4,-c]-pyridine-2-carboxamido) cyclohexyl) oxalamide; 4-methyl benzenesulfonate hydrate compound of Formula-I.

The reaction temperature may range from 50-85 °C and preferably at a temperature in the range from 65-75 °C. The duration of the reaction may range from 20-30 hours, preferably for a period of 24 hours.

A another embodiment of the present invention provides an improved process for the preparation of Ethyl 2-((5-chloropyridin-2-yl) amino)-2-oxoacetate compound of Formula-4.

which comprises:
i) condensation of 2-Amino-5-chloro pyridine compound of Formula-2

with Ethyl oxalyl chloride compound of Formula-3 in presence of dimethylformamide and water to obtain Ethyl 2-((5-chloropyridin-2-yl) amino)-2-oxoacetate compound of Formula-4.

The reaction temperature may range from 15-40 °C and preferably at a temperature in the range from 25-30 °C. The duration of the reaction may range from 1-5 hours, preferably for a period of 4 hours.

Another embodiment of the present invention provides an improved process for the preparation of Tert-butyl((1R,2S,5S)-2-(2-((5-chloropyridin-2-yl) amino)-2-oxoacetamido)-5 (dimethyl carbamoyl)-cyclohexyl) carbamate compound of Formula-6.

which comprises:
i) condensation of Ethyl 2-((5-chloropyridin-2-yl) amino)-2-oxoacetate compound of Formula-4;

with compound of Tert-butyl ((1R,2S,5S)-2-amino-5-(dimethyl carbamoyl) cyclohexyl) carbamate oxalate compound of Formula-5 in the presence of Dimethyl sulfoxide, Diisopropylamine and water to obtain Tert-butyl((1R,2S,5S)-2-(2-((5-chloropyridin-2-yl) amino)-2-oxoacetamido)-5 (dimethyl carbamoyl)-cyclohexyl) carbamate compound of Formula-6;

The reaction temperature may range from 45-90 °C and preferably at a temperature in the range from 65-75 °C. The duration of the reaction may range from 5-8 hours, preferably for a period of 7 hours.

Advantage of the present invention:
1. No work up needed after the reaction completion.
2. No multiple operations required for the isolation of the product.
3. No need of recrystallization.
4. Simple isolation procedure (after completion of the reaction cooling, addition of water and product filtration).

EXPERIMENTAL PORTION:
The details of the invention are given in the examples provided below, which are given to illustrate the invention only and therefore should not be construed to limit the scope of the invention.

EXAMPLES:
Example 1: Process for the preparation of Edoxaban Tosylate Monohydrate.
Stage-1: Preparation of Ethyl 2-((5-chloropyridin-2-yl) amino)-2- oxoacetate (Formula-4)
2-Amino-5-chloro pyridine (10 grams) is dissolved in 50 mL of dimethylformamide at 25-30 °C. To the above solution, added ethyl oxalyl chloride (12.74 grams) slowly at 25-30 ? and maintained for ~4 hours at 25-35 °C. After completion of the reaction, prechilled purified water (250 mL) was added to the reaction mixture at 25-35 °C and stirred further for ~1 hour at 25-35 °C. Solids were filtered the and washed with purified water (50 mL) and dried at 40-45 °C under vacuum to yield the title compound as a white colour solid. (Yield: 85%).

Stage-2: Preparation of Tert-butyl((1R,2S,5S)-2-(2-((5-chloropyridin-2-yl) amino)-2-oxoacetamido)-5-(dimethyl carbamoyl)-cyclohexyl) carbamate (Formula-6)
Tert-Butyl ((1R,2S,5S)-2-amino-5-(dimethyl carbamoyl) cyclohexyl) carbamate oxalate (10 grams) was dissolved in Dimethyl sulfoxide (74.2 mL). To the above reaction mass 0.48 grams of water and 8.35 grams of diisopropylamine were added at 25-35 ?. Stirred the contents for 5-10 minutes at 25-35 ?. To the above solution 10.96 grams of Ethyl 2-((5-chloropyridin-2-yl) amino)-2-oxoacetate was added at 25-35 ?. The reaction mixture was heated to 65-75 °C and maintained for ~7 hours at 65-75 ?. After completion of the reaction, contents were cooled to 25-30 ? and purified water (810 mL) was added to the reaction mixture. The reaction mass was stirred further for ~1.0 hour at 25-30 ?. Solids were filtered the and washed with purified water (30 mL). To the wet solid methylene chloride (15 volumes) and purified water were added and filtered through hyflo. Layers were separated and the organic layer was partially distilled and co-distilled with methanol (4 x 2 volumes). To the concentrated mass methanol (4 volumes) was added and stirred for 1 hour. product was filtered and dried at 40-45 °C under vacuum to yield the tile compound as a white colour solid. (Yield: 91 %).

