DESC:FIELD OF THE INVENTION
The present invention relates to an improved process for preparation of Edoxaban (I) or its pharmaceutically acceptable salts or solvates thereof.
(I)

BACKGROUND OF THE INVENTION
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.

Edoxaban has been developed by Daiichi Sankyo and approved by USFDA since January 2015, under the proprietary name SAVAYSA®. First approval for Edoxaban occurred in Japan in year 2011. Besides SAVAYSA®, it is also available under brand names LIXIANA® and ROTEAS® in different parts of the world. As per USFDA label, active ingredient of the drug SAVAYSA® is Edoxaban tosylate monohydrate, which is chemically also known as 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 and is represented by the following general Formula (Ia).
(Ia)
Edoxaban, its salt or a solvate thereof are disclosed for first time in patent US7365205B2 by Ohta et al. US’205 discloses a general process for preparation of Edoxaban (I) as per following Scheme I:

Scheme I

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

Scheme II

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

Scheme III

Besides the above mentioned references, there are several other disclosures in prior art for e.g. US8404847B2, US7547786B2, US8357808B2, US8901345B2, US9447118B2, US8541443B2, US8394821B2, WO2008156159A1, JP2010254615A US20170050983A1 and US20170022220A1, wherein a number of aspects regarding preparation and properties of Edoxaban and its pharmaceutically acceptable salts or solvates thereof have been discussed. But drawback with prior art processes is that these are difficult to handle at the industrial scale due to operational issues like reaction mass solidification, use of very low or high temperature, unacceptable level of fuming/foaming in the reactor, use of rigid reaction conditions and use of hazardous reagents. Also these processes use costly reagents and provide less yield as well as low purity API after unacceptably high reaction times, thus necessitating multiple purifications.

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

OBJECT OF THE INVENTION
Objective of the present invention is to provide an improved industrially viable process for preparation of Edoxaban or its pharmaceutically acceptable salts or solvates thereof.

SUMMARY OF THE INVENTION
The present invention relates to an improved industrially viable process for preparation of Edoxaban or its pharmaceutically acceptable salts or solvates thereof.

An aspect of the present invention provides, a process for preparation of Edoxaban or its pharmaceutically acceptable salts or solvates thereof, wherein the said process comprises, reaction of compound of Formula (i) or its ‘amine protected’ derivative

with compound of Formula (ii),

in presence of a ‘metal salt of organic acid’, to obtain compound of Formula (iii) or its ‘1° amine protected’ derivative.

A further aspect of the present invention provides, a process for preparation of Edoxaban or its pharmaceutically acceptable salts or solvates thereof, using compound of Formula (iii) or its ‘1° amine protected’ derivative as obtained by process of the present invention.

DETAILED DESCRIPTION
Before the present invention is described, it is to be understood that unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by person of ordinary skill, in the art to which this invention belongs. It is also to be understood that the terminology used in the description is for the purpose of describing the particular embodiments only, and is not intended to limit the scope of the present invention. Further, it is to be understood that the present invention is not limited to the illustrations herein; methodologies and materials similar to those described herein may also be used in the practice of the present invention. Unless stated to the contrary, any use of the words such as "including", "containing", "comprising", "having" and the like, means "including without limitation" and shall not be construed to limit any general statement or variables that follow these specific or similar terms. Embodiments of the invention are not mutually exclusive, but may be implemented in various combinations. The described embodiments and examples of the invention are given for the purpose of illustration rather than limitation of the invention as set forth.

Abbreviation Full Form of Abbreviation
ACN Acetonitrile
API Active Pharmaceutical Ingredient
BOC tert-butyloxycarbonyl
Cbz carboxybenzyl
DBN 1,8-diazabicyclo[4.3.0]non-5-ene
DBU 1,8-diazabicyclo[5.4.0]undec-7-ene
DCC 1,3-dicyclohexylcarbodiimide
DIPEA N,N-diisopropylethylamine
EDC.HCl 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride
FMOC fluorenylmethyloxycarbonyl
HBTU 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexa?uorophosphate
HOAt 1-hydroxy-7-azabenzotriazole
HOBt 1-hydroxybenzotriazole
m- molecule with substituent at position 3 wrt a fixed substituent at position 1
MDC Dichloromethane
MTBE Methyl tert-butyl ether
p- molecule with substituent at position 4 wrt a fixed substituent at position 1
PPTS pyridinium p-toluenesulfonate
PyBOP benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate
USFDA U S Food and Drug Administration

As set forth herein, an embodiment of the present invention provides a process for preparation of Edoxaban or its pharmaceutically acceptable salts or solvates thereof comprising the step of, reacting compound of Formula (i) or its ‘amine protected’ derivative

with compound of Formula (ii),

in presence of a ‘metal salt of organic acid’, to provide compound of Formula (iii) or its ‘1° amine protected’ derivative,

wherein, ‘X’ represents a group capable of assisting amide bond formation by reacting with an amine group of compound of Formula (i) or its ‘amine protected’ derivative.

