A process for the preparation of n-(5-chloropyridin-2-YL)-n'-[(1s,2r,4s)-4-(n, n-dimethylcarbamoyl)-2-(5-methyl-4,5,6,7-tetra hydro [1,3] thiazolo[5,4-c] pyridine-2-carboxamido) cyclohexyl] oxamide, 4-methylbenzenesulfonate

Abstract

The present invention relates to a process for the preparation of N-(5-chloropyridin-2- yl)-N'-[(1S,2R,4S)-4(N,N-dimethylcarbamoyl)-2-(5-methyl-4,5,6,7-tetrahydro [1,3] thiazolo[5,4-c] pyridine-2-carboxamido)cyclohexyl]oxamide, 4- methylbenzenesulfonate. It further relates to a process for the purification of N-(5- chloropyridin-2-yl)-N'-[(1S,2R,4S)-4(N,N-dimethylcarbamoyl)-2-(5-methyl-4,5,6,7- tetrahydro [1,3] thiazolo[5,4-c] pyridine-2-carboxamido)cyclohexyl]oxamide, 4- methylbenzenesulfonate is having purity greater than 99% by HPLC, preferably greater than 99.5% and more preferably 99.9% by HPLC.

Description

[0001] “A PROCESS FOR THE PREPARATION OF N-(5-CHLOROPYRIDIN-2-YL)-

[0002] N'-[(lS,2R,4S)-4-(N, N-DIMETHYLCARB AMO YL)-2-(5-METHYL-4, 5,6,7- TETRA HYDRO [1,3] THIAZOLO[5,4-C] PYRIDINE-2-CARBOXAMIDO) CYCLOHEXYL] OXAMIDE, 4-METHYLBENZENESULFONATE”

[0003] FIELD OF THE INVENTION

[0004] The present invention relates to a process for the preparation of N-(5-chloropyridin-2- yl)-N'-[(lS,2R,4S)-4-(N,N-dimethylcarbamoyl)-2-(5-methyl-4,5,6,7-tetrahydro [1,3] thiazolo[5,4-C] pyridine-2-carboxamido)cyclohexyl]oxamide, 4- methylbenzenesulfonate. It further relates to a process for the purification of N-(5- chloropyridin-2-yl)-N'-[(lS,2R,4S)-4(N,N-dimethylcarbamoyl)-2-(5-methyl-4,5,6,7- tetrahydro [1,3] thiazolo[5,4-C] pyridine-2-carboxamido)cyclohexyl]oxamide, 4- methylbenzenesulfonate is having purity greater than 99% by HPLC, preferably greater than 99.5% and more preferably greater than 99.9% by HPLC.

[0005] BACKGROUND OF THE INVENTION

[0006] Edoxaban tosylate is chemically known as N-(5-chloropyridin-2-yl)-N'-[(lS,2R,4S)- 4-(N,N-dimethylcarbamoyl)-2-(5-methyl-4,5,6,7-tetrahydro [1,3] thiazolo[5,4-C] pyridine-2-carboxamido)cyclohexyl]oxamide, 4-methylbenzenesulfonate and is represented by the following general Formula

[0007] Edoxaban has been developed by Daiichi Sankyo and approved by USFDA since January 2015, under the proprietary name SAVAYSA®. First approval for Edoxaban occurred in Japan in year 2011. Besides SAVAYSA®, it is also available under brand names LIXIANA® and ROTEAS® in different parts of the world. Edoxaban is an oral anticoagulant drug indicated to reduce the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation. It is also indicated for the treatment of deep vein thrombosis and pulmonary embolism.

[0008] Edoxaban and its salts were first disclosed in US7365205B2 by Ohta et al. US’205 discloses a general process for preparation of Edoxaban (1) as per following Scheme

[0009] Scheme-I

[0010] Another approach mentioned in patent US’205, for preparation of Edoxaban is as per Scheme II, wherein reaction sequence varies in comparison to process of Scheme I:

[0011] Scheme-II

[0012] Further to the disclosure of US’205, in US8686189B2, Sato et al, disclosed a modified process for preparation of Edoxaban, as per Scheme IIE

[0013]

[0014] Scheme-Ill

[0015] Besides the above-mentioned references, there are several other disclosures in prior art for e.g. US8404847B2, US7547786B2, US8357808B2, US8901345B2, US9447118B2, US8541443B2, US8394821B2, WO2008156159A1,

[0016] JP2010254615A, US20170050983 Al and US20170022220A1, wherein a number of aspects regarding preparation and properties of Edoxaban and its pharmaceutically acceptable salts or solvates thereof have been discussed. But drawback with prior art processes is that these are difficult to handle at the industrial scale due to operational issues like reaction mass solidification, use of very low or high temperature, unacceptable level of fuming / foaming in the reactor, use of rigid reaction conditions and use of hazardous reagents. Also, these processes use costly reagents and provide less yield as well as low purity API after unacceptably high reaction times, thus necessitating multiple purifications.

[0017] Thus, there is a need to explore new methods for the preparation of Edoxaban or its pharmaceutically acceptable salts or solvates thereof, wherein the above discussed limitations of already known processes can be resolved. In this direction, inventors of the present patent application provide an improved cost-effective process for preparations of highly pure Edoxaban or its pharmaceutically acceptable salts or solvates thereof.

