A process for the preparation of edoxaban and its intermediate

Abstract

The present invention relates to a process for preparation of Edoxaban intermediate namely alkyl 2-[(5-chloropyridin-2-yl)amino]-2-oxoacetate compound of Formula-I. The present invention also relates to a process for the preparation of Edoxaban of Formula-IV or salt thereof from alkyl 2-[(5-chloropyridin-2-yl)amino]-2-oxoacetate compound of Formula-I.

Description

[0001] A PROCESS FOR THE PREPARATION OF EDOXABAN AND ITS

[0002] INTERMEDIATE

[0003] RELATED APPLICATION:

[0004] This application claims the benefit of Indian Provisional Application No. IN202421011336, filed on Feb 19, 2024, the contents of which are incorporated by reference herein.

[0005] FIELD OF THE INVENTION

[0006] The present invention relates to a novel, economical, efficient, environment friendly and commercially viable process for the preparation of Edoxaban intermediate namely alkyl 2-((5- chloropyridin-2-yl)amino)-2-oxoacetate compound of formula-I. wherein R represents C1-C4 alkyl selected from the group consisting of methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, tert-butyl.

[0007] The present invention also relates to a process for preparation of Edoxaban or salts thereof using alkyl 2-((5-chloropyridin-2-yl)amino)-2-oxoacetate compound of formula-I.

[0008] BACKGROUND OF THE INVENTION

[0009] Edoxaban tosylate monohydrate 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[l,3]thiazolo[5,4-c] pyridine-2-carboxamido)cyclohexyl]oxamide mono(4-methylbenzenesulfonate) monohydrate and structurally represented as compound of formula- IVa; Edoxaban tosylate monohydrate has been developed and marketed by Daiichi Sankyo under the proprietary name Savaysa®. 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.

[0010] Alkyl 2-((5-chloropyridin-2-yl)amino)-2-oxoacetate is a one of the key intermediate for the synthesis of Edoxaban tosylate monohydrate and is represented as compound of formula-I having the following structure: wherein R represents C1-C4 alkyl selected from the group consisting of methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, tert-butyl.

[0011] Several methods for the preparation of Alkyl 2-((5-chloropyridin-2-yl)amino)-2-oxoacetate compound of formula-I, particularly when R is methyl or ethyl, have been described in the literature.

[0012] The European patent number EP 1405852 Bl disclosed the process for preparation of methyl 2-((5-chloropyridin-2-yl)amino)-2-oxoacetate compound by reacting 2-amino-5- chloropyridine with methyl oxalyl chloride in presence of sodium hydrogen carbonate and tetrahydrofuran. The above process is depicted as below in scheme- 1:

[0013] 2-amino-5 -chloropyridine Methyl oxalyl Methyl 2-((5-chloropyridin-2-yl) chloride amino)-2-oxoacetate

[0014] Scheme-1

[0015] The above process required tetrahydrofuran (THF) as a solvent during the reaction, which is costly and difficult to recover. The process also involved use of diethyl ether and ammonium chloride for the work-up and required additional purification steps. Therefore, the above process is uneconomical, unsuitable for industrial scale and causes hazards to the environment. The US publication number US 20050245565 disclosed a process for the preparation of methyl 2-((5-chloropyridin-2-yl)amino)-2-oxoacetate comprising reacting 2-amino-5-chloropyridine with methyl oxalyl chloride in presence of triethylamine and dichloro methane at room temperature for 14 hours, followed by purification using column chromatography results in 22.27% yield. The above process is depicted as below in scheme-2:

[0016] Column

[0017] 2-amino-5 -chloropyridine Methyl oxalyl Chromatography Methyl 2-((5-chloropyridin-2-yl) chloride amino)-2-oxoacetate

[0018] Scheme-2

[0019] Longer reaction time, tedious work up process, column chromatography and lower yield are the major disadvantages of the above process and make the process unsuitable for industrial scale.

