Description:FORM 2

THE PATENTS ACT 1970
(Act 39 of 1970)
&
THE PATENTS RULES 2003
(SECTION 10 AND RULE 13)

COMPLETE SPECIFICATION

“NOVEL PROCESSES FOR THE PREPARATION OF EDOXABAN TOSYLATE MONOHYDRATE AND ITS INTERMEDIATES”

SYMED LABS LIMITED
An Indian Company having its Office at
8-2-293/174/3, B.N. Reddy Colony,
Road No. 14, Banjara Hills,
Hyderabad-500 034,
Telangana, India

THE FOLLOWING SPECIFICATION PARTICULARLY DESCRIBES AND ASSERTAINS THE NATURE OF THE INVENTION AND THE MANNER IN WHICH IT IS TO BE PERFORMED

FIELD OF THE INVENTION
The present invention relates to novel, commercially viable and industrially advantageous processes for the preparation of Edoxaban Tosylate monohydrate and its intermediates. The present invention further relates to a consistently reproducible and commercially viable process for the production of highly pure crystalline Form I of Edoxaban Tosylate monohydrate.

BACKGROUND OF THE INVENTION
U.S. Patent No. 7,365,205B2 (hereinafter referred to as the US‘205 patent) discloses novel Factor Xa inhibitors such as diamine derivatives, salts, solvates and processes for their preparation, pharmaceutical compositions comprising the derivatives, and methods of use thereof. These compounds exhibit potent FXa inhibiting effect, anti-coagulant effect and anti-thrombotic effect. Among them, Edoxaban tosylate, chemically named 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 mono (4-methylbenzenesulfonate) monohydrate, is a selective Factor Xa inhibitor indicated to reduce the risk of stroke and systemic embolism (SE) in patients with nonvalvular atrial fibrillation (NVAF). Edoxaban tosylate monohydrate is represented by the following structural formula I(a):

Edoxaban tosylate monohydrate was developed by Daiichi Sankyo and it is sold under the brand names SAVAYSA® in the United States and LIXIANA® in the European Union. It is orally administered as tablets containing 60 mg, 30 mg and 15 mg of Edoxaban.
Various processes for the preparation of Edoxaban tosylate monohydrate and its intermediates are described in U.S. Patent Nos. US7365205B2, US7547786B2, US8357808B2, US8404847B2, US8686189B2, US9175012B2, US9233980B2, US9447118B2, US9920071B2, US10301322B2; U.S. Patent Application Publication Nos. US20110257401A1, US20120053349A1, US20150353577A1, US20150239909A1; PCT Publication Nos. WO2008156159A1, WO2011059080A1, WO2018083213A1, WO2018038426A1, WO2019158550A1, WO2019004114A1, WO2021001728A1; Indian Patent No. IN368219; Indian Patent Application Nos. IN201621013274A, IN201741033706A, IN201721013303A, IN201941000683 and IN202041026059; and Organic Process Research & Development, 2019, Volume: 23, Issue: 4, Pages: 524-534.
In the synthesis of Edoxaban tosylate, tert-butyl N-[(1R,2S,5S)-2-[[2-[(5-chloropyridin-2-yl)amino]-2-oxoacetyl]amino]-5-(dimethylcarbamoyl)cyclohexyl] carbamate of formula V (hereinafter referred to as the “key intermediate” or tert-butyl carbamate intermediate”):

is a key intermediate.
The synthetic routes of Edoxaban tosylate monohydrate and its intermediates were first described in the US7,365,205B2. As per the process described in the US’205 patent (Reference Example 434), the tert-butyl carbamate intermediate is prepared by reacting tert-butyl (1R,2S,5S)-2-amino-5-[(dimethylamino)carbonyl] cyclohexylcarbamate with lithium 2-[(5-chloropyridin-2-yl)amino]-2-oxoacetate in the presence of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 1-hydroxy benzotriazole monohydrate in methylene chloride solvent to produce a residue which is further purified by column chromatography on silica gel (ethyl acetate : hexane = 2:3) to produce the tert-butyl carbamate intermediate.
As per the process described in the US’205 patent, the tert-butyl carbamate intermediate is further converted into Edoxaban tosylate monohydrate by a process comprising the following steps: (i) the tert-butyl carbamate compound is reacted with ethanolic solution of hydrochloric acid in methylene chloride solvent to produce N1-[(1S,2R,4S)-2-amino-4-[(dimethylamino)carbonyl]-cyclohexyl]-N2-(5-chloropyridin-2-yl)ethanediamide hydrochloride; (ii) the resulting amino intermediate is reacted with lithium 5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]-pyridine-2-carboxylate in the presence of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 1-hydroxy benzotriazole monohydrate in N,N-dimethylformamide solvent followed by usual workup procedure to obtain a residue, which is purified by column chromatography on silica gel (methanol: methylene chloride= 7:93) to produce Edoxaban free base; and (iii) the resulting Edoxaban free base is dissolved in methylene chloride, ethanolic solution of p-toluenesulfonic acid is added and then the solvent is distilled off to form a residue, followed by crystallization of the solid from a solvent medium comprising ethanol and water to produce Edoxaban tosylate monohydrate (crystals).
U.S. Patent No. US 8,686,189B2 (hereinafter referred to as the US’189 patent) discloses a process for producing intermediates of Edoxaban tosylate. As per the process described in the US’189 patent (Reference Example 1), the tert-butyl carbamate intermediate” is prepared by reacting tert-butyl [(1R,2S,5S)-2-amino-5-[(dimethylamino)carbonyl]cyclohexyl]carbamate oxalate with ethyl 2-[(5-chloropyridin-2-yl)amino]-2-oxoacetate hydrochloride salt in the presence of triethylamine in acetonitrile solvent. As per the process described in the US’189 patent (Reference Examples 2 to 3), the resulting tert-butyl carbamate intermediate is further converted into Edoxaban tosylate monohydrate by a process comprising the following reaction steps: (i) reacting the tert-butyl carbamate intermediate with methanesulfonic acid in acetonitrile solvent to produce a reaction mixture containing an in situ amino-intermediate “N1-[(1S,2R,4S)-2-amino-4-[(dimethylamino) carbonyl]cyclohexyl]-N2-(5-chloro-2-pyridinyl)ethanediamide”, which is further (in situ) reacted with 5-methyl-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]-pyridine-2-carboxylic acid hydrochloride in the presence of triethylamine, 1-(ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride and 1-hydroxy benzotriazole to produce Edoxaban free base; and (ii) the Edoxaban free base is further treated with p-toluenesulfonic acid in aqueous ethanol solvent to produce Edoxaban tosylate monohydrate.
U.S. Patent No. US 8,357,808B2 (hereinafter referred to as the US’808 patent) discloses a process for the preparation of the tert-butyl carbamate intermediate which comprises the following steps: (i) treating ethyl 2-[(5-chloropyridin-2-yl)amino]-2-oxoacetate hydrochloride salt with a tertiary amine in a nitrile solvent; and (ii) then adding, to the mixed solution of step (i), tert-butyl [(1R,2S,5S)-2-amino-5-[(dimethylamino)carbonyl]cyclohexyl]carbamate oxalate salt to the tert-butyl carbamate intermediate. As per the process described in the US’808 patent (Reference Examples 4 & 5), the resulting tert-butyl carbamate intermediate is further converted into Edoxaban tosylate monohydrate.
PCT Publication No. WO2019/158550A1 (hereinafter referred to as the WO’550 publication) describes a process for the preparation of the tert-butyl carbamate intermediate of Edoxaban which comprises the following steps: a) mixing tert-butyl N-((1R,2S,5S)-2-amino-5-(dimethylcarbamoyl)cyclohexyl)carbamate (free base) with ethyl 2-((5-chloropyridin-2-yl)amino)-2-oxoacetate (free base) in an organic solvent such as acetonitrile; b) mixing a base with the resulting mixture from step (a) wherein the base is an amine selected from the group consisting of tertiary amines, aromatic amines and mixtures thereof; and c) stirring the mixture obtained in step (b).
Indian Patent Application No. IN202041026059 (hereinafter referred to as the IN’059 application) describes a process for the preparation of the tert-butyl carbamate intermediate of Edoxaban which comprises the following steps: a) condensation of tert-butyl N-((1R,2S,5S)-2-amino-5-(dimethylcarbamoyl) cyclohexyl)carbamate (free base) with ethyl 2-((5-chloropyridin-2-yl)amino)-2-oxoacetate (free base) in a reactor under pressure (the high pressure is exerted by an inert gas such as nitrogen or argon gas); and b) optionally purifying the the tert-butyl carbamate intermediate in one or more solvents.
Edoxaban tosylate exhibits polymorphism. US Patent No. 8,541,443B2 (hereinafter referred to as the US’443 patent) discloses two crystalline forms of Edoxaban tosylate monohydrate which are designated as Form I and Form II. The crystalline Form I of Edoxaban tosylate monohydrate is reported as a thermodynamically most stable form. The US’443 patent teaches that the crystals obtained by the process described in the US’205 patent are referred to as “Form I crystals”. According to the US’443 patent, the crystalline Form I of Edoxaban is characterized by X-ray powder diffraction pattern having 2-theta peaks at about 5.38, 8.08, 10.80, 13.5, 15.0, 16.9, 17.6, 20.5, 21.1, 22.7, 23.5, 26.0, 27.3, 27.6, and 30.0 ± 0.2 degrees; an infrared absorption spectrum (IR) having characteristic IR bands at about 3344±5, 1675±2, 1614±2, 1503±2, 1222±1, 1171±1, 1033±1, 1012±1, 843±1, 825±1, and 802±1 (cm−1); a DTA profile having two endothermic peaks at approximately 250°C to approximately 270°C; and/or a melting point (decomposition) of approximately 246°C to approximately 250°C.
The processes for the preparation of Edoxaban tosylate monohydrate and its key intermediate (tert-butyl carbamate intermediate) as described in the aforementioned prior art involve the use of highly expensive key raw materials such as ethyl 2-chloro-2-oxoacetate, ethyl 2-[(5-chloropyridin-2-yl)amino]-2-oxoacetate and/or lithium 2-[(5-chloropyridin-2-yl)amino]-2-oxoacetate.
A need still remains for novel, improved, commercially viable and industrially advantageous processes for the preparation of the Edoxaban tosylate monohydrate and its intermediates to resolve the problems associated with the processes described in the prior art, and that will be suitable for large-scale preparation.