[0018] OBJECTIVE OF THE INVENTION

[0019] Accordingly, in one objective, the present invention provides an improved industrially viable process for the preparation of Edoxaban tosylate (1).

[0020] In another objective, the present invention provides a process for the purification of Edoxaban tosylate (1).

[0021] In further objective, Edoxaban tosylate (1) obtained by any of the described methods is having purity greater than 99% by HPLC and more preferably greater than 99.5% and still more preferably greater than 99.9% by HPLC.

[0022] SUMMARY OF THE INVENTION

[0023] Accordingly, in one aspect, the present invention provides an improved industrially viable process for the preparation of Edoxaban tosylate (1).

[0024] In another aspect, the present invention provides a process for the preparation of Edoxaban tosylate (1) comprising the steps of: a) reacting tert-butyl (lR,2S,5S)-2-amino-5-(dimethyl carbamoyl) cyclohexyl carbamate of formula (7) with ethyl 2-(5-chloropyridin-2-ylamino)-2- oxoacetate hydrochloride (6) to provide tert-butyl (lR,2S,5S)-2-(2-(5- chloropyridin-2-ylamino)-2-oxoacetamido)-5-(dimethylcarbamoyl) cyclohexyl carbamate (5); b) deprotecting the compound of formula (5) to provide Nl-(2-amino-4-(dimethyl carbamoyl) cyclohexyl)-N2-(5-chloropyridin-2-yl) oxalamide of formula (4); followed by reacting the compound of formula (4) with 5-methyl-4, 5,6,7- tetrahydrothiazolo[5,4-c] pyridine-2-carboxylic acid HC1 of formula (3) to provide Edoxaban of formula (2); c) reacting the compound of formula (2) with p-toluene sulfonic acid to provide crude Edoxaban tosylate of formula (la); and d) purifying crude Edoxaban tosylate of formula (la) to provide Edoxaban tosylate of formula (1).

[0025] In another aspect, the present invention provides a process for the purification of Edoxaban tosylate (la), which comprises: i) dissolving Edoxaban tosylate of formula (la) in a solvent or mixture of solvents; and ii) isolating Edoxaban tosylate of formula (1).

[0026] In further aspect, Edoxaban tosylate (1) obtained by any of the described methods is having purity greater than 99% by HPLC, preferably greater than 99.5% and more preferably greater than 99.9% by HPLC.

[0027] BRIEF DESCRIPTION OF THE DRAWINGS

[0028] Figure 1: Illustrates X-Ray Diffraction (XRD) pattern of crystalline form of Edoxaban tosylate (1)

[0029] Figure 2: Illustrates X-Ray Diffraction (XRD) pattern of crystalline form of Edoxaban (2)

[0030] DETAILED DESCRIPTION OF THE INVENTION

[0031] As used herein the term “solvent” used in the present invention refers to “hydrocarbon solvents” such as n-hexane, n-heptane, cyclohexane, pet ether, toluene, pentane, cycloheptane, methyl cyclohexane, m-, o-, or p-xylene, nitromethane and the like; “ether solvents” such as dimethoxy methane, tetrahydrofuran, 1,3 -di oxane, 1,4- dioxane, furan, diethyl ether, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, diethylene glycol dimethyl ether, diethylene glycol diethyl ether, triethylene glycol dimethyl ether, anisole, methyl t-butyl ether, 1,2-dimethoxy ethane, anisole and the like; “ester solvents” such as methyl formate, methyl acetate, ethyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, vinyl acetate and the like; “polar- aprotic solvents such as dimethyl acetamide (DMA), dimethylformamide (DMF), dimethylsulfoxide (DMSO), N-methyl pyrrolidone (NMP) and the like; “chloro solvents” such as dichloromethane, di chloroethane, chloroform, carbon tetrachloride and the like; “ketone solvents” such as acetone, methyl ethyl ketone, acetyl acetone, methyl isobutyl ketone and the like; “nitrile solvents” such as acetonitrile, propionitrile, isobutyronitrile and the like; “alcoholic solvents” such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol, 2-nitroethanol, 2- fluoroethanol, 2,2,2-trifluoroethanol, ethylene glycol, polyethylene glycol, polyethylene gly col-400, 2-m ethoxy ethanol, 1,2-ethoxy ethanol, di ethylene glycol, 1, 2, or 3 -pentanol, neo pentyl alcohol, t-pentyl alcohol, di ethylene glycol mono ethyl ether, cyclohexanol, benzyl alcohol, phenol, or glycerol and the like; “polar solvents” such as water and or mixtures thereof.