‘X’ in compound of Formula (ii) is selected from halogen or –OR, wherein ‘R’ is selected from the group comprising of hydrogen, alkali or alkaline earth metal and C1-C4 alkyl. Preferred ‘R’ as per present invention includes but is not limited to H, Li, Na, K, methyl, ethyl, n-propyl, sec-propyl, n-butyl, sec-butyl or tert-butyl.

Compound of Formula (i) as mentioned herein above may be used in the reaction ‘as such’ or in the form of a ‘amine-protected’ derivative. Preferably, the said derivative of compound of Formula (i) is wherein one or both of 1° amine groups are protected. More preferably the ‘non-reacting’ 1° amine group i.e. amine at m-position to carbamoyl group, may be in suitably protected form and amide bond formation occurs via ‘reacting’ p-amine group. The amine protecting group may be selected from a group known in the literature and preferably from FMOC (fluorenylmethyloxycarbonyl), BOC (tert-butyloxycarbonyl), Cbz (carboxybenzyl), acetyl, trifluouroacetyl, benzyl, trityl or tosyl.

‘Metal salt of organic acid’ as used in the above reaction, can either be selected from group comprising of sodium butanoate, potassium 2,4-dimethyl pentanoate, calcium ethanoate, magnesium methanoate, calcium ethanedioate, sodium gluconate, sodium-2-ethyl hexanoate, sodium acetate, calcium acetate and the like or from metal salt of C4-C28 fatty acids such as sodium palmitate, sodium laurate, sodium myristate, sodium caprylate, sodium caprate and the like.

Another embodiment of the present invention provides, a process for preparation of Edoxaban or its pharmaceutically acceptable salt or solvate thereof, using compound of Formula (iii) or its ‘1° amine protected’ derivative as obtained by process of the present invention. ‘1° amine protected’ compound of Formula (iii) may be used ‘as such’ for further step or may be deprotected before further reaction. Said deprotection may be carried out as per any method known in art, preferably using acids for e.g. trifluoroacetic acid, methanesulfonic acid or by using reducing conditions for e.g. Palladium on Carbon (Pd/C), Pt/C, Rh/C, Raney Ni and the like.

In an embodiment of the present invention, compound of Formula (iii) or its ‘1° amine protected’ derivative as obtained by process of the present invention, is reacted with compound of Formula (iv) to prepare Edoxaban.

An embodiment of the present invention provides that the compounds (i), (ii), (iii) and (iv) may be used in a free acid/base form or optionally may be used in a suitable salt form as well. Suitable salt form may be selected from the group comprising of alkali metal salt, alkaline earth metal salt, hydrochloride, phosphate, nitrate, sulfate, oxalate, mesylate, tosylate, acetate or tartrate, preferably hydrochloride, oxalic acid or alkali metal salt.

As per requirement, free carboxyl group in any of the starting material of the process of present invention, may be converted to mixed acid anhydride, acid halide or activated ester derivative before proceeding with the corresponding reaction step. Suitable reagents used for such conversion may be selected from group comprising of thionyl chloride, oxalyl chloride, cyanuric chloride, pivaloyl chloride, ethyl chloroformate or the like.

Conversion of Edoxaban prepared according to the process of present invention, to its pharmaceutically acceptable salt or solvate thereof, for e.g. Edoxaban tosylate or its monohydrate can be performed by using any suitable process known in prior art. Other specific examples of pharmaceutically acceptable salts of Edoxaban include but are not limited to mineral acid salts such as hydrochlorides, hydrobromides, hydriodides, phosphates, nitrates and sulfates; benzoates; organic sulfonates such as methanesulfonates, 2-hydroxyethanesulfonates and p-toluenesulfonates; and organic carboxylates such as acetates, propanoates, oxalates, malonates, succinates, glutarates, adipates, tartrates, maleates, malates and mandelates. Some specific examples of pharmaceutically acceptable solvates of Edoxaban include but are not limited to hydrates and ethanolates.