[0020] The US publication number US20120035369A1 (herein after US’369) disclosed a process for the preparation of ethyl 2-((5-chloropyridin-2-yl)amino)-2-oxoacetate comprising reacting 2- amino-5-chloropyridine with ethyl oxalyl chloride in acetonitrile at 50°C for 2 hours. The above process is depicted as below in scheme-3:

[0021] 2-amino-5-chloropyridine ethyl oxalyl ethyl 2-((5-chloropyridin-2-yl) chloride amino)-2-oxoacetate

[0022] Scheme-3

[0023] The Chinese Patent publication number CN116410128 (herein after CN’128) disclosed a process for the preparation of methyl 2-((5-chloropyridin-2-yl)amino)-2-oxoacetate comprising reacting 2-amino-5-chloropyridine with methyl oxalyl chloride in acetonitrile at 70°C for 1 hours. After completion of reaction, the reaction quenched by using methanol. The above process is depicted as below in scheme-4:

[0024] 2-amino-5 -chloropyridine Methyl oxalyl Methyl 2-((5-chloropyridin-2-yl) chloride amino)-2-oxoacetate

[0025] Scheme-4

[0026] A major drawback of the process disclosed in US’369 and CN’128, is the use of acetonitrile solvent, which is costly and difficult to recover, and thus makes the process uneconomical, unsuitable for industrial scale and hazardous to the environment.

[0027] The IN publication number 202221038289 (herein after IN ‘289) disclosed a process for the preparation of methyl 2-((5-chloropyridin-2-yl)amino)-2-oxoacetate as its hydrochloride salt comprising reacting 2-amino-5-chloropyridine with methyl oxalyl chloride using ethyl acetate as solvent and in absence of base preferably at 60°C to 65°C. The above process is depicted as below in scheme-5:

[0028] Ethyl Acetate

[0029] 2-amino-5 -chloropyridine Methyl oxalyl chloride Methyl 2-((5-chloropyridin-2-yl) amino)-2-oxoacetate Hydrochloride

[0030] Scheme-5

[0031] The above process requires high temperature which makes the process unsuitable for industrial scale. In addition, the hydrochloride salt obtained has limited stability, requires specific storage and packing conditions, thereby increasing costs which limits its production and storage at commercial level and hence loses its commercial viability and cost efficiency.

[0032] Thus, the processes known in the prior art required tedious work up process, column chromatography, high temperature and are associated with lower yield and / or purity. Therefore, there is a need for an improved process for the preparation of alkyl 2-((5-chloropyridin-2- yl)amino)-2-oxoacetate having high purity and high yield which overcomes the drawbacks of the prior art processes. The inventors of the present invention have developed an efficient process for the preparation of alkyl 2-((5-chloropyridin-2-yl)amino)-2-oxoacetate compound of formula-I which offer advantage over the prior art processes in terms of use of commercially economical / recyclable solvents, high yield, high purity, less effluents and simple scalable procedure suitable for large scale industrial production. The process of the present invention enables isolation of the alkyl 2-((5-chloropyridin-2-yl)amino)-2-oxoacetate compound of formula-I simply by filtration and does not need any special isolation technique, for example extraction, distillation and / or chromatography.

[0033] OBJECT OF THE INVENTION

[0034] The main object of the present invention is to provide a process for the preparation of alkyl 2- ((5-chloropyridin-2-yl)amino)-2-oxoacetate compound of formula-I. wherein R represents C1-C4 alkyl selected from the group consisting of methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, tert-butyl.

[0035] Another object of the present invention is to provide a process for the preparation of Edoxaban using alkyl 2-((5-chloropyridin-2-yl)amino)-2-oxoacetate compound of formula-I.