[0032] The “base” as used in the present invention is selected from inorganic bases like “alkali metal hydroxides” such as lithium hydroxide, sodium hydroxide, potassium hydroxide and the like; “alkali metal carbonates” such as sodium carbonate, potassium carbonate, lithium carbonate and the like; “alkali metal bicarbonates” such as sodium bicarbonate, potassium bicarbonate, lithium bicarbonate and the like; “alkali metal hydrides” such as sodium hydride, potassium hydride, lithium hydride and the like; ammonia; and organic bases such as “alkali metal alkoxides” such as sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium methoxide, potassium ethoxide, potassium tert-butoxide and the like; triethyl amine, methyl amine, ethylamine, l,8-diazabicyclo[5.4.0]undec-7-ene (DBU), l,5-diazabicyclo(4.3.0)non- 5-ene (DBN), lithium di isopropyl amide (LDA), n-butyl lithium, tri benzylamine, isopropylamine, di isopropylamine, diisopropylethylamine, N-methyl morpholine, N- ethyl morpholine, piperidine, dimethyl aminopyridine, morpholine, pyridine, 2,6- lutidine, 2,4,6-collidine, imidazole, 1 -methylimidazole, 1,2,4-triazole, 1,4-diaza bicyclo [2.2.2]octane (DABCO) or mixtures thereof.

[0033] In one embodiment, the present invention provides a process for the preparation of Edoxaban tosylate (1), comprising one or more following steps:

[0034]

[0035] Scheme-IV

[0036] In step a) of the forgoing process, the reaction of tert-butyl (lR,2S,5S)-2-amino-5- (dimethyl carbamoyl)cyclohexyl carbamate of formula (7) with ethyl 2-(5- chloropyridin-2-ylamino)-2-oxoacetate hydrochloride (6) in the presence of a base and a solvent under appropriate reaction conditions to provide tert-butyl (lR,2S,5S)-2-(2- (5-chloropyridin-2-ylamino)-2-oxoacetamido)-5-(dimethylcarbamoyl) cyclohexyl carbamate of formula (5). The base is selected from triethyl amine, methyl amine, ethylamine, l,8-diazabicyclo[5.4.0]undec-7-ene (DBU), l,5-diazabicyclo(4.3.0)non- 5-ene (DBN), lithium di isopropyl amide (LDA), n-butyl lithium, tri benzylamine, isopropylamine, di isopropylamine, diisopropylethylamine, N-methyl morpholine, N- ethyl morpholine, piperidine, dimethyl aminopyridine, morpholine, pyridine, 2,6- lutidine, 2,4,6-collidine, imidazole, 1 -methylimidazole, 1,2,4-triazole, 1,4-diaza bicyclo [2.2.2]octane (DABCO) or mixtures thereof, preferably the base is triethylamine. The solvent is selected from acetonitrile, propionitrile, isobutyronitrile and the like, preferably the solvent is acetonitrile. The step a) reaction is carried out at a suitable temperature of about 60°C to about 65°C for a sufficient period till completion of the reaction.

[0037] In step b) of the forgoing process, the deprotection of compound of formula (5) with an acid and a solvent under appropriate reaction conditions to provide Nl- ((1 S,2R,4S)-2-amino-4-(dimethyl carbamoyl) cyclohexyl)-N2-(5-chloropyridin-2-yl) oxalamide of formula (4). The acid is selected from hydrochloric acid, trichloroacetic acid, methane sulfonic acid, preferably the acid is methane sulfonic acid. The solvent is selected from acetonitrile, propionitrile, isobutyronitrile and the like, preferably the solvent is acetonitrile. The step b) reaction is carried out at a suitable temperature of about 25°C to about 35°C for a sufficient period till completion of the reaction.

[0038] In step c) of the forgoing process, the reaction of compound of formula (4) with 5- methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxylic acid HC1 of formula (3) in the presence of base, condensing agent, hydroxybenzotri azole (HOBt) as an additive and a solvent under appropriate reaction conditions to provide Edoxaban of formula (2). The base is selected from triethyl amine, methyl amine, ethylamine, 1,8- diazabicyclo[5.4.0]undec-7-ene (DBU), l,5-diazabicyclo(4.3.0)non-5-ene (DBN), lithium di isopropyl amide (LDA), n-butyl lithium, tri benzylamine, isopropylamine, di isopropylamine, diisopropylethylamine, N-methyl morpholine, N-ethyl morpholine, piperidine, dimethyl aminopyridine, morpholine, pyridine, 2,6-lutidine, 2,4,6-collidine, imidazole, 1 -methylimidazole, 1,2,4-triazole, 1,4-diaza bicyclo [2.2.2]octane (DABCO) or mixtures thereof, preferably the base is triethylamine, the condensing agent is selected from the group consisting of 1,3- dicyclohexylcarbodiimide (DCC), isobutyl chloroformate, pivaloyl chloride, isovaleryl chloride, l-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC.HC1), 1 -cy cl oh exyl-3 -morpholinoethylcarbodiimide, l-cyclohexyl-3-(4- diethylaminocyclohexyl)carbodiimide, N,N'-carbonyldiimidazole, 2-chloro-l,3- dimethylimidazolinium chloride, isobutyl chloroformate or mixture thereof; preferably the condensing agent is l-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC.HC1). The solvent is selected from the group consisting of dichloromethane, di chloroethane, chloroform, carbon tetrachloride and the like, preferably the solvent is methylene dichloride. The step c) reaction is carried out at a suitable temperature of about 25°C to about 35°C for a sufficient period till completion of the reaction. In step d) of the forgoing process, the reaction of Edoxaban of formula (2) with p- toluenesulfonic acid in a solvent under appropriate reaction conditions to provide Edoxaban tosylate of formula (1). The solvent is selected from methanol, ethanol, n- propanol, isopropanol, n-butanol, isobutanol, t-butanol and the like, preferably using ethanol. The step d) reaction is carried out at a suitable temperature of about 70°C to about 75°C for a sufficient period till completion of the reaction.