SUMMARY OF THE INVENTION
The object of the present invention is to provide novel, commercially viable and industrially advantageous processes for the preparation of Edoxaban tosylate monohydrate and its intermediates with high yield and high purity by using less expensive key raw materials such as methyl 2-chloro-2-oxoacetate and methyl 2-[(5-chloropyridin-2-yl)amino]-2-oxoacetate.
The present inventors have surprisingly and unexpectedly found that the key intermediate of Edoxaban “tert-butyl N-[(1R,2S,5S)-2-[[2-[(5-chloropyridin-2-yl)amino]-2-oxoacetyl]amino]-5-(dimethylcarbamoyl)cyclohexyl]carbamate” can be prepared with high yield and high chemical and chiral purity by reacting methyl 2-[(5-chloropyridin-2-yl)amino]-2-oxoacetate or a salt thereof with tert-butyl [(1R,2S,5S)-2-amino-5-[(dimethylamino)carbonyl]cyclohexyl]carbamate or a salt thereof in the presence or absence of a base in a suitable solvent to produce the tert-butyl carbamate intermediate, which is further converted into Edoxaban or a pharmaceutically acceptable salt thereof, preferably Edoxaban tosylate monohydrate, by using the processes known in the art or by the processes described hereinafter.
The processes for preparation of Edoxaban and its key intermediate disclosed herein avoids the use of: (i) tedious and cumbersome procedures associated with the prior art processes; and/or (ii) highly expensive key raw materials such as ethyl 2-chloro-2-oxoacetate, ethyl 2-[(5-chloropyridin-2-yl)amino]-2-oxoacetate and/or lithium 2-[(5-chloropyridin-2-yl)amino]-2-oxoacetate, thereby resolving the problems associated with the processes described in the prior art and making the process commercially viable and industrially advantageous.
In another aspect, provided also herein is a commercially viable and consistently reproducible process for the preparation of highly pure crystalline Form I of Edoxaban tosylate monohydrate.

BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 is a characteristic powder X-ray diffraction (XRPD) pattern of highly pure crystalline Form I of Edoxaban tosylate monohydrate.
Figure 2 is a characteristic infra-red (IR) spectrum of highly pure crystalline Form I of Edoxaban tosylate monohydrate.
Figure 3 is a characteristic Differential Scanning Calorimetric (DSC) thermogram of highly pure crystalline Form I of Edoxaban tosylate monohydrate.

DETAILED DESCRIPTION OF THE INVENTION
Unless otherwise specified, the term ‘base’ as used herein includes, but is not limited to, organic bases and inorganic bases such as carbonates, bicarbonates, hydroxides, alkoxides, acetates and amides of alkali or alkali earth metals.
Specifically, the inorganic base is selected from the group consisting of sodium carbonate, potassium carbonate, lithium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, lithium bicarbonate, cesium bicarbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, sodium tert-butoxide, potassium tert.butoxide, sodium amide, potassium amide, ammonia, and mixtures thereof.
Specifically, the organic base is selected from the group consisting of dimethylamine, diethylamine, diisopropyl amine, diisopropylethylamine, di n-butylamine, diisobutylamine, triethylamine, tributylamine, tert-butyl amine, pyridine, 4-dimethylaminopyridine (DMAP), and mixtures thereof.
Unless otherwise specified, the term ‘salt’ or “pharmaceutically acceptable salt” of the compounds of formula I, II, III, IIIA, IV, V, VI and/or VII as used herein may include acid addition salts and/or base addition salts.
Acid addition salts of the compounds of formula I, II, III, IIIA, IV, V, VI and/or VII as used herein may be derived from organic and inorganic acids. For example, the acid addition salts are derived from a therapeutically acceptable acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, oxalic acid, acetic acid, propionic acid, phosphoric acid, succinic acid, maleic acid, fumaric acid, citric acid, glutaric acid, tartaric acid, benzenesulfonic acid, p-toluenesulfonic acid, malic acid, ascorbic acid, and the like.
Exemplary acid addition salts include, but are not limited to, hydrochloride, hydrobromide, sulphate, nitrate, phosphate, acetate, propionate, oxalate, succinate, maleate, fumarate, benzenesulfonate, p-toluene sulfonate, citrate, tartrate, and the like. A most specific acid addition salt is hydrochloride salt. A most specific pharmaceutically acceptable salt of Edoxaban is p-toluene sulfonate salt.
Base addition salts may be derived from an organic or an inorganic base. For example, the base addition salts are derived from alkali or alkaline earth metals such as sodium, calcium, potassium and magnesium, ammonium salt and the like.
As used herein, the term “reflux temperature” means the temperature at which the solvent or solvent system refluxes or boils at atmospheric pressure.
As used herein, the term “room temperature” refers to a temperature of about 20ºC to about 35ºC, and specifically to a temperature of about 25ºC to about 30ºC.
Unless otherwise specified, the solvent used for work-up, isolation, purification and/or recrystallization of the compounds obtained by the processes described in the present invention is selected from the group consisting of water, an alcohol, an ether, an ester, a hydrocarbon, a halogenated hydrocarbon, a nitrile solvent, a ketone, a polar aprotic solvent, and mixtures thereof. Specifically, the solvent used for work-up, isolation, purification and/or recrystallization of the compounds obtained by the processes described herein is selected from the group consisting of water, methanol, ethanol, 1-propanol, isopropyl alcohol, tetrahydrofuran, 2-methyl-tetrahydrofuran, diisopropyl ether, methyl tert-butyl ether, ethyl acetate, ketone, cyclohexane, toluene, xylene, dichloromethane, dichloroethane, chloroform, acetonitrile, dimethylformamide, dimethylacetamide, and mixtures thereof.
Unless otherwise specified, the carbon treatment is carried out by the methods known in the art, for example, by stirring the reaction mass/solution with finely powdered carbon at a temperature of about 40°C to the reflux temperature of the solvent used for at least 5 minutes, preferably for about 10 minutes to about 2 hours; and filtering the resulting mixture through charcoal bed to obtain a filtrate containing compound by removing charcoal. Specifically, finely powdered carbon is a special carbon or an active carbon.
According to one aspect, there is provided a process for the preparation of Edoxaban intermediate, tert-butyl N-[(1R,2S,5S)-2-[[2-[(5-chloropyridin-2-yl)amino]-2-oxoacetyl]amino]-5-(dimethylcarbamoyl)cyclohexyl]carbamate, of formula V:

or a salt thereof, comprising reacting methyl 2-[(5-chloropyridin-2-yl)amino]-2-oxoacetate of formula III:

or a salt thereof, with tert-butyl [(1R,2S,5S)-2-amino-5-[(dimethylamino) carbonyl]cyclohexyl]carbamate of formula IV:

or a salt thereof, in the presence or absence of a base in a suitable solvent to produce the tert-butyl carbamate compound of formula V or a salt thereof.
In one embodiment, the reaction between the compound of formula III or a salt thereof and the compound of formula IV or a salt thereof is carried out in the presence of a base.
In another embodiment, the base used in the above reaction between the compound of formula III or a salt thereof and the compound of formula IV or a salt thereof is an organic or inorganic base selected from the group as described hereinabove. In a preferred embodiment, the base used in the above reaction is an organic base. The organic base includes, but is not limited to, tertiary amines, aromatic amines, nitrogen containing heterocyclic compounds and mixtures thereof.
Specifically, the organic base used in the above reaction between the compound of formula III or a salt thereof and the compound of formula IV or a salt thereof is selected from the group consisting of dimethylamine, diethylamine, diisopropyl amine, diisopropylethylamine, di-n-butylamine, diisobutylamine, triethylamine, tributylamine, tert-butyl amine, pyridine, methylpyridine, dimethylpyridine, dibutylmethylpyridine, and dimethylaminopyridine, imidazole, benzimidazole, histidine, and mixtures thereof. A most preferable organic base used in the above reaction is triethylamine.
Exemplary solvents used in the above reaction between the compound of formula III or a salt thereof and the compound of formula IV or a salt thereof include, but are not limited to, a hydrocarbon solvent, an ester, an ether, a ketone, a chlorinated hydrocarbon solvent, an amide, a nitrile, and mixtures thereof.
Specifically the solvent used in the above reaction is selected from the group consisting of toluene, ethyl acetate, propyl acetate, isopropyl acetate, t-butyl acetate, isobutyl acetate, diethyl ether, di-isopropyl ether, methyl tert-butyl ether, 1,4-dioxane, tetrahydrofuran, 2-methyl tetrahydrofuran, acetone, butanone, 2-pentanone, 3-pentanone, methyl isobutyl ketone, methyl ethyl ketone, methylene dichloride, ethylene dichloride, carbon tetrachloride, chlorobenzene, dimethylformamide, dimethylacetamide, dimethyl sulfoxide, N-methyl pyrrolidone, acetonitrile, and mixtures thereof. A most preferable solvent used in the above reaction is acetonitrile or dichloromethane.
In another embodiment, the molar ratio between the compounds of formula (IV) and (III) in the above reaction is from about 1 : 0.75 to about 1 : 1.5, preferably from about 1 : 0.95 to about 1 : 1.25, and most preferably from about 1 : 1 to about 1 : 1.05.
In one embodiment, the above reaction between the compound of formula III or a salt thereof and the compound of formula IV or a salt thereof is carried out at a temperature of about 25°C to the reflux temperature of the solvent used, specifically at a temperature of about 45°C to about 100°C, and most specifically at a temperature of about 50°C to about 80°C. The reaction time may vary from about 1 hour to about 20 hours, specifically from about 3 hours to about 15 hours and most specifically from about 5 hours to about 12 hours.
The reaction mass containing the tert-butyl carbamate compound of formula V or a salt thereof obtained in the above reaction may be subjected to usual work up methods such as washing, quenching, extraction, pH adjustment, evaporation, layer separation, decolorization, carbon treatment, filtration, or a combination thereof.
In one embodiment, the tert-butyl carbamate compound of formula V or a salt thereof is isolated and/or re-crystallized from a suitable solvent by conventional methods such as cooling, seeding, partial removal of the solvent from the solution, by adding an anti-solvent to the solution, evaporation, vacuum distillation, filtration, drying, or a combination thereof.
In another embodiment, the solvent used for work-up, isolation, purification and/or recrystallization of the compound of formula V obtained by the process described in the present invention is selected from the group of solvents as described hereinabove.
The tert-butyl carbamate compound of formula V or a salt thereof obtained by the process disclosed herein has a chemical purity of greater than about 95%, more specifically greater than about 98%, and most specifically greater than about 99% as measured by HPLC.
The tert-butyl carbamate compound of formula V or a salt thereof obtained by the processes disclosed herein is further converted into Edoxaban or a pharmaceutically acceptable salt or a hydrate thereof (preferably Edoxaban tosylate monohydrate) by the processes described hereinafter, or by the known methods described in the art, for example, as per the processes described in the following patents and/or applications: US7,365,205B2, US8,686,189B2, US7,342,014B2, US8,357,808B2, US8,541,443B2, US8,901,345B2, US9,233,980B2, WO2019004114A1, WO2018083213A1 and WO2021001728A1.
The methyl 2-[(5-Chloropyridin-2-yl)amino]-2-oxoacetate of formula III used as a starting material in the processes described in the present invention can be prepared by using the methods described hereinafter.
According to another aspect, there is provided a process for the preparation of the methyl 2-[(5-chloropyridin-2-yl)amino]-2-oxoacetate of formula III:

or a salt thereof, which comprises:
a) reacting 2-amino-5-chloropyridine of formula II:

or a salt thereof, with methyl 2-chloro-2-oxoacetate in a suitable solvent to produce hydrochloride salt of methyl 2-[(5-chloropyridin-2-yl)amino]-2-oxoacetate of formula III, wherein the solvent is selected from the group consisting of a hydrocarbon solvent, a ketone, an amide, a nitrile solvent, and mixtures thereof; and
b) optionally, treating the hydrochloride salt of the compound of formula III with a base in a suitable solvent to produce the compound of formula III as a free base.
Specifically, the solvent used in in step-(a) is selected from the group consisting of toluene, acetone, butanone, 2-pentanone, 3-pentanone, methyl isobutyl ketone, methyl ethyl ketone, dimethylformamide, dimethylacetamide, acetonitrile, and mixtures thereof. A most preferable solvent used in step-(a) is acetonitrile.
In one embodiment, the reaction in step-(a) is carried out at a temperature of about 30°C to the reflux temperature of the solvent used; specifically, at a temperature of about 40°C to about 80°C; and most specifically at a temperature of about 45°C to about 65°C. The reaction time may vary from about 30 minutes to about 10 hours, specifically from about 1 hour to about 8 hours and most specifically from about 2 hours to about 5 hours.
The reaction mass containing the hydrochloride salt of methyl 2-[(5-chloropyridin-2-yl)amino]-2-oxoacetate of formula III obtained in step-(a) may be subjected to usual work up methods as described hereinabove. The reaction mass containing the hydrochloride salt of methyl 2-[(5-chloropyridin-2-yl)amino]-2-oxoacetate of formula III may be used directly in the next step to produce the compound of formula III as a free base, or the hydrochloride salt of the compound of formula III may be isolated and/or recrystallized and then used in the next step. In one embodiment, hydrochloride salt of methyl 2-[(5-chloropyridin-2-yl)amino]-2-oxoacetate of formula III obtained in step-(a) is isolated and/or re-crystallized from a suitable solvent by conventional methods as described hereinabove.
In another embodiment, the solvent used for work-up, isolation, purification and/or recrystallization of the hydrochloride salt of the compound of formula III obtained by the process described in the present invention is selected from the group of solvents as described hereinabove.
In another embodiment, the base used in step-(b) is an organic or inorganic base selected from the group as described hereinabove. In a preferred embodiment, the base used in step-(b) is an inorganic base.
Specifically, the inorganic base used in step-(b) is selected from the group consisting of sodium carbonate, potassium carbonate, lithium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, lithium bicarbonate, cesium bicarbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, sodium tert-butoxide, potassium tert.butoxide, ammonia, and mixtures thereof. A most preferable inorganic base used in step-(b) is sodium bicarbonate.
Exemplary solvents used in step-(b) include, but are not limited to, water, an alcohol, a ketone, a chlorinated hydrocarbon solvent, a nitrile solvent, and mixtures thereof.
Specifically, the solvent used in in step-(b) is selected from the group consisting of water, methanol, ethanol, 1-propanol, isopropyl alcohol, acetone, butanone, 2-pentanone, 3-pentanone, methyl isobutyl ketone, methyl ethyl ketone, methylene dichloride, ethylene dichloride, carbon tetrachloride, chlorobenzene, dimethylformamide, dimethylacetamide, acetonitrile, and mixtures thereof. A most preferable solvent used in step-(b) is water.
In one embodiment, the treatment with a base in step-(b) is carried out at a temperature of about 20°C to the reflux temperature of the solvent used; and most specifically at a temperature of about 25°C to about 40°C.
The reaction mass containing the compound of formula III (free base) obtained in step-(b) may be subjected to usual work up methods as described hereinabove. In another embodiment, the compound of formula III (free base) obtained in step-(b) is isolated and/or re-crystallized from a suitable solvent by conventional methods as described hereinabove.
In another embodiment, the solvent used for work-up, isolation, purification and/or recrystallization of the compound of formula III (free base) obtained by the process described in the present invention is selected from the group of solvents as described hereinabove.
The tert-butyl carbamate compound of formula III or a salt thereof obtained by the process disclosed herein has a chemical purity of greater than about 95%, more specifically greater than about 98%, and most specifically greater than about 99% as measured by HPLC.
According to another aspect, there is provided a process for the preparation of Edoxaban of formula I:

or a pharmaceutically acceptable salt thereof, which comprises:
a) reacting methyl 2-[(5-chloropyridin-2-yl)amino]-2-oxoacetate of formula III:

or a salt thereof, with tert-butyl [(1R,2S,5S)-2-amino-5-[(dimethylamino) carbonyl]cyclohexyl]carbamate of formula IV:

or a salt thereof, in the presence or absence of a base in a suitable solvent to produce the tert-butyl carbamate compound of formula V:

or a salt thereof; and
(b) converting the compound of formula V or a salt thereof into Edoxaban of formula I or a pharmaceutically acceptable salt thereof, preferably Edoxaban tosylate monohydrate.
The preparation of the tert-butyl carbamate compound of formula V or a salt thereof as described in the above process step-(a) can be carried out by using the suitable solvents, reagents, methods, parameters and conditions as described hereinabove for the reaction between the compound of formula III or a salt thereof and the compound of formula IV or a salt thereof.
The conversion of the compound of formula V or a salt thereof into Edoxaban of formula I or a pharmaceutically acceptable salt thereof, preferably Edoxaban tosylate monohydrate in step-(b) can be carried out by the processes described herein, or by the known methods described in the art, for example, as per the processes described and/or exemplified in the following patents and/or applications: US7,365,205B2, US8,686,189B2, US7,342,014B2, US8,357,808B2, US8,541,443B2, US8,901,345B2, US9,233,980B2, WO2019004114A1, WO2018083213A1 and WO2021001728A1.
According to another aspect, there is provided a process for the preparation of Edoxaban of formula I or a pharmaceutically acceptable salt thereof, which comprises:
a) reacting an alkyl 2-[(5-chloropyridin-2-yl)amino]-2-oxoacetate of formula IIIA:

or a salt thereof, wherein the radical ‘R’ is isopropyl, n-propyl, n-butyl or tert-butyl; with tert-butyl [(1R,2S,5S)-2-amino-5-[(dimethylamino)carbonyl] cyclohexyl]carbamate of formula IV or a salt thereof, in the presence or absence of a base in a suitable solvent to produce the tert-butyl carbamate compound of formula V or a salt thereof; and
(b) converting the compound of formula V or a salt thereof into Edoxaban of formula I or a pharmaceutically acceptable salt thereof, preferably Edoxaban tosylate monohydrate.
The preparation of the tert-butyl carbamate compound of formula V or a salt thereof as described in the above process step-(a) can be carried out by using the suitable solvents, reagents, methods, parameters and conditions as described hereinabove for the reaction between the compound of formula III or a salt thereof and the compound of formula IV or a salt thereof.
The conversion of the compound of formula V or a salt thereof into Edoxaban of formula I or a pharmaceutically acceptable salt thereof, preferably Edoxaban tosylate monohydrate, can be carried out by the processes described hereinafter, or by the known methods described in the prior art references as mentioned hereinabove.
According to another aspect, the compound of formula V or a salt thereof obtained by the processes disclosed herein is further converted into Edoxaban of formula I or a pharmaceutically acceptable salt thereof, preferably Edoxaban tosylate monohydrate, by a process comprising the following steps:
i) reacting the compound of formula V or a salt thereof with a deprotecting agent in a suitable solvent to produce N1-[(1S,2R,4S)-2-amino-4-[(dimethylamino)carbonyl] cyclohexyl]-N2-(5-chloro-2-pyridinyl)ethanediamide of formula VI:

or a salt thereof;
ii) reacting the compound of formula VI or a salt thereof with 5-methyl-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridine-2-carboxylic acid of formula VII:

or a salt thereof, in the presence of a suitable activating agent and a base in a suitable solvent to produce Edoxaban of formula I or a salt thereof; and
(iii) converting the Edoxaban of formula I or a salt thereof obtained in step-(ii) into highly pure Edoxaban tosylate monohydrate of formula I(a) by treating with p-toluene sulfonic acid in a suitable solvent.
In one embodiment, the deprotecting agent used in step-(i) is selected from the group consisting of hydrochloric acid, methanesulfonic acid, trifluoroacetic acid, ethyl acetate hydrochloride, IPA-HCl, methanol-HCl, ethanol-HCl, or a combination thereof. A most specific deprotecting agent used in step-(i) is methane sulfonic acid or hydrochloric acid.
Exemplary solvents used in step-(i), step-(ii) and step-(iii) include, but are not limited to, water, a nitrile, an alcohol, a ketone, an ester, an ether, a hydrocarbon solvent, a chlorinated hydrocarbon solvent, and mixtures thereof.
Specifically, the solvent used in step-(i), step-(ii) and/or step-(iii) is, each independently, selected from the group consisting of water, acetonitrile, methanol, ethanol, isopropyl alcohol, acetone, methyl ethyl ketone, methyl isobutyl ketone, methyl acetate, ethyl acetate, isopropyl acetate, dioxane, dimethyl sulfoxide, tetrahydrofuran, toluene, xylene, methylene dichloride, dimethyl formamide, and mixtures thereof. A most preferable solvent used in step-(i) and/or step-(ii) is acetonitrile or methylene dichloride. A most preferable solvent used in step-(iii) is water, acetonitrile, methanol, ethanol, isopropyl alcohol, or a mixture thereof.
Specifically, the reaction in step-(i) is carried out at a temperature of about 15°C to about 55°C; and more specifically at a temperature of about 25°C to about 35°C. The reaction time may vary about 1 hour to about 5 hours; and more specifically from about 2 hours to about 4 hours.
The reaction mass containing the N1-[(1S,2R,4S)-2-amino-4-[(dimethylamino)carbonyl]cyclohexyl]-N2-(5-chloro-2-pyridinyl)-ethane diamide of formula VI or a salt thereof obtained in step-(i) may be subjected to usual work up methods as described hereinabove. The reaction mass containing the compound of formula VI or a salt thereof may be used directly (in situ) in the next step to produce the compound of formula I or a salt thereof, or the compound of formula VI or a salt thereof may be isolated and/or recrystallized and then used in the next step.
In one embodiment, the compound of formula VI or a salt thereof obtained in step-(i) may be isolated and/or re-crystallized from a suitable solvent by conventional methods as described hereinabove.
In a preferred embodiment, the reaction mass containing the compound of formula VI or a salt thereof obtained in step-(i) is used directly (in situ) in the next step to produce the compound of formula I or a salt thereof.
In one embodiment, the base used in step-(ii) is an organic base or inorganic base selected from the group as described hereinabove. In a preferred embodiment, the base used in step-(ii) is an organic base selected from the group as described hereinabove. Specifically, the organic base used in step-(ii) is selected from the group consisting of dimethylamine, diethylamine, diisopropyl amine, diisopropylethylamine, di-n-butylamine, diisobutylamine, triethylamine, tributylamine, tert-butyl amine, pyridine, N-methylpyridine, dimethylpyridine, dibutylmethylpyridine, and dimethylaminopyridine, imidazole, benzimidazole, histidine, and mixtures thereof. A most preferable organic base used in step-(ii) is triethylamine.
In another embodiment, the activating agent used in step-(ii) is selected from the group consisting of N,N’-dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIPC), l-ethyl-3-(3- dimethylaminopropyl)-carbodiimide hydrochloride (EDC), carbonyldiimidazole, thionyl chloride, methyl chloroformate, ethyl chloroformate, phenyl chloroformate, benzyl chloroformate, and the like. A most preferable activating agent used in step-(ii) is l-ethyl-3-(3- dimethylaminopropyl)-carbodiimide hydrochloride (EDC. HCl).
In another embodiment, the reaction step-(ii) is optionally carried out in the presence of an additive to suppress racemization of the resulting product. In one embodiment, the additive used in step-(ii) is selected from the group consisting of 1-hydroxybenzotriazole (HOBt), l-hydroxy-7-azabenzotriazole (HOAt), 3,4-dihydro-3-hydroxy-4-oxo-l,2,3-benzotriazine (DHOBt) and the like. A most preferable additive used in step-(ii) is 1-hydroxybenzotriazole (HOBt).
The reaction mass containing the Edoxaban of formula I or a salt thereof obtained in step-(ii) may be subjected to usual work up methods as described hereinabove. The reaction mass containing the compound of formula I or a salt thereof may be used directly (in situ) in the next step to produce Edoxaban tosylate monohydrate, or the Edoxaban of formula I or a salt thereof may be isolated and/or recrystallized and then used in the next step.
In one embodiment, the Edoxaban of formula I or a salt thereof obtained in step-(ii) may be isolated and/or re-crystallized from a suitable solvent by conventional methods as described hereinabove.
In another embodiment, the conversion of the Edoxaban of formula I or a salt thereof into Edoxaban tosylate monohydrate in step-(iii) can be carried out by the processes described herein, or by the known methods described in the art, for example as per the processes disclosed in the US7,365,205B2, US8,686,189B2, US7,342,014B2, US8,357,808B2, US8,541,443B2 and WO2018083213A1.
Unless otherwise specified, the compounds of formula I, III, IIIA, V, VI or a salt thereof obtained by the processes described herein are further dried, under reduced pressure and/or at atmospheric pressure, at a temperature of about 40°C to about 140°C, specifically at a temperature of about 50°C to about 130°C, and most specifically at a temperature of about 55°C to about 120°C. In another embodiment, the drying is carried out for any desired time period that achieves the desired result, specifically for a period of about 15 minutes to 25 hours, more specifically for a period of about 30 minutes to 15 hours.
According to another aspect, there is provided a process for the preparation of highly pure crystalline Form I of Edoxaban tosylate monohydrate, comprising:
a) providing a suspension of Edoxaban tosylate (crude or pure) in a solvent medium comprising water and a water-miscible organic solvent;
b) heating the suspension formed in step-(a) at a temperature of above about 40°C to form a clear solution;
c) optionally, subjecting the solution obtained in step-(a) or step-(b) to carbon treatment to obtain a filtrate;
d) cooling the solution obtained in step-(b) or step-(c) at a temperature below 35°C to cause crystallization; and
e) collecting the highly pure crystalline Form I of Edoxaban tosylate monohydrate formed in step-(d).
In one embodiment, the water-miscible organic solvent used in step-(a) is selected from the group consisting of methanol, ethanol, 1-propanol and isopropyl alcohol, acetone, acetonitrile, dimethylformamide and mixtures thereof. A most specific water-miscible organic solvent used in step-(a) is ethanol or methanol.
Usually, the amount of solvent medium employed in step-(a) is about 2 volumes to about 30 volumes, specifically about 5 volumes to about 25 volumes, with respect to the quantity of Edoxaban tosylate used.
In one embodiment, the amount of water-miscible organic solvent employed in step-(a) is about 1 to 10 volumes, specifically about 2 to 6 volumes, with respect to the quantity of water used.
Step-(a) of providing a suspension of Edoxaban tosylate includes suspending Edoxaban tosylate in the solvent medium comprising water and a water-miscible organic solvent while stirring at temperature below 35ºC, specifically at a temperature of about 20-30ºC, or obtaining an existing suspension from a previous processing step.
In one embodiment, the suspension in step-(b) is heated while stirring at a temperature of about 45ºC to about 90 ºC for at least 5 minutes, specifically at a temperature of about 50ºC to about 85ºC for about 10 minutes to 5 hours, and most specifically at a temperature of about 55ºC to about 80ºC for about 15 minutes to 2 hours.
The carbon treatment in step-(c) is carried out by the methods as described hereinabove.
In another embodiment, the cooling of the solution in step-(d) is carried out under stirring at a temperature of below about 30ºC for at least 5 minutes, specifically at a temperature of about 10ºC to about 30ºC for about 30 minutes to 8 hours, and most specifically at a temperature of about 25ºC to about 30ºC for about 2 hours to 5 hours.
The collection of the highly pure crystalline Form I of Edoxaban tosylate monohydrate in step-(e) is carried out by filtration, filtration under vacuum, decantation, centrifugation or a combination thereof.
In one embodiment, the crystalline Form I of Edoxaban tosylate monohydrate obtained by the process disclosed herein is characterized by an X-ray powder diffraction pattern having peaks expressed as 2-theta angle positions at about 5.41, 8.12, 10.82, 13.55, 15.08, 16.93, 17.64, 20.57, 21.16, 22.82, 23.6, 26.04, 27.31, 27.61, and 30.12 ± 0.2 degrees substantially in accordance with Figure 1; and/or an infrared absorption spectrum (IR) having characteristic IR bands at about 3344±5, 1674±2, 1614±2, 1502±2, 1221±2, 1171±2, 1119±2, 1032±2, 1012±2, 842±2, 683±2 (cm−1) substantially in accordance with Figure 2; and/or a Differential Scanning Calorimetric (DSC) thermogram having two endotherm peaks at about 250.34°C and 265.58°C substantially in accordance with Figure 3.
In one embodiment, the crystalline Form I of Edoxaban tosylate monohydrate obtained by the processes disclosed herein is essentially free from other crystalline forms of Edoxaban tosylate.
The term “crystalline Form I of Edoxaban tosylate monohydrate essentially free of other solid-state forms” means that no other solid-state forms of Edoxaban tosylate can be detected within the limits of a powder X-ray diffractometer. The term “other crystalline forms of Edoxaban tosylate monohydrate” is intended to mean the crystalline forms of Edoxaban tosylate monohydrate other than crystalline Form I, including crystalline form II, amorphous form and mixtures thereof.
Surprisingly, the processes disclosed herein above advantageously produces the crystalline Form I of Edoxaban tosylate monohydrate with high chemical, chiral and polymorphic purity.
The highly pure Edoxaban or a pharmaceutically acceptable thereof, preferably Edoxaban tosylate monohydrate, obtained by the process disclosed herein has a purity of greater than about 99%, specifically greater than about 99.3%, more specifically greater than about 99.5%, and most specifically greater than about 99.9% as measured by HPLC. For example, the purity of the highly pure Edoxaban tosylate monohydrate obtained by the processes disclosed herein is about 99.8% to about 99.99% as measured by HPLC.
The highly pure crystalline Form I of Edoxaban Tosylate monohydrate obtained by the processes described herein is further dried, under reduced pressure and/or at atmospheric pressure, at a temperature of about 30°C to about 100°C, and most specifically at a temperature of about 40°C to about 55°C under vacuum. In another embodiment, the drying is carried out for any desired time period that achieves the desired result, specifically for a period of about 15 minutes to 20 hours, more specifically for a period of about 1 hour to 10 hours.
Drying can be suitably carried out in a tray dryer, a vacuum oven, an air oven, or using a fluidized bed drier, a spin flash dryer, a flash dryer and the like. Drying equipment selection is well within the ordinary skill in the art. The drying can be carried out in, for example, a Vacuum Tray Dryer, a Rotocon Vacuum Dryer, a Vacuum Paddle Dryer or a pilot plant Rota vapor, to further lower residual solvents. Drying can be carried out under reduced pressure or at atmospheric pressure until the residual solvent content reduces to the desired amount such as an amount that is within the limits given by the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (“ICH”) guidelines.
Further encompassed herein is the use of the highly pure crystalline Form I of Edoxaban Tosylate monohydrate obtained by the processes disclosed herein for the manufacture of a pharmaceutical composition together with a pharmaceutically acceptable carrier/excipient.
A specific pharmaceutical composition of highly pure crystalline Form I of Edoxaban Tosylate monohydrate obtained by the processes disclosed herein is a solid dosage form.
In another aspect, the highly pure crystalline Form I of Edoxaban Tosylate monohydrate made by the processes disclosed herein for use in the pharmaceutical compositions, has a D90 particle size of less than or equal to about 200 microns, specifically about 2 microns to about 150 microns, and most specifically about 4 microns to about 100 microns.
In another aspect, the highly pure crystalline Form I of Edoxaban tosylate monohydrate made by the processes disclosed herein for use in the pharmaceutical compositions, has a D50 particle size of less than or equal to about 100 microns, specifically about 2 microns to about 80 microns, and most specifically about 3 microns to about 50 microns.
In another embodiment, the particle sizes of the highly pure crystalline Form I of Edoxaban Tosylate monohydrate obtained by the processes disclosed herein are accomplished by a mechanical process of reducing the size of particles which includes any one or more of cutting, chipping, crushing, milling, grinding, micronizing, trituration or other particle size reduction methods known in the art, to bring the solid state form to the desired particle size range.
The term “micronization” used herein means a process or method by which the size of a population of particles is reduced.
As used herein, the term “micron” or “μm” both are equivalent and refer to “micrometer” which is 1x10–6 meter.
As used herein, “crystalline particles” means any combination of single crystals, aggregates and agglomerates.
According to another aspect, there are provided pharmaceutical compositions comprising highly pure crystalline Form I of Edoxaban Tosylate monohydrate obtained by the processes disclosed herein and one or more pharmaceutically acceptable excipients.
According to another aspect, there is provided a process for preparing a pharmaceutical formulation comprising combining highly pure crystalline Form I of Edoxaban Tosylate monohydrate obtained by the processes disclosed herein, with one or more pharmaceutically acceptable excipients.
Yet in another embodiment, pharmaceutical compositions comprise at least a therapeutically effective amount of highly pure crystalline Form I of Edoxaban Tosylate monohydrate obtained by the processes disclosed herein. Such pharmaceutical compositions may be administered to a mammalian patient in a dosage form, e.g., solid, liquid, powder, syrups. Oral dosage forms include, but are not limited to, tablets, pills, capsules, syrup, troches, sachets, suspensions, powders, and the like. Specifically, the dosage form is a film coated tablet for oral use.
The pharmaceutical compositions further contain one or more pharmaceutically acceptable excipients. Suitable excipients and the amounts to use may be readily determined by the formulation scientist based upon experience and consideration of standard procedures and reference works in the field, e.g., the buffering agents, sweetening agents, binders, diluents, fillers, lubricants, wetting agents and disintegrants described hereinbelow.
Other excipients include binders, such as acacia gum, pregelatinized starch, sodium alginate, glucose and other binders used in wet and dry granulation and direct compression tableting processes; disintegrants such as sodium starch glycolate, crospovidone, low-substituted hydroxypropyl cellulose and others; lubricants like magnesium and calcium stearate and sodium stearyl fumarate; flavorings; sweeteners; preservatives; pharmaceutically acceptable dyes and glidants such as silicon dioxide.