[0036] SUMMARY OF THE INVENTION

[0037] In first aspect, the present invention provides a process for the preparation of alkyl 2-((5- chloropyridin-2-yl)amino)-2-oxoacetate compound of formula-I wherein R represents C1-C4 alkyl selected from the group consisting of methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, tert-butyl. comprising the step of: reacting 2-Amino-5-chloropyridine compound of formula-II, with alkyl chloro oxoacetate compound of formula-III, o Vf o

[0038] (III) wherein R represents C1-C4 alkyl selected from the group consisting of methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, tert-butyl. using solvent in presence of base, wherein base is a cyclic amine.

[0039] In second aspect, the present invention provides a process for the preparation of Edoxaban of formula- IV or salt thereof, comprising the step of: i) reacting 2-Amino-5-chloropyridine compound of formula-II, with alkyl chloro oxoacetate compound of formula-III, o ■W o

[0040] (III) wherein R represents C1-C4 alkyl selected from the group consisting of methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, tert-butyl. using solvent in presence of base to obtain alkyl 2-((5-chloropyridin-2-yl)amino)-2- oxoacetate compound of formula-I; wherein R represents C1-C4 alkyl selected from the group consisting of methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, tert-butyl; and base is a cyclic amine, ii) reacting compound of formula-I, wherein R is as defined above, with compound of formula-V or its salt thereof, using solvent in presence of base to obtain compound of formula- VI; iii) deprotecting the compound of formula- VI with deprotecting agent, and then reacting deprotected compound with compound of formula- VII or its salt thereof, using solvent in presence of base to edoxaban compound of formula-IV or salt thereof

[0041] DETAILED DESCRIPTION OF THE INVENTION

[0042] The present invention now will be described more fully hereinafter. The invention may be embodied in many different forms and should not be construed as limited to the embodiments set forth herein; rather, these embodiments are provided so that this disclosure will satisfy applicable legal requirements.

[0043] As used in the specification, the singular forms “a”, “an”, “the”, include plural referents unless the context clearly indicates otherwise.

[0044] The term solvent used herein refers to the single solvent or mixture of solvents.

[0045] The term dissolving as used herein refers to the process by which a solid substance is dispersed in a medium in a molecular form.

[0046] As used herein, "comprising" means the elements recited, or their equivalents in structure or function, plus any other element or elements that may or may not be recited.

[0047] The term "about", as used herein, refers to any value which lies within the range defined by a number up to ± 10% of the value.

[0048] The inventors of the present invention developed a process which does not require separate and / or multiple purification steps.

[0049] The present invention is more broadly elaborated in following embodiment. According to first embodiment, the present invention provides a process for the preparation of alkyl 2-((5-chloropyridin-2-yl)amino)-2-oxoacetate compound of formula-I wherein R represents C1-C4 alkyl selected from the group consisting of methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, tert-butyl; comprising the step of reacting 2-Amino-5-chloropyridine compound of formula-II, with alkyl chloro oxoacetate compound of formula-III, o

[0050] RoV o

[0051] (III) wherein R represents C1-C4 alkyl selected from the group consisting of methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, tert-butyl. using solvent in presence of base, wherein base is a cyclic amine.

[0052] In the first embodiment of the present invention, wherein solvent is halogenated solvent selected from dichloro methane, dichloroethane, chloroform, chlorobenzene; ether solvent selected from tetrahydro furan, diethyl ether, anisole; ester solvent selected from methyl acetate, ethyl acetate, butyl acetate; ketone solvent selected from acetone, methyl ethyl ketone, cyclohexanone; alcohol solvent selected from methanol, ethanol, isopropyl alcohol, n-butanol; hydrocarbon solvent selected from hexane, heptane, toluene, xylene, cyclohexane; or mixtures thereof. Preferably solvent is hydrocarbon solvent for example, toluene.

[0053] In the first embodiment of the present invention, wherein base is a cyclic amine selected from pyridine, N-methylpiperidine, N-phenylpiperidine, pyrimidine, imidazole, pyrrole, piperidine, piperazine, pyrrolidine, N-methyl pyrrole, pyrazine, N-methyl piperazine, N-methyl pyrrolidine and the like; preferably the base is pyridine.

