DESC:FIELD OF THE INVENTION

The present invention relates process for preparing diamine compound. In particular, the present invention relates to process for preparing edoxaban or salts or hydrates thereof. More particularly the present invention relates to process for preparing edoxaban tosylate monohydrate.

BACKGROUND OF THE INVENTION

The following discussion of the prior art is intended to present the invention in an appropriate technical context and allow its significance to be properly appreciated. Unless clearly indicated to the contrary, however, reference to any prior art in this specification should be construed as an admission that such art is widely known or forms part of common general knowledge in the field.

Edoxaban having Formula (I), is an orally administered coagulation factor Xa inhibitor.

(I)

Edoxaban is supplied as edoxaban tosylate monohydrate. The chemical name is N1-(5-Chloropyridin-2-yl)-N2-[(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-methyl benzenesulfonate) monohydrate having Formula (Ia).

(Ia)

Edoxaban is indicated to reduce the risk of stroke and systemic embolism (SE) in patients with nonvaluvular atrial fibrillation (NVAF) and also indicated for the treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE) following 5-10 days of initial therapy with a parenteral anticoagulant. It is available under the trade name of SAVAYSA® as a factor Xa inhibitor and SAVAYSA tablets are supplied in 15, 30, and 60 mg strengths for oral administration.

International (PCT) Publication Nos. WO 2003/000657, WO 2003/000680, WO 2003/016302, WO 2004/058715, WO 2005/047296, WO 2007/032498, WO 2008/129846, and WO 2008/156159 discloses edoxaban tosylate monohydrate as a compound that exhibits an inhibitory effect on activated blood coagulation factor X (FXa) and is useful as a preventive and/or therapeutic drug for thrombotic diseases.

U.S. Patent No. 7,365,205 B2 discloses the compound edoxaban tosylate monohydrate and process for its preparation, which is incorporated herein by reference.

U.S. Patent Nos. 8,686,189 B2, 8,357,808 B2, 9,175,012 B2, 8,404,847 B2, 9,233,980 B2, 8,901,345 B2 and US PG-Pub. No. 2015/353577 A1 discloses process for preparation of edoxaban tosylate monohydrate and intermediates thereof.
In view of the above prior art, there is provided a novel, efficient and convenient process for preparation of edoxaban or salt thereof, which is at least a useful alternative to the prior art as well as an economic, efficient and convenient method.

SUMMARY OF THE INVENTION

In one general aspect, there is provided a process for the preparation of edoxaban, the process comprising:
(a) reacting a compound of Formula (VI) or salts thereof, with a compound of Formula (V);

(VI) (V)
to obtain a compound of Formula (IV);

(IV)
(b) converting the compound of Formula (IV) to a compound of Formula (III);

(III)
(c) reacting the compound of Formula (III) with a compound of Formula (II),

(II)
to obtain edoxaban and optionally converting the edoxaban to its pharmaceutically acceptable salts or hydrates thereof.

In another general aspect, there is provided a process for preparation of edoxaban, the process comprising:
(a) reacting a compound of Formula (VIIa) or salts thereof, with a compound of Formula (V)

(VIIa) (V)
wherein L is –OTf, –OMs, –OTs;
to obtain a compound of Formula (Va);

(Va)
(b) converting the compound of Formula (Va) to a compound of Formula (IVa);

(IVa)
wherein R is benzyl, substituted benzyl or p-toluenesulfonyl;
(c) converting the compound of Formula (IVa) to a compound of Formula (III); and

(III)
(d) reacting the compound of Formula (III) with a compound of Formula (II);

(II)
to obtain edoxaban and optionally converting the edoxaban to its pharmaceutically acceptable salts or hydrates thereof.

In another general aspect, there is provided a compound of the general Formula (Va),

(Va)
wherein, R is –OTf, –OMs, –OTs, –NHTs or –NHR1 wherein R1 is benzyl or substituted benzyl.

DETAILED DESCRIPTION OF THE INVENTION

The above and other objects of the present invention are achieved by the process of the present invention, which leads to edoxaban, edoxaban tosylate, pharmaceutical composition comprising same, methods for its preparation and use thereof as an anticoagulant agent which acts as a direct factor Xa inhibitor.

The present invention is based on the new process for preparation of edoxaban with better purity.

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.