[0039] In another embodiment, the present invention provides a process for the purification of Edoxaban tosylate of formula (la), which comprises: i) dissolving Edoxaban tosylate of formula (la) in one or more solvents, and ii) isolating Edoxaban tosylate of formula (1).

[0040] In another embodiment, the present invention provides a process for the preparation of tert-butyl (lR,2S,5S)-2-amino-5-(dimethyl carbamoyl)cyclohexyl carbamate of

[0041] Scheme-V

[0042] In step a) of the forgoing process, the reaction of compound of formula (13) with bromine in the presence of a base and a solvent under appropriate reaction conditions to provide compound of formula (12). The base is selected from triethyl amine, methyl amine, ethylamine, l,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,5- diazabicyclo(4.3.0)non-5-ene (DBN), lithium di isopropyl amide (LDA), n-butyl lithium, tri benzylamine, isopropylamine, di isopropylamine, diisopropylethylamine, N-methyl morpholine, N-ethyl morpholine, piperidine, dimethyl aminopyridine, morpholine, pyridine, 2,6-lutidine, 2,4,6-collidine, imidazole, 1 -methylimidazole, 1,2,4-triazole, 1,4-diaza bicyclo [2.2.2]octane (DABCO) or mixtures thereof. The solvent is selected from dichloromethane, di chloroethane, chloroform, carbon tetrachloride. The step a) reaction is carried out at a suitable temperature of about 0°C to about 5°C for a sufficient period till completion of the reaction.

[0043] In step b) of the forgoing process, the reaction of compound of formula (12) with Boc anhydride in the presence of base and a solvent under appropriate reaction conditions to provide compound of formula (11). The base is selected from lithium hydroxide, sodium hydroxide, potassium hydroxide. The solvent is selected from methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol. The step b) reaction is carried out at a suitable temperature of about 40°C to about 45°C for a sufficient period till completion of the reaction.

[0044] In step c) of the forgoing process, the reaction of compound of formula (11) with Methanesulfonyl chloride in the presence of a base and a solvent under appropriate reaction conditions followed by reacting the obtained compound with sodium azide and benzyltri ethyl ammonium chloride to provide compound of formula (10). The base is selected from tri ethyl amine, methyl amine, ethylamine, 1,8- diazabicyclo[5.4.0]undec-7-ene (DBU), l,5-diazabicyclo(4.3.0)non-5-ene (DBN), lithium di isopropyl amide (LDA), n-butyl lithium, tri benzylamine, isopropylamine, di isopropylamine, diisopropylethylamine, N-methyl morpholine, N-ethyl morpholine, piperidine, dimethyl aminopyridine, morpholine, pyridine, 2,6-lutidine, 2,4,6-collidine, imidazole, 1 -methylimidazole, 1,2,4-triazole, 1,4-diaza bicyclo [2.2.2]octane (DABCO) or mixtures thereof. The solvent is selected from dichloromethane, di chloroethane, chloroform, carbon tetrachloride. The step c) reaction is carried out at a suitable temperature of about 60°C to about 65°C for a sufficient period till completion of the reaction. In step d) of the forgoing process, the hydrogenation of compound of formula (10) with hydrogenating agent and a solvent under appropriate reaction conditions followed by reacting the obtained compound with benzyl chloroformate in the presence of a base and a solvent under appropriate reaction conditions to provide compound of formula (9). The hydrogenating agent is selected from The hydrogenating agent is selected from catalytic hydrogenation (using hydrogen gas) and a catalyst such as Pt, Pt / C, PtO2 , Pd, Pd / C, Rh, Ru, Ni or Raney Ni; Zn, Sn or Fe and an acid, preferably the hydrogenating is Pd / C. The base is selected from sodium bicarbonate, potassium bicarbonate, lithium bicarbonate. The solvent is selected from methanol, ethanol, n- propanol, isopropanol, n-butanol, isobutanol, t-butanol, methyl formate, methyl acetate, ethyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, vinyl acetate. The step d) reaction is carried out at a suitable temperature of about 25°C to about 35°C for a sufficient period till completion of the reaction.