[0054] In the first embodiment of the present invention, wherein the reaction of compound of formula- II with compound of formula-III can be carried out at temperature of about 0°C to about 30°C up to 5 hours, preferably at 15°C to 20°C for 1 hour to 4 hours. After completion of the reaction, the resulting mixture can be cooled to temperature of about 0°C to 10°C for 1 hour and filtered to obtain compound of the formula-I.

[0055] In the preferred embodiment of the present invention, R represents methyl or ethyl, more preferably methyl.

[0056] The resulting compound of the formula-I have purity greater than 99%, preferably greater than 99.8%, more preferably greater than 99.9% by HPLC (High-performance liquid chromatography) .

[0057] The resulting compound of the formula-I have yield greater than 75%, preferably greater than 80%, more preferably greater than 88%.

[0058] The compound of formula-II used as a starting material for the preparation of preparation alkyl 2-((5-chloropyridin-2-yl)amino)-2-oxoacetate compound of formula-I can be prepared by the processes known in art.

[0059] According to second embodiment, the present invention provides a process for the preparation of Edoxaban of formula- IV or salt thereof, comprising the steps of: i) reacting 2-Amino-5-chloropyridine compound of formula-II, with alkyl chloro oxoacetate compound of formula-III, wherein R represents C1-C4 alkyl selected from the group consisting of methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, tert-butyl. using solvent in presence of base to obtain alkyl 2-((5-chloropyridin-2-yl)amino)-2- oxoacetate compound of formula-I; wherein R represents C1-C4 alkyl selected from the group consisting of methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, tert-butyl; and base is a cyclic amine; ii) reacting compound of formula-I, wherein R is as defined above, with compound of formula-V or its salt thereof, using solvent in presence of base to obtain compound of formula- VI; iii) deprotecting the compound of formula- VI with deprotecting agent, and then reacting deprotected compound with compound of formula- VII or its salt thereof, using solvent in presence of base and coupling agent to obtain edoxaban compound of formula- IV or salt thereof,

[0060] In the second embodiment of the present invention, wherein solvent in step i) is halogenated solvent selected from dichloromethane, dichloroethane, chloroform, chlorobenzene; ether solvent selected from tetrahydro furan, diethyl ether, anisole; ester solvent selected from methyl acetate, ethyl acetate, butyl acetate; ketone solvent selected from acetone, methyl ethyl ketone, cyclohexanone; alcohol solvent selected from methanol, ethanol, isopropyl alcohol, n-butanol; hydrocarbon solvent selected from hexane, heptane, toluene, xylene, cyclohexane; or mixtures thereof. Preferably solvent is hydrocarbon solvent for example, toluene.

[0061] In the second embodiment of the present invention, wherein base in step i) is a cyclic amine selected from pyridine, N methylpiperidine, N-phenylpiperidine, Pyrimidine, imidazole, pyrrole, piperidine, piperazine, pyrrolidine, N-methyl pyrrole, pyrazine, N-methyl piperazine, N-methyl pyrrolidine and the like; preferably the base is pyridine. In the second embodiment of the present invention, the reaction of 2-Amino-5-chloropyridine with methyl chloro oxoacetate can be carried out at temperature of about 0°C to about 30°C up to 5 hours, preferably at 15°C to 20°C for 1 hour to 4 hours. After completion of the reaction, the resulting mixture can be cooled to temperature of about 0°C to 10°C for 1 hour and filtered to obtain compound of the formula-I.

[0062] In the second embodiment of the present invention, R preferably represents methyl or ethyl, more preferably methyl.

[0063] In second embodiment of the present invention, wherein solvent in step ii) is solvent selected from dimethylformamide, dimethyl sulfoxide, dimethylacetamide, methanol, ethanol, isopropanol, N-methylpyrrolidone or a mixture(s) thereof; more preferably the solvent is dimethyl sulfoxide.