All ranges recited herein include the endpoints, including those that recite a range “between” two values. Terms such as “about”, “generally”, “substantially,” and the like are to be construed as modifying a term or value such that it is not an absolute. Such terms will be defined by the circumstances and the terms that they modify as those terms are understood by those skill in the art. This includes, at very least, the degree of expected experimental error, technique error and instrument error for a given technique used to measure a value.

As used herein the term “edoxaban tosylate” refers to compound N1-(5-chloropyridin-2-yl)-N2-[(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-methyl benzenesulfonate) or monohydrate thereof of Formula (Ia) as herein below.

(Ia)

The terms used throughout the description is defined herein below.
“HOBT” refers to hydroxybenzotriazole.
“EDC” refers to 1-ethyl-3-(3-dimethylaminopropyl)carbodimide.
“DCC” refers to N,N'-Dicyclohexyl carbodiimide.
“TBTU” refers to O-(Benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate
“DMAP” refers to 4-dimethylaminopyridine.
“DMF” refers to N,N-dimethylforamide.
“DMAc” refers to N,N-dimethylacetamide.
“MDC” refers to methylene dichloride.
“DMSO” refers to N,N-dimethylsulfoxide.
“NMP” refers to N-methylpyrrolidone.
“THF” refers to tetrahydrofuran.
“IPA” refers to isopropanol.
“TEA” refers to triethylamine.
“TBA” refers to tert-butyl amine.
“DIPA” refers to diisopropyl amine.
“DIPEA” refers to diisopropyl ethylamine.
“DBU” refers to 1,8-diazabicyclo[5.4.0]undec-7-ene.
“DABCO” refers to 1,4-diazabicyclo[2.2.2]octane.
“DBN” refers to 1,5-Diazabicyclo[4.3.0]non-5-ene
“HPLC” refers to high performance liquid chromatography.
“PTSA” refers to p-Toluenesulfonic acid.
“–OTf” refers to Trifluoromethanesulfonate
“–OMs” refers to Methanesulfonate
“–OTs” refers to toluenesulfonate
“Cbz” refers to Carboxybenzyl
“Ts” refers to p-Toluenesulfonyl
“Bz” refers to benzyl

In one general aspect, there is provided a process for the preparation of edoxaban, the process comprising:
(a) reacting a compound of Formula (VI) or salts thereof, with a compound of Formula (V);

(VI) (V)
to obtain a compound of Formula (IV);

(IV)
(b) converting the compound of Formula (IV) to a compound of Formula (III);

(III)
(c) reacting the compound of Formula (III) with a compound of Formula (II),

(II)
to obtain edoxaban and optionally converting the edoxaban to its pharmaceutically acceptable salts or hydrates thereof.

In general, the compound of Formula (VI) may be reacted with an acid, followed by adding the compound of Formula (V) in the presence of a coupling reagent to obtain the compound of Formula (IV).

Particularly, the compound of Formula (VI) is reacted with an acid in one or more solvents to deprotect the boc protection, followed by addition of the compound of Formula (V) and a coupling reagent optionally in the presence of a base to obtain the compound of Formula (IV).

In general, the acid used in step (a) comprises one or more of methane sulfonic acid, hydrochloric acid, trifluoro acetic acid, hydrobromic acid, sulphuric acid, pivalic acid, acetic acid and formic acid, or mixture thereof.

In general, the coupling reagent used in step (a) comprises one or more of HOBT, TBTU and DCC or mixture thereof, optionally in presence of base. In general, the base comprises one or more of EDC, DMAP, TEA, TBA, DIPA, DIPEA, DBU, DABCO and DBN, or mixture thereof.

In general, the compound of Formula (III) may be prepared by reacting the compound of Formula (IV) with Pd/C and hydrogen source.

Particularly, the compound of Formula (IV) in a solvent may be reacted with Pd/C (10% w/w) and a hydrogen source to obtain the compound of Formula (III).

In general, edoxaban may be prepared by reacting compound of Formula (III) with compound of Formula (II) in the presence of a base. In particular, the compound of Formula (III) is reacted with the compound of Formula (II) in one or more solvents in the presence of a base to obtain edoxaban.

In general, the edoxaban obtained may be converted to its pharmaceutically acceptable salts or hydrates. In particular, the edoxaban obtained may be converted to edoxaban tosylate hydrate by reacting with PTSA hydrate in one or more solvents.