[0045] In step e) of the forgoing process, the reaction of compound of formula (9) with Lithium hydroxide monohydrate and mixture of solvents under appropriate reaction conditions followed by reacting the obtained compound with DMA. HC1 in the presence of base, condensing agent, Hydroxybenzotriazole (HOBt) as an additive and a solvent under appropriate reaction conditions to provide compound of formula (8). The base is selected from tri ethyl amine, methyl amine, ethylamine, 1,8- diazabicyclo[5.4.0]undec-7-ene (DBU), l,5-diazabicyclo(4.3.0)non-5-ene (DBN), lithium di isopropyl amide (LDA), n-butyl lithium, tri benzylamine, isopropylamine, di isopropylamine, diisopropylethylamine, N-methyl morpholine, N-ethyl morpholine, piperidine, dimethyl aminopyridine, morpholine, pyridine, 2,6-lutidine, 2,4,6-collidine, imidazole, 1 -methylimidazole, 1,2,4-triazole, 1,4-diaza bicyclo [2.2.2]octane (DABCO) or mixtures thereof, preferably the base is triethylamine, the condensing agent is selected from the group consisting of 1,3- dicyclohexylcarbodiimide (DCC), isobutyl chloroformate, pivaloyl chloride, isovaleryl chloride, l-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC.HC1), 1 -cy cl oh exyl-3 -morpholinoethylcarbodiimide, l-cyclohexyl-3-(4- diethylaminocyclohexyl)carbodiimide, N,N'-carbonyldiimidazole, 2 -chi oro-1, 3- dimethylimidazolinium chloride, isobutyl chloroformate or mixture thereof; preferably the condensing agent is l-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC.HC1). The solvent is selected from the group consisting of ethanol, methanol, propanol, isopropanol, butanol, tert-butanol, dimethyl acetamide (DMA), dimethylformamide (DMF), dimethylsulfoxide (DMSO), N-methyl pyrrolidone (NMP), water or mixture thereof, preferably the solvent is water, ethanol, dimethylformamide (DMF). The step e) reaction is carried out at a suitable temperature of about 25°C to about 35°C for a sufficient period till completion of the reaction.

[0046] In step f) of the forgoing process, the hydrogenation of compound of formula (8) with hydrogenating agent and a solvent under appropriate reaction conditions to provide compound of formula (7). The hydrogenating agent is selected from catalytic hydrogenation (using hydrogen gas) and a catalyst such as Pt, Pt / C, PtO2 , Pd, Pd / C, Rh, Ru, Ni or Raney Ni; Zn, Sn or Fe and an acid, preferably the hydrogenating is Pd / C. The solvent is selected from the group consisting of methanol, ethanol, n- propanol, isopropanol, n-butanol, isobutanol, t-butanol or mixture thereof, preferably the solvent is ethanol. The step f) reaction is carried out at a suitable temperature of about 25°C to about 35°C for a sufficient period till completion of the reaction.

[0047] In another embodiment, the present invention provides a process for the preparation of tert-butyl (lR,2S,5S)-2-amino-5-(dimethyl carbamoyl) cyclohexyl carbamate of formula (7), comprising one or more following steps:

[0048]

[0049] In another embodiment, Edoxaban tosylate (1) obtained in the present invention could be anhydrous or hydrates such as monohydrate, dihydrate and the like. In another embodiment, Edoxaban tosylate (1) obtained in the present invention is having water content not more than 3.0% (w / w).

[0050] In another embodiment, Edoxaban tosylate (1) obtained in the present invention is crystalline form.

[0051] In another embodiment, crystalline form of Edoxaban tosylate (1) obtained according to the present invention is characterised by X-ray powder diffractions (XRD) pattern as shown in figure 1 and 2 theta values as provided in Table 1 :

[0052] Table 1:

[0053] In another embodiment, Edoxaban tosylate (1) obtained according to the present invention is having total impurities less than 1.0% (w / w), preferably less than 0.5% (w / w) which forms another embodiment of the invention.

[0054] In another embodiment, Edoxaban tosylate (1) obtained in the present invention exists in monohydrate form.

[0055] In another embodiment Edoxaban tosylate (1) obtained according to the present invention is having purity greater than 99.5% as measured by High performance liquid chromatography (HPLC).

[0056] The process described in the present invention is demonstrated in examples illustrated below. These examples are provided as illustration only and therefore should not be construed as limitation of the scope of the invention.

[0057] Examples:

[0058] Example 1: Preparation of tert-butyl (lR,2S,5S)-2-(2-(5-chloropyridin-2- ylamino)-2-oxoacetamido)-5-(dimethylcarbamoyl)cyclohexylcarbamate of formula (5).

[0059] Tert-butyl (lR,2S,5S)-2-amino-5-(dimethylcarbamoyl)cyclohexylcarbamate (7) (100 g) was added to acetonitrile (500 mL) at room temperature. To this triethyl amine (78 g) and ethyl 2-(5-chloropyridin-2-ylamino)-2-oxoacetate hydrochloride (6) (98 g) were added. The reaction mass temperature was raised to 60-65 °C and stirred. After completion of the reaction, the reaction mass was cooled to 10-15°C and further cooled to 0-5°C. The obtained solid was filtered, washed with precooled acetonitrile and water and dried to get the title compound. Yield: 85%; Purity: 99.6%

[0060] Example 2: Preparation of Edoxaban of formula (2).