An embodiment of the present invention provides that process for the preparation of Edoxaban or its pharmaceutically acceptable salts or solvates thereof, as mentioned herein may be optionally carried out in presence of an organic or inorganic base, said base being selected from the group comprising of hydroxides, phosphates, carbonates, hydrogencarbonates, and alkoxides of an alkali metal or an alkaline earth metal (e.g., sodium, potassium, lithium, magnesium, or calcium); metal hydrides such as sodium hydride, potassium hydride, lithium hydride; alkyllithium reagents such as n-butyllithium, methyllithium, and lithium diisopropylamide; tertiary amines such as triethylamine and N,N-diisopropylethylamine (DIPEA); and heterocyclic compound such as 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,8-diazabicyclo[4.3.0]non-5-ene (DBN), dimethylaniline and N-methylmorpholine.

In an embodiment of the present invention, condensation reactions as mentioned hereinabove are optionally carried out in presence of one or more of a ‘condensing agent’ and/or ‘additive’ for promoting reaction and enhancing production yield. Among the many examples of the ‘condensing agent’, the preferable condensing agents include 1,3-dicyclohexylcarbodiimide (DCC), isobutyl chloroformate, pivaloyl chloride, isovaleryl chloride, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC.HCl), 1-cyclohexyl-3-morpholinoethylcarbodiimide, 1-cyclohexyl-3-(4-diethylaminocyclohexyl)carbodi-imide, N,N'-carbonyldiimidazole, 2-chloro-1,3 - dimethylimidazolinium chloride and/or isobutyl chloroformate. Similarly, among the many examples of the ‘additives’, the preferable additives include p-nitrophenol, hydroxysuccinimide, hydroxyphthalimide, 1-hydroxybenzotriazole, 3-hydroxy-4-oxo -3,4-dihydro-1,2,3-benzotriazine, N-hydroxy-5-norbornene-2,3-dicarboximide, 2-hydroxyimino-2-cyanoethyl acetate, 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexa?uorophosphate (HBTU), 1-hydroxy-7-azabenzotriazole (HOAt), benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate (PyBOP) and/or 1-hydroxybenzotriazole (HOBt).

Another embodiment of the present invention, provides that reaction for preparation of Edoxaban or its pharmaceutically acceptable salts or solvates thereof, as mentioned hereinabove are carried out in presence of an organic or aqueous solvent, the said solvent being selected from groups comprising of hydrocarbon solvent like n-hexane, n-pentane, benzene, toluene, and xylene; alcoholic solvent like C1-C4 alcohols such as methanol, ethanol, propanol, isopropanol, n-butanol, and t-butanol; ether solvent like diethyl ether, diisopropyl ether, methyl t-butyl ether, tetrahydrofuran, cyclopentyl methyl ether, dimethoxyethane, and 1,4-dioxane; amide solvent like dimethylformamide, dimethylacetamide, and N-methyl-2-pyrrolidone; halohydrocarbon solvent like chloroform, methylene chloride, and 1,2-dichloroethane and other solvents like water, dimethylsulfoxide, sulfolane, acetonitrile, 4-methyl-2-pentanone, methyl ethyl ketone, (C1-C4 alkyl)acetate esters such as ethyl acetate, and acetone or a combination thereof.

Based on solubility of the reaction mass, suitable phase transfer catalyst may be used to practice the present invention. Reaction temperature employed in the reaction may range from 0°C to the reflux temperature of the solvent(s) used. Above mentioned solvents may also be used for isolation of intermediates or final API, which may further involve processes known in the art such as acid-base work up and purification by recrystallization. Optionally, the solution, prior to any solids formation, can be filtered to remove any undissolved solids and/or solid impurities prior to the removal of the solvent. Any filtration system and techniques known in the art can be used.

Any sequence of addition/reaction of the starting materials/intermediates shall be construed within the scope of the present invention. Overall reaction process may be carried out in a step-wise manner or as an one-pot process and reaction intermediates may be isolated or carried forward in-situ to the next step.

Another embodiment of the present invention provides the use of catalyst in the reaction of present invention, wherein the catalyst is selected from group comprising of boronic acids, Pd-NHC complexes, copper sulfate, pyridinium p-toluenesulfonate (PPTS), DBU, FeCl3/glacial acetic acid, 1,2,4-triazole, pyridinium hydrochloride and the like. Whenever, the reaction is carried out in presence of said catalyst, the use of ‘metal salt of organic acid’ as mentioned above may or may not be done for corresponding reaction step.

The improved process for preparation of Edoxaban or its pharmaceutically acceptable salts or solvates thereof, as per present invention, is industrially scalable, economical, and provides API of high purity in high yield within reduced reaction time. The currently provided novel process is efficient and convenient w.r.t. handling, as it provides easy work-up, there is no heavy solid formation and the process is not affected by sequence of addition of starting materials.

The following examples 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.