INSTRUMENTAL DETAILS:
X-Ray Powder Diffraction (P-XRD):
The X-ray powder diffraction spectrum was measured on a BRUKER AXS D8 FOCUS X-ray powder diffractometer equipped with a Cu-anode (copper-Kα radiation). Approximately 500 mg of sample was gently flattered on a sample holder and scanned from 2 to 50 degrees 2-theta, at 0.03 degrees to theta per step and a step time of 0.4 seconds. The sample was simply placed on the sample holder. The sample was maintained at a voltage 40 KV and current 35 mA.
HPLC Method for measuring Chemical Purity:
The chemical purity was measured by HPLC system with UV detector or its equivalent under the following conditions: Column = X-Bridge C18 (150 x 4.6) mm, 3.5µm; Detector wavelength = UV at 290 nm; Flow Rate = 1.0 ml/min; Injection volume = 10 µl; Column Oven temperature = 45°C; Run time = 50 minutes; Diluent = A mixture of water and acetonitrile in a ratio of 80:20, (v/v); Sample concentration: 0.5 mg/ml and Elution mode: Gradient. Mobile phase-A: Buffer; Mobile phase-B: Methanol.

The following examples are given only to illustrate the present invention. However, they should not be considered as limitation on the scope or spirit of the invention.

EXAMPLES
Example 1
Preparation of Methyl 2-[(5-chloropyridin-2-yl)amino]-2-oxoacetate
2-Amino-5-chloropyridine (100 g) was added to acetonitrile (1200 ml) at 25-30°C. The resulting mixture was heated to 50-55°C, followed by the addition of methyl 2-chloro-2-oxoacetate (105 g) and then stirred for 2-3 hours at the same temperature. After completion of the reaction, the resulting mass was cooled to 5-15°C and then stirred for 1 hour to 1 hour 30 minutes at the same temperature. The resulting mass was filtered at 5-15°C and washed with cold acetonitrile (100 ml). The filter bed was suck dried at room temperature till the mother liquor was expelled completely to produce hydrochloride salt of methyl 2-[(5-chloropyridin-2-yl)amino]-2-oxoacetate. To the resulting wet material, water (980 ml) and a solution of sodium bicarbonate (98 g) in water (980 ml) was added. The resulting mass was stirred at room temperature for 45 minutes to 1 hour 15 minutes and then filtered the material at 25-30°C and washed with water. The resulting wet material was dried at 45-55°C for 9 to 11 hours to produce 155 g of methyl 2-[(5-chloropyridin-2-yl)amino]-2-oxoacetate [Purity by HPLC: 98.69%; IR Bands (KBr Pellet): 3318, 3329, 3287, 1749, 1740, 1703, 1627, 1575, 1456, 1315, 1171, 1126, 1108, 989, 834 and 744, 729 cm-1].

Example 2
Preparation of Tert-butyl N-[(1R,2S,5S)-2-[[2-[(5-chloropyridin-2-yl)amino]-2-oxoacetyl]amino]-5-(dimethylcarbamoyl)cyclohexyl] carbamate
Methyl 2-[(5-chloropyridin-2-yl)amino]-2-oxoacetate (100 g) was added to acetonitrile (640 ml) at 25-30°C and the resulting mixture was stirred for 5-15 minutes at the same temperature. To the resulting mass, tert-butyl [(1R,2S,5S)-2-amino-5-[(dimethylamino)carbonyl]cyclohexyl]carbamate (127.7 g) was added at 25-30°C and then heated the mixture to 45-55°C, followed by slow addition of triethylamine (30.9 g) at the same temperature for about 20 to 40 minutes. The resulting mass was heated to 55-65°C and then stirred for 7-9 hours at the same temperature. After completion of reaction, the resulting mass was cooled to room temperature and then further cooled to 0-5°C, followed by stirring for 30-60 minutes at the same temperature. The solid obtained was filtered and washed with cold water. The resulting wet material was dried under vacuum at 45-55°C for 10-12 hours to produce 185 g of tert-butyl N-[(1R,2S,5S)-2-[[2-[(5-chloropyridin-2-yl)amino]-2-oxoacetyl]amino]-5-(dimethyl carbamoyl)cyclohexyl]carbamate (Purity by HPLC: 99.30%).

Example 3
Preparation of Edoxaban free base
Tert-butyl N-[(1R,2S,5S)-2-[[2-[(5-chloropyridin-2-yl)amino]-2-oxoacetyl]amino]-5-(dimethylcarbamoyl)cyclohexyl]carbamate (100 g) was added to acetonitrile (2000 ml) at 25-30°C and the resulting mixture was stirred for 5-15 minutes at the same temperature. To the resulting mass, methanesulfonic acid (103.6 g) was added at 25-30°C and stirred for 1 hour 30 minutes to 2 hours 30 minutes at the same temperature. After completion of reaction, the resulting mass was cooled to 0-5°C. To the resulting mass, triethyl amine (163 g), 5-methyl-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]-pyridine-2-carboxylic acid hydrochloride (55.2 g), 1-hydroxybenzotriazole (HOBt, 34.8 g) and 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDC.HCl, 49.2 g) were added at 0-5°C and then stirred for 5-15 minutes at the same temperature. Thereafter, the temperature of the reaction mass was allowed to raise to room temperature and the resulting mass was stirred for about 16-18 hours at the same temperature. After completion of the reaction, water (800 ml) and triethylamine (164 g) were added to the reaction mass at 25-30°C and then stirred for 5-15 minutes at the same temperature. The resulting mass was cooled to 0-5°C and then stirred for 1-2 hours at the same temperature. The solid obtained was filtered, washed with water and dried the material for 9-12 hours under vacuum at 45-55°C to obtain crude Edoxaban. The resulting crude material was cooled to room temperature, followed by the addition of dichloromethane (1940 ml) and a solution of potassium carbonate (45 g) in water (450 ml) and the resulting mass was stirred for 5-15 minutes. The layers were separated. A solution of acetic acid (45 g) in water (450 ml) was added to the resulting organic layer at 25-30°C and then stirred for 5-15 minutes at the same temperature. The layers were separated. To the resulting organic layer, water (450 ml) was added at 25-30°C and then stirred for 5-15 minutes at the same temperature. The layers were separated and the activated carbon powder (10 g) was added to the resulting organic layer at 25-30°C and then stirred for 5-15 minutes at the same temperature. The resulting material was filtered and washed with dichloromethane (200 ml). The resulting organic layer was distilled off under reduced pressure at below 50°C to produce 100 g of Edoxaban free base (Purity by HPLC: 95.36%).