Stage-3: Preparation of N1-((1S,2R,4S)-2-amino-4-dimethylcarbamoyl)-cyclo hexyl)-N2-(5-chloropyridin-2-yl) oxalamide (Edoxaban free base) (Formula-9)
To a solution of Tert-butyl((1R,2S,5S)-2-(2-((5-chloropyridin-2-yl) amino)-2-oxoacetamido)-5-(dimethyl carbamoyl)-cyclohexyl) carbamate (40 grams) in methylene chloride (320 mL) at 10-15 ?, added 24.64 grams of methanesulfonic acid and the reaction was maintained for ~2 hours at 10-15 ?. Thereafter, raised the temperature of the reaction mixture to 25-35 ? and maintained for ~3 hours at 25-35 ?. After completion of reaction, triethylamine was slowly added 30.27 grams to the reaction mass at 25-35 ? and maintained for 2-3 hours at this temperature. After completion of reaction, purified water (200 mL) and methylene chloride (120 mL) were added to reaction mixture and stirred for ~15 minutes. Separated the organic layer and washed the organic layer with purified water (2×120 mL) at 25-35 ?. The resultant organic layer washed with 120 mL of brine solution. This organic layer is used as such for the next operation without further purification.

To a suspension of 5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c] pyridine-2-carboxylic acid hydrochloride (3.54 grams) in (50 mL) in acetonitrile at 20-25?, 2.86 grams of EDC.HCl, 2.02 grams of HOBt.H2O and (4.12 grams) of triethylamine were added under nitrogen atmosphere. To the above reaction mixture, a solution of N1-((1S,2R,4S)-2-amino-4-(dimethylcarbamoyl)-cyclohexyl)-N2-(5-chloropyridin-2-yl) oxalamide (Formula-7) (5.0 grams) in 20 mL of acetonitrile was slowly added at 20-25 ?. Thereafter, raised the temperature of the reaction mixture to 25-35 ? and maintained for 25-30 hours. After completion of the reaction, Ethyl acetate (50 mL) and water (30 mL) were added to reaction mass at 25-35 ? and stirred the mass for ~15 minutes. Layers were separated and the aqueous layer was extracted with (50 mL) ethyl acetate. Combined organic layer was washed with Sat. Sodium bicarbonate solution (50 mL) at 25-35 ?. Layers were separated and organic layer was washed with water (30 mL) and brine solution (30 mL) at 25-35 ?. Organic layer was partially distilled under vacuum and purified water is added to the reaction mass and distillation continued under atmospheric pressure to remove methylene chloride. The resultant suspension was filtered and to the crude product at 25-30 ?, 10% aqueous methanol (25 mL) was added and stirred for ~2 hours at 25-35 ?. Solids were filtered and washed the solid with 10% aqueous methanol (5 mL) to give the title compound as white to off-white colour solid. (Yield: 85 %).

Stage-4: Preparation of N1-(5-Chloropyridin-2-yl)-N2-((1S,2R,4S)-4-(di-methylcarbamoyl)-2-(5-methyl-4,5,6,7-tetrahydrothiazolo-[5,4,-c]-pyridine-2-carboxamido) cyclohexyl) oxalamide; 4-Methyl benzenesulfonate hydrate (Edoxaban Tosylate Monohydrate) Formula-I.

To the solution of N1-((1S,2R,4S)-2-amino-4-dimethylcarbamoyl)-cyclohexyl)-N2-(5-chloropyridin-2-yl) oxalamide (Edoxaban free base) (5.0 grams) in (96.75 mL) methylene chloride, a solution of PTSA.H2O solution in ethanol (1.89 grams of PTSA.H2O in 10 mL of Ethanol) at 25-35 ? and stirred for 10 minutes at 25-35 ?. The reaction mas was distilled out completely under reduced pressure to remove the solvents to obtain crude product. To the above concentrated mass aqueous ethanol solution (76.5 mL) was added at 25-35 ? and heated to 65-75 ?. The reaction mass was maintained for ~2 hours at 65-75 ? and slowly cooled to 25-35 ?. The contents were further stirred for 12 hours at 25-30 ?. Solids were filtered and washed with ethanol (5 mL) to yield the title compound as a white to off-white solid. (Yield: 80 %).

1H NMR (d ppm, DMSO): 10.28 (1H, s), 10.17 (1H, br), 9.19-9.16 (1H, d), 8.76-8.73(1H, d, Aromatic- CH), 8.45 (1H, s, Aromatic-CH) 8.01 (2H, s, Aromatic-CH), 7.47-7.44 (2H, d, Aromatic -CH), 7.11-7.08 (2H, d, Aromatic-CH)4.88-4.44 (3H, m, Aliphatic-CH), 4.12-4.00(1H, m, Aliphatic-CH), 3.79-3.67 (2H, br, Aliphatic-CH),3.18 (2H, s, Aliphatic-CH), 2.99-2.93 (3H, m, N-CH3), 2.99-2.93 (4H, m, Aliphatic-CH), 2.78 (3H, s, CH3), 2.27 (3H, s, -CH3), 2.05-2.01 (2H, m, Aliphatic-CH), 1.78-1.65 (3H, m, Aliphatic-CH), 1.55-1.43 (1H, m, Aliphatic-CH).

Mass (m/z): 548.47 (M+1).