[0061] Tert-butyl (lR,2S,5S)-2-(2-(5-chloropyridin-2-ylamino)-2-oxoacetamido)-5- (dimethylcarbamoyl) cyclohexyl carbamate (5) (100 g) was added to acetonitrile (700 mL) at room temperature. To this methane sulfonic acid (88 g) was slowly added and stirred. After completion of the reaction, the solid was filtered and washed with acetonitrile (200 ml) to obtain formula (4). To the reaction mass, methylene dichloride (1000 mL), 5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c] pyridine-2-carboxylic acid HC1 of formula (3) (60 g), l-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC. HC1) (81.7 g) and Hydroxy benzotriazole (HOBt) (65 g) were added to the reaction mass at room temperature. The reaction mass was cooled to 0- 5°C, then triethylamine was slowly added and raised the reaction temperature to 25- 35°C and stirred till completion of the recti on. After completion of the reaction, the reaction mass was cooled to 0-5°C, then 300 ml of 5% SBC was added. The reaction mass temperature was raised to 25-35°C and stirred. Layers were separated. Distilled the methylene di chloride layer and 100 ml of methanol was added, then distilled the methanol completely, thereafter 400 ml of water was added at 50-55°C and stirred. The reaction mass was cooled to room temperature and stirred. Filtered the solid, washed with water and methanol then dried to get the title compound. Yield: 85%;

[0062] Purity: 99.7%

[0063] Example 3: Preparation of Edoxaban tosylate of formula (1)

[0064] 100 g of Edoxaban was dissolved in 30% aqueous ethanol solution at room temperature. The reaction mass was raised to 70-75°C and then p-Toluenesulfonic acid (PTS A) solution was slowly added. The reaction mass was stirred, then 5 g of activated carbon was added to the reaction mass and stirred. Filtered the reaction mass, washed with 30% Aqueous ethanol. The reaction mass temperature was cooled to 25-35°C and stirred, further cooled to 0-5°C. Filtered the solid, washed with precooled 30% Aqueous ethanol and dried to get the title compound. Yield: 80%; Purity: 99.5% Example 4: Preparation of compound of formula (12) 100 g of (S)-cyclohex-3-enecarboxylic acid (13) was added to methylene dichloride (1000 mL) and then 80.2 g triethyl amine was added at 0-5 °C followed by 127 g of bromine at the same temperature. After stirring for 12 hours at 0-5 °C, water was added to the reaction mass. Layers were separated and methylene dichloride layer washed with 5% Sodium bicarbonate solution. Distillation of methylene dichloride layer to get crude product, which was isolated in hexane to get the tittle compound. Yield: 90% Example 5: Preparation of compound of formula (11)

[0065] To a stirred solution of 100 g of (lS,4S,5S)-4-bromo-6-oxabicyclo [3.2.1] octan-7-one in Ethanol (500 mL) was added 20 g sodium hydroxide (NaOH) at 25-35 °C. Reaction mass temperature was raised to 40-45 °C and stirred for 12 hours. Ethanol was distilled under vacuum below 40 °C and water (200 mL) was added. Compound was extracted into methylene dichloride (MDC) (500 mL) and methylene dichloride (MDC) was distilled. To the residue was added Ethanol (500 mL) and aqueous ammonia (500 mL) was added and stirred at 40 °C for 12 hours. Ethanol was distilled completely under vacuum below 40 °C to remove traces ammonia. Fresh Ethanol (500 mL) and 160g of Boc anhydride was added and stirred for 12 hours at 25-35 °C. After completion of reaction, Ethanol was distilled and compound was extracted into methylene dichloride (500 mL). methylene dichloride layer washed with water and distilled to get crude product, which was isolated from ethyl acetate and hexane mixture (2:8) to provide 93 g of pure tittle compound. Yield: 66%

[0066] Example 6: Preparation of compound of formula (10)

[0067] To a stirred solution of 100 g (lS,3R,4S)-ethyl 3-(tert-butoxycarbonylamino)-4- hydroxy cyclohexanecarboxylate in methylene dichloride (500 mL) was added 71 g triethyl amine and cooled to 0-5 °C. To the reaction was slowly added 44 g of Methanesulfonyl chloride at 0-5 °C. Reaction mixture was stirred at 0-5 °C for 3 hours. Water (200 mL) was added into the reaction mixture and methylene dichloride layer separated and washed with 2x100 mL of water, methylene di chloride layer was distilled below 35 °C under vacuum and added N, N-dimethyl formamide (300 mL), 34 g sodium azide and 8 g of Benzyl tri ethyl ammonium chloride. Reaction mixture was heated to 60-65 °C and stirred for 12 hours. Reaction mass was cooled to 25-35 °C and water (300 mL) was added to the reaction mass. Compound was extracted into Ethyl acetate (500 mL) and Ethyl acetate layer was washes with chilled water (2x100 mL). Distillation of ethyl acetate under vacuum below 45 °C to get 76 g of tittle compound. Yield: 70%

[0068] Example 7: Preparation of compound of formula (9)