[0064] In the second embodiment of the present invention, wherein base in step ii) is selected from organic base or inorganic base. The organic base is selected from tertiary amines such as triethylamine, N,N-diisopropylethylamine (DIPEA), or mixture thereof. The inorganic base is selected from the sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, sodium acetate, sodium 2-ethylhexanoate or mixture thereof; more preferably the base is triethylamine.

[0065] In the second embodiment of the present invention, the reaction of compound of formula-I with compound of formula- V can be carried out at temperature of about 0°C to 70°C for 1 hour to 10 hours, preferably at 60°C to 65°C for 3 hours to 8 hours.

[0066] The resulting compound of the formula- VI have purity greater than 99%, preferably greater than 99.51%, more preferably greater than 99.89% by HPLC (High-performance liquid chromatography) .

[0067] The resulting compound of the formula- VI have yield greater than 70%, preferably greater than 72%, more preferably greater than 75%.

[0068] In the second embodiment of the present invention, wherein deprotecting agent in step iii) is selected from trifluoro acetic acid, hydrochloric acid, sulfuric acid, p-toulenesulfonic acid, or methanesulfonic acid; preferably deprotecting agent is methane sulfonic acid. In the second embodiment of the present invention, wherein solvent used for deprotecting compound of formula- VI is selected from ethyl acetate, acetone, isopropyl alcohol, dioxane, methanol, dimethyl sulfoxide, tetrahydrofuran, toluene, xylene, dichloro methane, dimethyl formamide and the like; more preferably the solvent is dichloro methane.

[0069] In the second embodiment of the present invention, deprotection of compound of formula- VI can be carried out at temperature of about 20°C to 35 °C for 2 hours to 3 hours.

[0070] In the second embodiment of the present invention, wherein solvent in step iii) for reacting deprotected compound of formula- VI with compound of formula- VII is selected from dioxane, methylene dichloride, ethylene dichloride, chlorobenzene, chloroform, ethyl acetate, dimethyl formamide, tetrahydrofuran, dimethyl sulfoxide, and the like; preferably the solvent is dichloromethane.

[0071] In the second embodiment of the present invention, wherein base in step iii) for reacting deprotected compound of formula- VI with compound of formula- VII is selected from organic base or inorganic base; organic base is selected from tertiary amines such as triethylamine, N,N- diisopropylethylamine (DIPEA) or mixture thereof; inorganic base is selected from the sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate or mixture(s) thereof; preferably the base is triethylamine.

[0072] In the second embodiment of the present invention, wherein coupling agent in step iii) for reacting deprotected compound of formula- VI with compound of formula- VII is selected from 1,3-dicyclo hexylcarbodiimide (DCC), isobutyl chloroformate, pivaloyl chloride, iso valeryl chloride, l-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC.HC1), 1- cyclohexyl-3-morpholinoethylcarbodiimide, l-cyclohexyl-3-(4-Diethyl amino cyclo hexyl) carbodiimide, N,N'-carbonyl diimidazole, 2-chloro-l,3-dimethyl imidazolinium chloride, isobutyl chloroformate, Hexafluorophosphate azabenzotriazole tetramethyl uronium (HATU), 2-( IH-Benzotriazole- 1-yl)- 1 , 1 ,3,3-tetramethylaminium tetrafluoroborate (TBTU), Hexafluorophosphate benzotriazole tetramethyl uronium(HBTU), 1,3 -diisopropyl carbodiimide (DIC), Bis(2-oxo-3-oxazolidinyl)phosphinic chloride (BOP. Cl), and the like; more preferably the coupling agent is l-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC.HC1). In the second embodiment of the present invention, wherein in step iii) for reacting deprotected compound of formula- VI with compound of formula- VII additive selected from 1- hydroxybenzotriazole (HOBt), l-hydroxy-7-azabenzotriazole (HOAt), 3,4-dihydro-3-hydroxy- 4-oxo-l,2,3-benzotriazine (DHOBt) can optionally be used.