,CLAIMS:1. An improved process for the preparation of Edoxaban Tosylate Monohydrate of compound of Formula-I;

which comprises:
i) condensation of 2-Amino-5-chloro pyridine compound of Formula-2

with Ethyl oxalyl chloride compound of Formula-3 in presence of dimethylformamide and water to obtain Ethyl 2-((5-chloropyridin-2-yl) amino)-2-oxoacetate compound of Formula-4;

ii) condensation of Ethyl 2-((5-chloropyridin-2-yl) amino)-2-oxoacetate compound of Formula-4;

with compound of tert-Butyl ((1R,2S,5S)-2-amino-5-(dimethyl carbamoyl) cyclohexyl) carbamate oxalate compound of Formula-5 in the presence of Dimethyl sulfoxide, Diisopropylamine and water to obtain Tert-butyl((1R,2S,5S)-2-(2-((5-chloropyridin-2-yl)amino)-2-oxoacetamido)-5 (dimethyl carbamoyl)-cyclohexyl) carbamate compound of Formula-6;

iii) deprotection of Tert-butyl((1R,2S,5S)-2-(2-((5-chloropyridin-2-yl)amino)-2-oxoacetamido)-5-(dimethylcarbamoyl)-cyclohexyl)carbamate compound of Formula-6 in the presence of acid, base and solvent to obtain N1-((1S,2R,4S)-2-amino-4-(dimethyl carbamoyl) cyclohexyl)-N2-(5-chloropyridin-2-yl)oxalamide compound of Formula-7 (in-situ);

iv) condensation N1-((1S,2R,4S)-2-amino-4-(dimethylcarbamoyl)cyclohexyl)-N2-(5-chloropyridin-2-yl)oxalamide compound of Formula-7 (in-situ);

with 5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxylic acid hydrochloride compound of Formula-8 in the presence of EDC.HCl, HOBt.H2O, base and solvent to obtain N1-(5-chloropyridin-2-yl)-N2-((1S,2R,4S)-4-(dimethyl carbamoyl)-2-(5-methyl-4,5,6,7-tetra hydrothiazolo[5,4-c]pyridine-2-carboxamido) cyclohexyl) oxalamide (Edoxaban free base) compound of Formula-9;

v) salt formation of N1-(5-chloropyridin-2-yl)-N2-((1S,2R,4S)-4-(dimethyl carbamoyl)-2-(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamido) cyclohexyl) oxalamide (Edoxaban free base) compound of Formula-9 in the presence of PTSA.H2O, methylene chloride, ethanol and water to obtain N1-(5-chloropyridin-2-yl)-N2-((1S,2R,4S)-4-(di-methylcarbamoyl)-2-(5-methyl-4,5,6,7-tetrahydrothiazolo-[5,4,-c]-pyridine-2-carboxamido) cyclohexyl) oxalamide; 4-methyl benzenesulfonate hydrate compound of Formula-I.

2. The process as claimed in claim 1, wherein acid is selected from the group consisting of methanesulfonic acid, ethanolic hydrochloride, hydrochloric acid, oxalyl chloride, sulphuric acid, sulphurous acid, nitric acid, nitrous acid, hydrobromic acid, acetic acid, sulfonic acid or phosphoric acid.

3. The process as claimed in claim 1, wherein base is selected from the organic base or inorganic base.

4. The process as claimed in claim 3, wherein organic base is selected from the group consisting of pyridine, triethyl amine, diisopropylamine, methylamine, imidazole, benzimidazole, histidine or guanidine and quaternary ammonium cations; inorganic base is selected from the group consisting of sodium carbonate, potassium carbonate, cesium carbonate, potassium hydroxide or sodium hydroxide.

5. The process as claimed in claim 1, wherein solvent selected from the group consisting of methylene chloride, acetonitrile, heptane, hexane, ethanol, methanol or water.

6. An improved process for the preparation of Ethyl 2-((5-chloropyridin-2-yl) amino)-2-oxoacetate compound of Formula-4.

which comprises:
i) condensation of 2-Amino-5-chloro pyridine compound of Formula-2

with Ethyl oxalyl chloride compound of Formula-3 in presence of dimethylformamide and water to obtain Ethyl 2-((5-chloropyridin-2-yl) amino)-2-oxoacetate compound of Formula-4.

7. An improved process for the preparation of Tert-butyl((1R,2S,5S)-2-(2-((5-chloropyridin-2-yl) amino)-2-oxoacetamido)-5 (dimethyl carbamoyl)-cyclohexyl) carbamate compound of Formula-6.

which comprises:
i) condensation of Ethyl 2-((5-chloropyridin-2-yl) amino)-2-oxoacetate compound of Formula-4;

with compound of tert-Butyl ((1R,2S,5S)-2-amino-5-(dimethyl carbamoyl) cyclohexyl) carbamate oxalate compound of Formula-5 in the presence of Dimethyl sulfoxide, Diisopropylamine and water to obtain Tert-butyl((1R,2S,5S)-2-(2-((5-chloropyridin-2-yl) amino)-2-oxoacetamido)-5 (dimethyl carbamoyl)-cyclohexyl) carbamate compound of Formula-6;