In general, solvent comprises but not limited to methanol, ethanol, n-propanol, isopropanol, n-butanol, acetone, methyl ethyl ketone, methyl isobutyl ketone, MDC, chloroform, ethylene dichloride, chlorobenzene, toluene, xylene, ethylbenzene, ethyl acetate, isopropyl acetate, n-butyl acetate, tetrahydrofuran, diethyl ether, diisopropyl ether, methyl tert-butyl ether, water, DMF, DMAc, DMSO and NMP or mixture thereof.

In another general aspect, there is provided a process for preparation of edoxaban of Formula (I), comprising:
(a) reacting a compound of Formula (VIIa) or salt thereof, with a compound of Formula (V),

(VIIa) (V)
wherein L is –OTf, –OMs, –OTs;
to obtain a compound of Formula (Va);

(Va)
(b) converting the compound of Formula (Va) to a compound of Formula (IVa);

(IVa)
wherein R is benzyl, substituted benzyl or p-toluenesulfonyl;
(c) converting the compound of Formula (IVa) to a compound of Formula (III); and

(III)
(d) reacting the compound of Formula (III) with a compound of Formula (II);

(II)
to obtain edoxaban and optionally converting edoxaban to its pharmaceutically acceptable salts or hydrates thereof.
In general, the compound of Formula (VIa) is reacted with an acid, followed by adding compound of Formula (Va) in the presence of a coupling reagent to obtain the compound of Formula (IVa).

Particularly, the compound of Formula (VIa) may be reacted with an acid to remove boc protection followed by addition of compound of Formula (Va) in presence of a coupling reagent in one or more solvents.

In general, the compound of Formula (IVa) is prepared by reacting compound of Formula (Va) with an amine or amide selected from benzyl amine, substituted benzylamine, and tosylamide in presence of a base in one or more solvents.

Particularly the compound of Formula (Va) may be reacted with benzylamine in a solvent in presence of a base to obtain compound of Formula (IVa).

Particularly the compound of Formula (Va) may be reacted with tosylamide in presence of a base and a solvent to obtain the compound of Formula (IVa).

In general, the compound Formula (IVa) may be converted to compound of Formula (III). In particular the compound of Formula (IVa), wherein R is benzyl or substituted benzyl, may be reacted with Pd/C in the presence of a solvent and hydrogen source to obtain compound of Formula (III).

In general, the compound of Formula (IVa), wherein R is tosyl may be reacted with an acid to obtain compound of Formula (III). In particular, the compound of Formula (IVa), wherein R is tosyl may be reacted with aq. H2SO4 to obtain compound of Formula (III). The compound of Formula (III) may be converted to edoxaban and its pharmaceutically acceptable salt or hydrate.

In general, solvent comprises but not limited to methanol, ethanol, n-propanol, isopropanol, n-butanol, acetone, methyl ethyl ketone, methyl isobutyl ketone, MDC, chloroform, ethylene dichloride, chlorobenzene, toluene, xylene, ethylbenzene, ethyl acetate, isopropyl acetate, n-butyl acetate, tetrahydrofuran, diethyl ether, diisopropyl ether, methyl tert-butyl ether, water, DMF, DMAc, DMSO and NMP or mixture thereof.

In another general aspect, there is provided a compound of the general Formula (Va);

(Va)
wherein, R is –OTf, –OMs, –OTs, –NHTs or –NHR1 wherein R1 is benzyl or substituted benzyl.

In particularly, there is provided the compounds selected from,

(Va1) (Va2)

(Va3) (Va4)

(Va5)
or salts thereof.

The present invention is further illustrated by the following example which is provided merely to be exemplary of the invention and do not limit the scope of the invention.

Examples:
Example 1: Preparation of Benzyl ((1S,2R,4S)-4-(dimethylcarbamoyl)-2-(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamido)cyclohexyl) carbamate
To 100 mL 4-necked RBF, benzyl tert-butyl ((1S,2R,4S)-4-(dimethylcarbamoyl)- cyclohexane-1,2-diyl)dicarbamate (1 g) and acetonitrile (10 ml) were added and stirred for 30 min at room temperature. Methanesulfonic acid (1.3 g) was added and stirred for 2 hours. Triethyl amine (1.5 g) and 5-methyl-4,5,6,7-tetrahydro- thiazolo[4,5-c]pyridine-2-carboxylic acid hydrochloride (1.1 M eq) were then added to the resulting mixture and stirred at room temperature overnight. The completion of the reaction was monitored by TLC. After the completion of the reaction, the reaction mixture was quenched with water (20 ml) to obtain the solid precipitates. The product thus obtained was filtered, washed with water and dried under vacuum to obtain the title compound (1 g).