Example 1: Preparation of Edoxaban intermediate i.e. Compound of Formula (iii-a)
100 mL THF, 8 g compound of Formula (i-a), sodium 2-ethyl hexanoate and 6.8 g compound of Formula (ii-a) were added to a RB flask. Reaction mixture was heated, then cooled and solvent was distilled out. The reaction mass obtained was treated with water/MDC along with use of sodium bicarbonate and citric acid. From the organic layer a solid crude material was isolated, which was further treated with MTBE. The solid material obtained is then suck dried under vacuum to obtain 7.31 g compound of Formula (iii-a).

Example 2: Preparation of Edoxaban intermediate i.e. Compound of Formula (iii-a)

160 mL MDC, 8 g compound of Formula (i-a), 11 g DIPEA, 16 g PPTS and 4 g EDC.HCl were charged into RB flask. Reaction mass was stirred and 3 g HOBt and 5 g compound of Formula (ii-b) were added to it. The reaction mass is stirred for 16-20 h and then 80 mL water was added to it. Reaction mass obtained was treated with sodium bicarbonate and citric acid. Then organic layer was separated and subjected to vacuum. Thus obtained reaction mass was then treated with MTBE and dried to obtain 5.5 g of compound of Formula (iii-a).

Example 3: Preparation of Edoxaban from intermediate i.e. Compound of Formula (iii-a)

ACN, 20 g compound of Formula (iii-a), methane sulfonic acid and triethylamine were added to a RB flask and heated. Then 11 g compound of Formula (iv-a), HOBt and DCC were added to the reaction mixture and on completion of reaction as confirmed by HPLC, the solvent was distilled out. The reaction mass obtained was treated with water/MDC, sodium bicarbonate and acetic acid. A crude reaction mass was obtained using vacuum, and then treated with cyclohexane and methanol. The solid obtained was then suck dried under vacuum to obtain 17.5 g Edoxaban.

While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.
,CLAIMS:We Claim:
1. A process for preparation of compound of Formula (iii) or its ‘1° amine protected’ derivative,

comprising the step of:
reacting compound of Formula (i) or its ‘m-amine protected’ derivative

with compound of Formula (ii),

in the presence of a ‘metal salt of organic acid’; wherein, ‘X’ represents a group capable of assisting amide bond formation by reacting with the p-amine group of compound of Formula (i) or its ‘m-amine protected’ derivative.

2. The process as claimed in claim 1, further comprising reaction of compound of Formula (iii) or its ‘1° amine protected’ derivative, with the compound of Formula (iv),

to prepare Edoxaban or its pharmaceutically acceptable salts or solvates thereof.

3. The process as claimed in claim 1, wherein ‘X’ is selected from halogen or –OR, ‘R’ being further selected from alkali or alkaline earth metal, H, Li, Na, K, methyl, ethyl, n-propyl, sec-propyl, n-butyl, sec-butyl or tert-butyl.

4. The process as claimed in claim 1, wherein the amine protecting group of, ‘m-amine protected’ derivative of compound of Formula (i) or ‘1° amine protected’ derivative of compound of Formula (iii), is selected from FMOC, BOC, Cbz, acetyl, trifluouroacetyl, benzyl, trityl or tosyl.

5. The process as claimed in claim 1, wherein ‘metal salt of organic acid’ is selected from sodium butanoate, potassium 2,4-dimethyl pentanoate, calcium ethanoate, magnesium methanoate, calcium ethanedioate, sodium gluconate, sodium-2-ethyl hexanoate, sodium acetate, calcium acetate or metal salt of C4-C28 fatty acids, sodium palmitate, sodium laurate, sodium myristate, sodium caprylate or sodium caprate.

6. The process as claimed in claim 2, wherein ‘1° amine protected’ compound of Formula (iii) is optionally deprotected before reaction with compound of Formula (iv), wherein deprotection is carried out by trifluoroacetic acid or methanesulfonic acid or by reducing conditions, Pd/C, Pt/C, Rh/C or Raney Ni.

7. The process as claimed in claims 1 and 2, wherein compounds (i), (ii), (iii) and (iv) may optionally be used in a suitable salt form selected from alkali metal salt, alkaline earth metal salt, hydrochloride, phosphate, nitrate, sulfate, oxalate, mesylate, tosylate, acetate or tartrate.

8. The process as claimed in claim 2, wherein pharmaceutically acceptable salt or solvate of Edoxaban is Edoxaban tosylate or the monohydrate form thereof.

9. The process as claimed in claims 1 and 2, wherein reactions are carried out optionally in presence of a base or ‘condensing agent’ or ‘additive for promoting reaction’ or a mixture thereof.

10. The process as claimed in claim 9, wherein ‘condensing agent’ is selected from DCC or EDC or hydrochloride thereof and ‘additive for promoting reaction’ is selected from HBTU, HOAt, PyBOP or HOBt.