[0073] In the second embodiment of the present invention, reaction of deprotected compound of formula- VI with compound of formula- VII can be carried out at temperature of about 0°C to about 70°C for 1 hours to 10 hours, preferably at 15°C to 45°C for 2 hours to 4 hours.

[0074] The resulting compound of the formula- IV may have purity greater than 99%, preferably greater than 99.80%, more preferably greater than 99.92% by HPLC (High-performance liquid chromatography) .

[0075] The resulting compound of the formula- IV have yield greater than 80%, preferably greater than 85%, more preferably greater than 90%.

[0076] In the second embodiment of the present invention, wherein edoxaban compound of formula- IV can be converted to its pharmaceutically acceptable salts, preferably to tosylate monohydrate by reacting edoxaban with - toluene sulphonic acid or p-tolucnc sulphonic acid monohydrate in solvent selected from methanol, ethanol, iso-propanol, acetone, dimethyl sulfoxide, or mixture(s) thereof in presence of water.

[0077] In the second embodiment of the present invention, wherein the conversion of edoxaban compound of Formula-IV to edoxaban tosylate monohydrate compound formula- IVa can be carried out at temperature of about 25°C to about 70°C for up to 2 hours, preferably at 65°C to 70°C for 1 hour.

[0078] The resulting Edoxaban tosylate monohydrate have purity of greater than 99%, preferably greater than 99.98% by HPLC (High-performance liquid chromatography).

[0079] The resulting Edoxaban tosylate monohydrate have yield greater than 75%, preferably greater than 80%, more preferably greater than 85%.

[0080] The process for preparation of Edoxaban as per the process of the present invention can be summarized in the following schematic representation:

[0081] The following example(s) illustrate the nature of the invention and are provided for illustrative purposes only and should not be construed to limit the scope of the invention.

[0082] EXPERIMENTAL:

[0083] Example 1: Preparation of methyl 2-((5-chloropyridin-2-yl)amino)-2-oxoacetate.

[0084] Pyridine (1.01 mol) was added to the solution of 2-Amino-5-chloropyridine (0.78 mol) in toluene (1500 mL) at 25-30 °C, followed by addition of methyl chloro oxoacetate at 10-15°C and stirred for 1-3 hours at 10-20°C. The reaction mixture was then cooled at 5-10°C under stirring for 1-2 hours, solid obtained was filtered and washed with toluene (150 mL). Water (800 ml) was added to the above wet solid, stirred for up to 1 hour at 25-30°C, filtered and dried under vacuum for 6-8 hours at 55-65°C.

[0085] Yield: 146 g, 88%.

[0086] Purity: 99.8% by HPLC.

[0087] Example 2: Preparation of tert-Butyl ((lR,2S,5S)-2-(2-((5-chloropyridin-2-yl)amino)-2- oxoacetamido)-5-(dimethylcarbamoyl)cyclohexyl)carbamate compound of formula- VI

[0088] Triethylamine (0.78 mol) was added to the solution of tert-Butyl ((lR,2S,5S)-2-amino-5- (dimethylcarbamoyl)cyclohexyl)carbamate oxalate compound of formula-V (0.25 mol) and methyl 2-((5-chloropyridin-2-yl)amino)-2-oxoacetate (0.29 mol) in (300 mL) in dimethyl sulfoxide at 25-35 °C. The reaction mixture was heated to 50-70°C and stirred for 6-8 hours.

[0089] After completion of reaction, the resulting mixture was cooled to 25°C to 30°C, methanol (500 mL) was added to the mixture, resulting mixture was further cooled to 0°C to 5 °C and stirred for 1 hour. The solid obtained was filtered, washed with methanol (100 mL), and dried under vacuum at 60°C to 70°C for 6-8 hours to obtain desired compound of formula-VI.

[0090] Yield: 101 g, 85%.

[0091] Purity: 99.89% by HPLC.

[0092] Example 3: 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 compound of formula-IV.