[0069] To a stirred solution of 100 g of (lS,3R,4S)-ethyl 4-azido-3-(tert- butoxycarbonylamino)cyclohexanecarboxylate in autoclave was added Ethanol (750 mL), 2 g of 10% Pd-C and placed under 3 Kg Hydrogen pressure. Reaction mixture was stirred for 6 hours and filtered over Hyflo. Ethanol MLSs were collected and distilled under vacuum below 50 °C to obtain crude mass. Ethyl acetate (500 mL) was added to the obtained mass and added water (500 mL), 54 g of Sodium Bicarbonate and 60 g of benzyl chloroformate at 25-35 °C. Reaction mixture was stirred for 6 hours at 25-35 °C. Layers were separated, Ethyl acetate layer washed with water (2x100 mL) and distilled under vacuum below 45 °C to get crude product. Isolation of prude product from Ethyl acetate and Hexane mixture (2:8) provided 122 g of tittle compound. Yield: 91%

[0070] Example 8: Preparation of compound of formula (8)

[0071] To a stirred solution of 100 g of (lS,3R,4S)-ethyl 4-(benzyloxycarbonylamino)-3- (tert-butoxycarbonylamino)cyclohexanecarboxylate in Ethanol (500 ml) and water (200 mL) was added 15 g of Lithium hydroxide monohydrate at 25-35 °C. Reaction mixture was stirred for 8 hours. After completion of reaction Ethanol was distilled under vacuum below 40 °C and pH was adjusted to 4 using Hydrochloric acid solution. Precipitated solids were filtered and dried. Dried material was taken in DMF (500 mL) and added 69 g EDC HC1, 55 g HOBt, 85 DMA.HC1 followed be 96 g of TEA at 25- 35 °C and stirred for 48 hours. After completion reaction, water (500 mL) was added to the reaction mass. Compound was extracted into methylene dichloride (2x200 mL), combined methylene dichloride layers washed with water and 20% sodium chloride solution. Methylene dichloride was distilled under vacuum below 40 °C to provide 82 g of tittle compound. Yield: 82%; purity: > 95%

[0072] Example 9: Preparation of compound of formula (7)

[0073] To a stirred solution of 100 g of (1S,2R,4S)-N1 -Benzyloxy carbonyl-N2-(tert- butoxycarbonyl)-4-(N,N-dimethylcarbamoyl)- 1 ,2-cyclohexanediamine in an autoclave was added Ethanol (1000 mL), 3 g of 10% Pd-C and placed under 5 Kg Hydrogen pressure. Reaction mixture was stirred for 12 hours and filtered over Hyflo. Ethanol filtrate was collected and distilled under vacuum below 50 °C to obtain crude product. Fresh Ethanol (100 mL) was added and heated to 65-70 °C and stirred for 1 hour. Reaction mixture was slowly cooled to 25-30 °C and stirred for 2 hours.

[0074] Precipitated solid was collected by filtration and dried to get pure 67 g of tittle compound. Yield: 97%; Purity: >95%

Claims

We claim:

1. A process for the preparation of Edoxaban tosylate (1) having purity greater than 99.5% as measured by High performance liquid chromatography (HPLC), which comprises the following steps:a) reacting tert-butyl (lR,2S,5S)-2-amino-5-(dimethyl carbamoyl) cyclohexyl carbamate of formula (7)with ethyl 2-(5-chloropyridin-2-ylamino)-2-oxoacetate hydrochloride (6)in the presence of a base and a solvent under appropriate reaction conditions to provide tert-butyl (lR,2S,5S)-2-(2-(5-chloropyridin-2- ylamino)-2-oxoacetamido)-5-(dimethylcarbamoyl) cyclohexyl carbamate (5);b) deprotecting the compound of formula (5) with an acid and a solvent under appropriate reaction conditions to provide Nl-(2-amino-4-(dimethyl carbamoyl) cyclohexyl)-N2-(5-chloropyridin-2-yl) oxalamide of formula (4);c) reacting the compound of formula (4) with 5-methyl-4, 5,6,7- tetrahydrothiazolo[5,4-c] pyridine-2-carboxylic acid HC1 of formula (3)in the presence of base, condensing agent and a solvent under appropriate reaction conditions to provide crystalline form of Edoxaban of formulad) reacting the compound of formula (2) with p-toluene sulfonic acid in a solvent under appropriate reaction conditions to provide crude Edoxaban tosylate of formula (la); and e) purifying crude Edoxaban tosylate of formula (la) to provide crystalline Edoxaban tosylate of formula (1).