Example 4
Preparation of Edoxaban tosylate monohydrate (crude)
Edoxaban free base (100 g) was added to a mixture of ethanol (850 ml) and water (150 ml) at 25-30°C. To the resulting mass, a solution of p-toluene sulfonic acid (34.8 g) in ethanol (200 ml) was added at 25-30°C. The resulting mass was heated to 55-65°C and then stirred for 30 minutes to 1 hour at the same temperature. The resulting mass was cooled to 25-30°C and then stirred for 1-2 hours at the same temperature. The resulting solid was filtered, washed with ethanol and then dried the material under vacuum at 40-45°C for 5-7 hours to produce 115 g of crude Edoxaban tosylate monohydrate (Purity by HPLC: 99.52%).

Example 5
Preparation of pure Edoxaban tosylate monohydrate crystalline Form I
Ethanol (1700 ml) and water (300 ml) were added to crude Edoxaban tosylate monohydrate (100 g, obtained in Example 4) at 25-30°C and the resulting mixture was heated at 65-75°C to form a clear solution. Carbon powder (10 g) was added to the resulting solution at 65-75°C and then stirred for 10-15 minutes at the same temperature. The reaction mixture was filtered through charcoal bed and then washed the bed with a mixture of ethanol (85 ml) and water (15 ml). The resulting filtrate was cooled to 25-30°C, followed by stirring the mass for 2 hours to 2 hours 30 minutes at the same temperature. The separated solid was filtered, washed with a mixture of ethanol and water and then dried the material under vacuum at 40-45°C for 5 to 7 hours to produce 80 g of pure crystalline Form I of Edoxaban tosylate monohydrate (Purity by HPLC: 99.77%).
, Claims:We claim:
1. A process for the preparation of Edoxaban intermediate, tert-butyl N-[(1R,2S,5S)-2-[[2-[(5-chloropyridin-2-yl)amino]-2-oxoacetyl]amino]-5-(dimethylcarbamoyl)cyclohexyl]carbamate, of formula V:

or a salt thereof, comprising reacting methyl 2-[(5-chloropyridin-2-yl)amino]-2-oxoacetate of formula III:

or a salt thereof, with tert-butyl [(1R,2S,5S)-2-amino-5-[(dimethylamino) carbonyl]cyclohexyl]carbamate of formula IV:

or a salt thereof, in the presence or absence of a base in a suitable solvent to produce the tert-butyl carbamate compound of formula V or a salt thereof.
2. The process as claimed in claim 1, wherein the base used is an organic or an inorganic base, wherein the organic base is selected from the group consisting of dimethylamine, diethylamine, diisopropyl amine, diisopropylethylamine, di-n-butylamine, diisobutylamine, triethylamine, tributylamine, tert-butyl amine, pyridine, methylpyridine, dimethylpyridine, dibutylmethylpyridine, and dimethylaminopyridine, imidazole, benzimidazole, histidine, and mixtures thereof; wherein the solvent used is selected from the group consisting of toluene, ethyl acetate, propyl acetate, isopropyl acetate, t-butyl acetate, isobutyl acetate, diethyl ether, diisopropyl ether, methyl tert-butyl ether, 1,4-dioxane, tetrahydrofuran, 2-methyl tetrahydrofuran, acetone, butanone, 2-pentanone, 3-pentanone, methyl isobutyl ketone, methyl ethyl ketone, methylene dichloride, ethylene dichloride, carbon tetrachloride, chlorobenzene, dimethylformamide, dimethylacetamide, dimethyl sulfoxide, N-methylpyrrolidone, acetonitrile, and mixtures thereof; wherein the reaction between the compound of formula III or a salt thereof and the compound of formula IV or a salt thereof is carried out at a temperature of about 25°C to the reflux temperature of the solvent used.
3. The process as claimed in claim 2, wherein the organic base is triethylamine; wherein the solvent is acetonitrile or dichloromethane; wherein the reaction between the compound of formula III or a salt thereof and the compound of formula IV or a salt thereof is carried out at a temperature of about 50°C to about 80°C.
4. A process for the preparation of the methyl 2-[(5-chloropyridin-2-yl)amino]-2-oxoacetate of formula III:

or a salt thereof, which comprises:
a) reacting 2-amino-5-chloropyridine of formula II:

or a salt thereof, with methyl 2-chloro-2-oxoacetate in a suitable solvent to produce hydrochloride salt of methyl 2-[(5-chloropyridin-2-yl)amino]-2-oxoacetate of formula III, wherein the solvent is selected from the group consisting of a hydrocarbon solvent, a ketone, an amide, a nitrile solvent, and mixtures thereof; and
b) optionally, treating the hydrochloride salt of the compound of formula III with a base in a suitable solvent to produce the compound of formula III as a free base.

5. The process as claimed in claim 4, wherein the solvent used in in step-(a) is selected from the group consisting of toluene, acetone, butanone, 2-pentanone, 3-pentanone, methyl isobutyl ketone, methyl ethyl ketone, dimethylformamide, dimethylacetamide, acetonitrile, and mixtures thereof; wherein the reaction in step-(a) is carried out at a temperature of about 30°C to the reflux temperature of the solvent used; wherein the base used in step-(b) is an organic or an inorganic base, wherein the inorganic base is selected from the group consisting of sodium carbonate, potassium carbonate, lithium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, lithium bicarbonate, cesium bicarbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, sodium tert-butoxide, potassium tert.butoxide, ammonia, and mixtures thereof; wherein the solvent used in step-(b) is selected from the group consisting of water, methanol, ethanol, 1-propanol, isopropyl alcohol, acetone, butanone, 2-pentanone, 3-pentanone, methyl isobutyl ketone, methyl ethyl ketone, methylene dichloride, ethylene dichloride, carbon tetrachloride, chlorobenzene, dimethylformamide, dimethylacetamide, acetonitrile, and mixtures thereof; wherein the treatment with a base in step-(b) is carried out at a temperature of about 20°C to the reflux temperature of the solvent used.
6. The process as claimed in claim 5, wherein the solvent used in step-(a) is acetonitrile; wherein the reaction in step-(a) is carried out at a temperature of about 40°C to about 80°C; wherein the solvent used in step-(a) is acetonitrile; wherein the base used in step-(b) is sodium bicarbonate; wherein the solvent used in step-(b) is water; and wherein the treatment with a base in step-(b) is carried out at a temperature of about 25°C to about 40°C.

7. A process for the preparation of Edoxaban of formula I:

or a pharmaceutically acceptable salt thereof, which comprises:
a) reacting methyl 2-[(5-chloropyridin-2-yl)amino]-2-oxoacetate of formula III:

or a salt thereof, with tert-butyl [(1R,2S,5S)-2-amino-5-[(dimethylamino) carbonyl]cyclohexyl]carbamate of formula IV:

or a salt thereof, in the presence or absence of a base in a suitable solvent to produce the tert-butyl carbamate compound of formula V:

or a salt thereof; and
b) converting the compound of formula V or a salt thereof into Edoxaban of formula I or a pharmaceutically acceptable salt thereof, preferably Edoxaban tosylate monohydrate.