[0093] Methane sulfonic acid (0.66 mol) was added to the solution of tert-Butyl ((lR,2S,5S)-2-(2-((5- chloropyridin-2-yl)amino)-2-oxoacetamido)-5 (dimethyl carbamoyl)cyclohexyl)carbamate compound of formula-VI (0.21 mol) in dichloromethane (1000 mL) at 25-35 °C, resulting mixture was stirred for 2-3 hours at same temperature and then was cooled to 15 °C to 20°C to obtain dimesylate salt of compound for formula-VI.

[0094] To the above reaction mixture containing dimesylate salt was added Triethyl amine (1.11 mol), 1- (3- dimethylamino-propyl)-ethyl-carbodiimide Hydrochloride (EDC.HC1) (0.25 mol) compound of Formula-VII and 1 -Hydroxybenzotriazole hydrate (HOBt.H2O) (0.25 mol) at 15 °C to 35 °C and stirred for 5 hours. After completion of the reaction, purified water (500 mL) was added to the above reaction mixture, stirred at 10°C to 35°C for up to 0.5 hour, allowed to separate the layers, organic layer was washed with sodium bicarbonate solution, and then distilled the organic layer under vacuum below 40°C to obtained solid. Methanol (200 mL) was added to the resulting solid and stirred for 1-2 hours at 60°C to 65°C, cooled the mixture at 25°C to 30°C and stirred for 1-2 hours. The solid obtained was filtered, washed with methanol (100 mL), and dried under vacuum at 60°C to 70°C for 6-8 hours to obtain desired compound of formula-IV.

[0095] Yield: 105 g, 90%.

[0096] Purity: 99.92% by HPLC.

[0097] Example 4: Preparation of Edoxaban tosylate monohydrate compound of formula-Iva

[0098] / ^-Toluene sulphonic acid monohydrate (0.18 mol) was added to the solution of N-(5- chloropyridin-2-yl)-N'-[( IS, 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 compound of formula-IV (0.18 mol) in methanol (350 mL) and water (150 mL) at 25-30 °C, the resulting mixture was heated at 65 °C to 70°C and stirred for 1 hour. After completion of reaction, the resulting mixture was cooled at 25°C to 30°C and stirred for 2.0 hours. The solid obtained was filtered, washed with methanol (100 mL), and dried under vacuum at 60°C to 70°C for 6-8 hours to obtain desired compound of formula-IVa.

[0099] Yield: 115 g, 85%.

[0100] Purity: 99.98% by HPLC.