Example 2: Preparation of N-((1R,2S,5S)-2-amino-5-(dimethylcarbamoyl) cyclohexyl)-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamide
In 50 ml Autoclave assembly, benzyl ((1S,2R,4S)-4-(dimethylcarbamoyl)-2-(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamido)cyclohexyl) carbamate (1 g) and methanol (10 ml) were dissolved and stirred for 30 min. Pd/C (10 %w/w) was added to the reaction mixture and hydrogen source was connected at 4 kg/cm2 pressure at 55 to 60oC for 5 hours. The reaction mixture thus obtained was filtered by celite filter and washed with methanol (2 ml). Methanol was distilled and cyclohexane (10 ml) was added to the reaction mixture to obtain solid precipitates. The product thus obtained was filtered, washed with cyclohexane (2 ml) and dried under vacuum to obtain the title compound (0.65 g).

Example 3: Preparation of N1-(5-chloropyridin-2-yl)-N2-((1S,2R,4S)-4-(dimethylcarbamoyl)-2-(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamido)cyclohexyl)oxalamide
To the 100 mL 3-neck RBF, N-((1R,2S,5S)-2-amino-5-(dimethylcarbamoyl) cyclohexyl)-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamide (1 g) and acetonitrile (10 ml) were added and stirred for 30 min. To the reaction mixture, triethyl amine (5 M eq) and ethyl 2-((5-chloropyridin-2-yl)amino)-2-oxoacetate hydrochloride (1 M eq) were added and heated at 50 to 55oC for 5 hours. Water (20 ml) was added and stirred for 1 hour to obtain solid precipitates. The solid precipitates was filtered, washed with water and dried to obtain the title compound (1 g).

Example-4: Preparation of edoxaban tosylate hydrate
To 100 mL 3-necked RBF, added compound obtained in example 3 (1 g) and MDC (20 ml), stirred for 30 min at room temperature. PTSA hydrate (1.05 meq) in ethanol (2 ml) was added to the reaction mixture, stirred for 1 hour. The reaction mixture was distilled at 40oC to obtain solid mass. Ethanol (15 % aq, 10 ml) was added to the solid mass and stirred for 4 hours to obtain solid mass, filtered and dried to obtain edoxaban tosylate hydrate (1 g).

Example-5: Preparation of (1R,2R,4S)-4-(dimethylcarbamoyl)-2-(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamido)cyclohexyl methanesulfonate
Title compound was synthesized from (1R,2R,4S)-2-((tert-butoxycarbonyl) amino)-4-(dimethylcarbamoyl)cyclohexyl methanesulfonate similar to process of example 1.

Example-6: Preparation of N-((1R,2S,5S)-2-(benzylamino)-5-(dimethyl carbamoyl)cyclohexyl)-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamide
To 100 mL 4-necked RBF, Benzylamine (1 M eq) was dissolved in acetonitrile followed by addition of KOH (1.5 mol) at 0 to 5oC. (1R,2R,4S)-4-(dimethyl- carbamoyl)-2-(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamido)cyclohexyl methanesulfonate (1 g) was then added to reaction mixture and stirred for 10 hour at room temperature. Water (10 ml) was added to the reaction mixture to obtain solid. Solid was filtered and dried under vacuum to obtain the title compound (1 g).

Example-7: Preparation of N-((1R,2S,5S)-2-amino-5-(dimethylcarbamoyl) cyclohexyl)-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamide
To autoclave assembly, added methanol (10 ml), Pd/C (10% w/w) and N-((1R,2S,5S)-2-(benzylamino)-5-(dimethylcarbamoyl)cyclohexyl)-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamide (1 gm). Hydrogen source was connected at 5 kg/cm2 and maintained at room temperature for 1 to 2 hour. reaction mixture was filtered by celite filter. Methanol was distilled and cyclohexane was added to the reaction mixture to obtain solid. Solids were filtered, dried under vacuum to obtain the title compound (0.6 g).