2. The process as claimed in claim 1, wherein the suitable base used in Step a) & c) is selected from tri ethyl amine, methyl amine, ethylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), l,5-diazabicyclo(4.3.0)non-5-ene (DBN), lithium di isopropyl amide (LDA), n-butyl lithium, tri benzylamine, isopropylamine, di isopropylamine, diisopropylethylamine, N-methyl morpholine, N-ethyl morpholine, piperidine, dimethyl aminopyridine, morpholine, pyridine, 2,6-lutidine, 2,4,6-collidine, imidazole, 1 -methylimidazole, 1,2,4-triazole, 1,4- diaza bicyclo [2.2.2]octane (DABCO) or mixtures thereof,3. The process as claimed in claim 1, wherein the suitable solvent used in Step a) & b) is selected from acetonitrile, propionitrile, isobutyronitrile and the like, step-c) solvent is selected from the group consisting of dichloromethane, dichloroethane, chloroform, carbon tetrachloride and the like, preferably the solvent is methylene dichloride, step-d) solvent is selected from methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol and the like,4. The process as claimed in claim 1, wherein the suitable acid used in Step b) is selected from hydrochloric acid, trichloroacetic acid, methane sulfonic acid,5. The process as claimed in claim 1, wherein the suitable condensing agent used inStep c) is selected from the group consisting of 1,3 -di cyclohexylcarbodiimide (DCC), isobutyl chloroformate, pivaloyl chloride, isovaleryl chloride, l-ethyl-3-(3- dimethylaminopropyl)carbodiimide hydrochloride (EDC.HC1), l-cyclohexyl-3- morpholinoethylcarbodiimide, l-cyclohexyl-3-(4- diethylaminocyclohexyl)carbodiimide, N,N'-carbonyldiimidazole, 2-chloro-l,3- dimethylimidazolinium chloride, isobutyl chloroformate or mixture thereof;6. A process for the purification of Edoxaban tosylate (1), which comprises: i) dissolving crude Edoxaban tosylate of formula (la) in a solvent or mixture of solvents; and ii) isolating Edoxaban tosylate of formula (1).

7. The process as claimed in claim 6, wherein the suitable solvent used is selected from methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol and the like,8. A process for the preparation of tert-butyl (lR,2S,5S)-2-amino-5-(dimethyl carbamoyl) cyclohexyl carbamate of formula (7), comprising one or more following steps:a) reacting of compound of formula (13)with bromine in the presence of a base and a solvent under appropriate reaction conditions to provide compound of formula (12).b) reacting of compound of formula (12) with Boc anhydride in the presence of base and a solvent under appropriate reaction conditions to provide compound of formula (11).c) reaction of compound of formula (11) with sodium azide in the presence of Benzyltriethylammonium chloride, base and a solvent under appropriate reaction conditions to provide compound of formula (10).d) the hydrogenation of compound of formula (10) with hydrogenating agent and a solvent under appropriate reaction conditions followed by reacting the obtained compound with benzyl chloroformate in the presence of a base and a solvent under appropriate reaction conditions to provide compound of formula (9).e) reaction of compound of formula (9) with Lithium hydroxide monohydrate and mixture of solvents under appropriate reaction conditions followed by reacting the obtained compound with DMA. HC1 in the presence of base, condensing agent, Hydroxybenzotriazole (HOBt) as an additive and a solvent under appropriate reaction conditions to provide compound of formula (8).f) the hydrogenation of compound of formula (8) with hydrogenating agent and a solvent under appropriate reaction conditions to provide compound of formula (7).

9. The process as claimed in claim 8, wherein the suitable base used in step a) & c), e) is selected from tri ethyl amine, methyl amine, ethylamine, 1,8- diazabicyclo[5.4.0]undec-7-ene (DBU), l,5-diazabicyclo(4.3.0)non-5-ene (DBN),lithium di isopropyl amide (LDA), n-butyl lithium, tri benzylamine, isopropylamine, di isopropylamine, diisopropylethylamine, N-methyl morpholine, N-ethyl morpholine, piperidine, dimethyl aminopyridine, morpholine, pyridine, 2,6-lutidine, 2,4,6-collidine, imidazole, 1 -methylimidazole, 1,2,4-triazole, 1,4- diaza bicyclo [2.2.2]octane (DABCO) or mixtures thereof, step b) The base is selected from lithium hydroxide, sodium hydroxide, potassium hydroxide. Step d) The base is selected from sodium bicarbonate, potassium bicarbonate, lithium bicarbonate.

10. The process as claimed in claim 8, wherein the suitable solvent used in step a) & c) is selected from dichloromethane, dichloroethane, chloroform, carbon tetrachloride. Step b), d) & e) The solvent is selected from methanol, ethanol, n- propanol, isopropanol, n-propanol, n-butanol, isobutanol, t-butanol, methyl formate, methyl acetate, ethyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, vinyl acetate, dimethyl acetamide (DMA), dimethylformamide (DMF), dimethylsulfoxide (DMSO), N-methyl pyrrolidone (NMP), water or mixture thereof,11. The process as claimed in claim 8, Step d) & f) The hydrogenating agent is selected from hydrogenating agent is selected from catalytic hydrogenation (using hydrogen gas) and a catalyst such as Pt, Pt / C, PtO2, Pd, Pd / C, Rh, Ru, Ni or Raney Ni; Zn, Sn or Fe and an acid.

12. The process as claimed in claim 8, Step e) the condensing agent is selected from the group consisting of 1,3-dicyclohexylcarbodiimide (DCC), isobutyl chloroformate, pivaloyl chloride, isovaleryl chloride, l-ethyl-3-(3- dimethylaminopropyl)carbodiimide hydrochloride (EDC.HC1), l-cyclohexyl-3- morpholinoethylcarbodiimide, 1 -cyclohexyl-3-(4- diethylaminocyclohexyl)carbodiimide, N,N'-carbonyldiimidazole, 2-chloro-l,3- dimethylimidazolinium chloride, isobutyl chloroformate or mixture thereof; preferably the condensing agent is l-ethyl-3-(3- dimethylaminopropyl)carbodiimide hydrochloride (EDC.HC1).

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