Claims

CLAIM:1) A process for the preparation of alkyl 2-((5-chloropyridin-2-yl)amino)-2-oxoacetate compound of formula-Iwherein R represents C1-C4 alkyl selected from the group consisting of methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, tert-butyl; comprising the step of reacting 2-Amino-5-chloropyridine compound of formula-II,with alkyl chloro oxoacetate compound of formula-III,wherein R is as defined above using solvent in presence of base, wherein base is a cyclic amine.2) The process according to claim 1, wherein the cyclic amine is selected from pyridine, N-methylpiperidine, N-phenylpiperidine, pyrimidine, imidazole, pyrrole, piperidine, piperazine, pyrrolidine, N-methyl pyrrole, pyrazine, N-methyl piperazine, N-methyl pyrrolidine.3) The process according to claim 1, wherein the solvent is halogenated solvent selected from di chloromethane, di chloroethane, chloroform, chlorobenzene; ether solvent selected from tetrahydrofuran, diethyl ether, anisole; ester solvent selected from methyl acetate, ethyl acetate, butyl acetate; ketone solvent selected from acetone, methyl ethyl ketone, cyclohexanone; alcohol solvent selected from methanol, ethanol, isopropyl alcohol, n-butanol; hydrocarbon solvent selected from hexane, heptane, toluene, xylene, cyclohexane; or mixtures thereof.4) The process according to claim 1, wherein R preferably represents methyl or ethyl.5) The process according to claim 1, wherein the reaction is carried out at temperature of 0°C to 30°C.6) The process according to claim 1, wherein the compound of the formula-I have purity greater than 99% by HPLC.7) A process for the preparation of Edoxaban of formula-IV or salt thereof,comprising the steps of: i) reacting 2-Amino-5-chloropyridine compound of formula-II,with alkyl chloro oxoacetate compound of formula-III, o R-oAr ocl(III) wherein R represents C1-C4 alkyl selected from the group consisting of methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, tert-butyl; using solvent in presence of base to obtain alkyl 2-((5-chloropyridin-2-yl)amino)- 2-oxoacetate compound of formula-I;wherein R is as defined above, and base is a cyclic amine; ii) reacting compound of formula-I,wherein R is as defined above, with compound of formula-V or its salt thereof,using solvent in presence of base to obtain compound of formula- VI;iii) deprotecting the compound of formula- VI with deprotecting agent, and then reacting deprotected compound with compound of formula- VII or its salt thereof,using solvent in presence of base and coupling agent to obtain edoxaban compound of formula-IV or salt thereof,8) The process according to claim 3 step i), wherein the cyclic amine is selected from pyridine, N-methylpiperidine, N-phenylpiperidine, pyrimidine, imidazole, pyrrole, piperidine, piperazine, pyrrolidine, N-methyl pyrrole, pyrazine, N-methyl piperazine, N-methyl pyrrolidine.9) The process according to claim 3 step i), wherein the solvent is halogenated solvent selected from dichloromethane, di chloroethane, chloroform, chlorobenzene; ether solvent selected from tetrahydrofuran, diethyl ether, anisole; ester solvent selected from methyl acetate, ethyl acetate, butyl acetate; ketone solvent selected from acetone, methyl ethyl ketone, cyclohexanone; alcohol solvent selected from methanol, ethanol, isopropyl alcohol, n-butanol; hydrocarbon solvent selected from hexane, heptane, toluene, xylene, cyclohexane; or mixtures thereof.10) The process according to claim 3 step ii) and step iii), wherein the base is selected from triethylamine, N,N-diisopropylethylamine (DIPEA), sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, sodium acetate, sodium 2- ethylhexanoate or mixture thereof.11) The process according to claim 3 step ii), wherein the solvent is selected from dimethylformamide, dimethyl sulfoxide, dimethylacetamide, methanol, ethanol, isopropanol, N-methylpyrrolidone or a mixture thereof.12) The process according to claim 3 step iii), wherein the solvent selected from dioxane, methylene dichloride, ethylene dichloride, chlorobenzene, chloroform, ethyl acetate, dimethyl formamide, tetrahydrofuran, dimethyl sulfoxide or mixture thereof.13) The process according to claim 3 step iii), wherein the deprotecting agent is selected from trifluoroacetic acid, hydrochloric acid, sulfuric acid, p-toulenesulfonic acid, or methanesulfonic acid.14) The process according to claim 3 step iii), wherein the coupling agent is selected from1,3 -di cyclohexylcarbodiimide (DCC), isobutyl chloroformate, pivaloyl chloride, isovaleryl chloride, l-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC.HC1), 1 -cyclohexyl -3-morpholinoethylcarbodiimide, l-cyclohexyl-3-(4-Diethyl amino cyclohexyl) carbodiimide, N,N'-carbonyl diimidazole, 2-chloro-l,3-dimethyl imidazolinium chloride, isobutyl chloroformate,Hexafluorophosphate azabenzotriazole tetramethyl uronium (HATU), 2-(lH-Benzotriazole-l-yl)-l, 1,3,3 -tetramethylaminium tetrafluoroborate (TBTU),Hexafluorophosphate benzotriazole tetramethyl uronium(HBTU), 1,3 -diisopropyl carbodiimide (DIC), Bis(2-oxo-3-oxazolidinyl)phosphinic chloride (BOP.C1).

Images