8. The process as claimed in claim 7, wherein the conversion of the compound of formula V or a salt thereof into Edoxaban of formula I or a pharmaceutically acceptable salt thereof in step-(b) is carried out by a process comprising the following steps:
i) reacting the compound of formula V or a salt thereof with a deprotecting agent in a suitable solvent to produce N1-[(1S,2R,4S)-2-amino-4-[(dimethylamino)carbonyl]cyclohexyl]-N2-(5-chloro-2-pyridinyl)ethane- diamide of formula VI:

or a salt thereof;
ii) reacting the compound of formula VI or a salt thereof with 5-methyl-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridine-2-carboxylic acid of formula VII:

or a salt thereof, in the presence of a suitable activating agent and a base in a suitable solvent to produce Edoxaban of formula I or a salt thereof; and
iii) converting the Edoxaban of formula I or a salt thereof obtained in step-(ii) into highly pure Edoxaban tosylate monohydrate of formula I(a) by treating with p-toluene sulfonic acid in a suitable solvent.

9. The process as claimed in claim 8, wherein the deprotecting agent used in step-(i) is selected from the group consisting of hydrochloric acid, methanesulfonic acid, trifluoroacetic acid, ethyl acetate hydrochloride, IPA-HCl, methanol-HCl, ethanol-HCl, or a combination thereof; wherein the solvent used in step-(i), step-(ii) and/or step-(iii) is, each independently, selected from the group consisting of water, acetonitrile, methanol, ethanol, isopropyl alcohol, acetone, methyl ethyl ketone, methyl isobutyl ketone, methyl acetate, ethyl acetate, isopropyl acetate, dioxane, dimethyl sulfoxide, tetrahydrofuran, toluene, xylene, methylene dichloride, dimethyl formamide, and mixtures thereof; wherein the base used in step-(ii) is an organic base or inorganic base, wherein the organic base is selected from the group consisting of dimethylamine, diethylamine, diisopropyl amine, diisopropylethylamine, di-n-butylamine, diisobutylamine, triethylamine, tributylamine, tert-butyl amine, pyridine, N-methylpyridine, dimethylpyridine, dibutylmethylpyridine, and dimethylaminopyridine, imidazole, benzimidazole, histidine, and mixtures thereof; wherein the activating agent used in step-(ii) is selected from the group consisting of N,N’-dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIPC), l-ethyl-3-(3- dimethylaminopropyl)-carbodiimide hydrochloride (EDC), carbonyldiimidazole, thionyl chloride, methyl chloroformate, ethyl chloroformate, phenyl chloroformate and benzyl chloroformate; and wherein the reaction step-(ii) is optionally carried out in the presence of an additive to suppress racemization of the resulting product, wherein the additive is selected from the group consisting of 1-hydroxybenzotriazole (HOBt), l-hydroxy-7-azabenzotriazole (HOAt) and 3,4-dihydro-3-hydroxy-4-oxo-l,2,3-benzotriazine (DHOBt).

10. The process as claimed in claim 9, wherein the deprotecting agent used in step-(i) is methane sulfonic acid or hydrochloric acid; wherein the solvent used in step-(i) and/or step-(ii) is acetonitrile or methylene dichloride; wherein the organic base used in step-(ii) is triethylamine; wherein the activating agent used in step-(ii) is l-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (EDC. HCl); wherein the additive used in step-(ii) is 1-hydroxybenzotriazole (HOBt); and wherein solvent used in step-(iii) is water, acetonitrile, methanol, ethanol, isopropyl alcohol, or a mixture thereof.

11. A process for the preparation of Edoxaban of formula I or a pharmaceutically acceptable salt thereof, which comprises:
a) reacting an alkyl 2-[(5-chloropyridin-2-yl)amino]-2-oxoacetate of formula IIIA:

or a salt thereof, wherein the radical ‘R’ is isopropyl, n-propyl, n-butyl or tert-butyl; with tert-butyl [(1R,2S,5S)-2-amino-5-[(dimethylamino) carbonyl]cyclohexyl]carbamate of formula IV or a salt thereof, in the presence or absence of a base in a suitable solvent to produce the tert-butyl carbamate compound of formula V or a salt thereof; and
b) converting the compound of formula V or a salt thereof into Edoxaban of formula I or a pharmaceutically acceptable salt thereof, preferably Edoxaban tosylate monohydrate.

12. A process for the preparation of highly pure crystalline Form I of Edoxaban tosylate monohydrate, comprising:
a) providing a suspension of Edoxaban tosylate (crude or pure) in a solvent medium comprising water and a water-miscible organic solvent;
b) heating the suspension formed in step-(a) at a temperature of above about 40°C to form a clear solution;
c) optionally, subjecting the solution obtained in step-(a) or step-(b) to carbon treatment to obtain a filtrate;
d) cooling the solution obtained in step-(b) or step-(c) at a temperature below 35°C to cause crystallization; and
e) collecting the highly pure crystalline Form I of Edoxaban tosylate monohydrate formed in step-(d).

13. The process as claimed in claim 12, wherein the water-miscible organic solvent used in step-(a) is selected from the group consisting of methanol, ethanol, 1-propanol and isopropyl alcohol, acetone, acetonitrile, dimethylformamide and mixtures thereof; wherein the amount of solvent medium employed in step-(a) is about 2 volumes to about 30 volumes with respect to the quantity of Edoxaban tosylate used; wherein the amount of water-miscible organic solvent employed in step-(a) is about 1 to 10 volumes with respect to the quantity of water used; wherein the suspension of Edoxaban tosylate in step-(a) is provided by suspending Edoxaban tosylate in the solvent medium comprising water and a water-miscible organic solvent while stirring at temperature below 35ºC; wherein the suspension in step-(b) is heated while stirring at a temperature of about 45ºC to about 90 ºC for at least 5 minutes; wherein the cooling of the solution in step-(d) is carried out under stirring at a temperature of below about 30ºC for at least 5 minutes; wherein the collection of the highly pure crystalline Form I of Edoxaban tosylate monohydrate in step-(e) is carried out by filtration, filtration under vacuum, decantation, centrifugation or a combination thereof; wherein the highly pure crystalline Form I of Edoxaban Tosylate monohydrate obtained is further dried, under reduced pressure and/or at atmospheric pressure, at a temperature of about 30°C to about 100°C; and wherein the highly pure Edoxaban or a pharmaceutically acceptable thereof obtained has a purity of greater than about 99% as measured by HPLC; and wherein the highly pure crystalline Form I of Edoxaban Tosylate monohydrate obtained has a D90 particle size of less than or equal to about 200 microns.

14. The process as claimed in claim 13, wherein the water-miscible organic solvent used in step-(a) is ethanol or methanol; wherein the amount of solvent medium employed in step-(a) is about 5 volumes to about 25 volumes with respect to the quantity of Edoxaban tosylate used; wherein the amount of water-miscible organic solvent employed in step-(a) is about 2 to 6 volumes with respect to the quantity of water used; wherein the suspension of Edoxaban tosylate in step-(a) is provided by suspending Edoxaban tosylate in the solvent medium comprising water and a water-miscible organic solvent while stirring at a temperature of about 20-30ºC; wherein the suspension in step-(b) is heated while stirring at a temperature of about 50ºC to about 85ºC for about 10 minutes to 5 hours; wherein the cooling of the solution in step-(d) is carried out under stirring at a temperature of about 10ºC to about 30ºC for about 30 minutes to 8 hours; wherein the highly pure crystalline Form I of Edoxaban Tosylate monohydrate obtained is further dried, under reduced pressure and/or at atmospheric pressure, at a temperature of about 40°C to about 55°C under vacuum; and wherein the purity of the highly pure Edoxaban tosylate monohydrate obtained by the processes is about 99.8% to about 99.99% as measured by HPLC; and wherein the highly pure crystalline Form I of Edoxaban Tosylate monohydrate obtained has a D90 particle size of about 2 microns to about 150 microns.

15. The process as claimed in claim 12, wherein the crystalline Form I of Edoxaban tosylate monohydrate obtained is characterized by an X-ray powder diffraction pattern having peaks expressed as 2-theta angle positions at about 5.41, 8.12, 10.82, 13.55, 15.08, 16.93, 17.64, 20.57, 21.16, 22.82, 23.6, 26.04, 27.31, 27.61, and 30.12 ± 0.2 degrees substantially in accordance with Figure 1; and/or an infrared absorption spectrum (IR) having characteristic IR bands at about 3344±5, 1674±2, 1614±2, 1502±2, 1221±2, 1171±2, 1119±2, 1032±2, 1012±2, 842±2, 683±2 (cm−1) substantially in accordance with Figure 2; and/or a Differential Scanning Calorimetric (DSC) thermogram having two endotherm peaks at about 250.34°C and 265.58°C substantially in accordance with Figure 3.