Example-8: Preparation of N-((1R,2S,5S)-5-(dimethylcarbamoyl)-2-((4-methylphenyl)sulfonamido)cyclohexyl)-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamide
To 100 mL, 3-necked RBF, added KOH (1.5 M eq) and DMF (10 mL) stirred at 120°C and tosylamide (1.5 M eq) was added to the resulting solution. After 30 min a solution of the (1R,2R,4S)-4-(dimethylcarbamoyl)-2-(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamido)cyclohexyl methanesulfonate (1 g) in DMF (10 mL) was added. After 1 h the reaction mixture was cooled, diluted with water (100 mL) and extracted with MDC (40 × 50 mL). The combined organic layers were washed with water (30 × 50 mL), brine (30 × 50 mL), dried (MgSO4) and evaporated. The crude product was purified by ethanol, dried under vacuum to obtain title compound (0.5 g).

Example-9: Preparation of N-((1R,2S,5S)-2-amino-5-(dimethylcarbamoyl) cyclohexyl)-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamide
To 100 mL 3-necked RBF, added N-((1R,2S,5S)-5-(dimethylcarbamoyl)-2-((4-methylphenyl)sulfonamido)cyclohexyl)-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamide (1 gm) added 40% aq. H2SO4 (4 ml) at 5oC and stirred for 2 hour. 20 % aq. NaOH (5 ml) was added to the resulting solution and extracted with MDC and treated with Na2SO4, dried to obtain the title compound (0.6 g).

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 compound of general Formula (Va),

(Va)
wherein, R is –OTf, –OMs, –OTs, –NHTs or –NHR1 wherein R1 is benzyl or substituted benzyl.
2. The compound according to claim 1 is selected from,

(Va1) (Va2)

(Va3) (Va4)

(Va5)
or salts thereof.
3. A process for the preparation of edoxaban, the process comprising:
(a) reacting a compound of Formula (VI) or salts thereof, with a compound of Formula (V);

(VI) (V)
to obtain a compound of Formula (IV);

(IV)
(b) converting the compound of Formula (IV) to a compound of Formula (III);

(III)
(c) reacting the compound of Formula (III) with a compound of Formula (II),

(II)
to obtain edoxaban and optionally converting the edoxaban to its pharmaceutically acceptable salts or hydrates thereof.
4. The process according to claim 3, wherein the compound of Formula (VI) is reaction with an acid in one or more solvents to deprotect the boc protection, followed by addition of the compound of Formula (V) and a coupling reagent optionally in the presence of a base to obtain the compound of Formula (IV).
5. The process according to claim 4, wherein the acid comprises one or more of methane sulfonic acid, hydrochloric acid, trifluoro acetic acid, hydrobromic acid, sulphuric acid, pivalic acid, acetic acid and formic acid, or mixture thereof.
6. The process according to claim 3, wherein the edoxaban obtained in step (c) is converted to edoxaban tosylate monohydrate by reaction with PTSA hydrate in one or more solvents.
7. The process according to claim 4, wherein the coupling agent comprises one or more of HOBT, TBTU and DCC or mixture thereof.
8. The process according to claim 3, wherein the base comprises one or more of EDC, DMAP, TEA, TBA, DIPA, DIPEA, DBU, DABCO and DBN or mixture thereof.
9. A process for preparation of edoxaban of Formula (I), comprising:
(a) reacting a compound of Formula (VIIa) or salt thereof, with a compound of Formula (V),

(VIIa) (V)
wherein L is –OTf, –OMs, –OTs;
to obtain a compound of Formula (Va);

(Va)
(b) converting the compound of Formula (Va) to a compound of Formula (IVa);

(IVa)
wherein R is benzyl, substituted benzyl or p-toluenesulfonyl;
(c) converting the compound of Formula (IVa) to a compound of Formula (III); and

(III)
(d) reacting the compound of Formula (III) with a compound of Formula (II);

(II)
to obtain edoxaban and optionally converting edoxaban to its pharmaceutically acceptable salts or hydrates thereof.
10. The process according to claim 7, wherein the compound of Formula (IVa) in step (b) is prepared by reacting the compound of Formula (Va) with amine or amide selected from benzyl amine, substituted benzylamine, and tosylamide in the presence of a base in one or more solvents.

Dated this 10th day of April 2017.

(AAYSU MAHLA)
(IN/PA-1490)
Of SUBRAMANIAM & ASSOCIATES
Attorneys for the Applicants