DESC:CROSS-REFERENCE TO RELATED APPLICATIONS
This application claims the priority of earlier Indian provisional patent application no. 201641023903, filed on July 13, 2016, which is incorporated herein in its entirety by reference.

FIELD OF THE INVENTION
The present invention relates generally to the synthesis of active pharmaceutical agents and more specifically to the preparation of an amine-protected (1S,2R,4S)-1,2-amino-N,N-dimethylcyclohexane-4-carboxamide) camphor sulfonate, which may be an intermediate used in the synthesis of Edoxaban and pharmaceutically acceptable salts, solvates, or salt of solvates thereof. Further, the present invention further provides methods for the synthesis of this intermediate with improved purity.

BACKGROUND OF THE INVENTION
Edoxaban exhibits an inhibitory effect on activated blood coagulation factor X (FXa) and as such, is an oral anticoagulant drug used to prevent or treat thrombotic diseases. Edoxaban is marketed in the United States as SAVAYSA® and LIXIANA® by Daiichi Sankyo. Edoxaban is chemically known as N'-(5-chloropyridin-2-yl)-N-[(1S,2R,4S)-4-(dimethylcarbamoyl)-2-[(5-methyl-6,7-dihydro-4H-[1,3]thiazolo[5,4-c]pyridine-2-carbonyl)amino]cyclohexyl]oxamide and is represented by the formula below:

SAVAYSA® and LIXIANA® contain Edoxaban as monohydrate of the tosylate salt (Edoxaban tosylate monohydrate) which is represented below as Formula 1:

Formula 1

Edoxaban (and salts/solvates thereof) may be prepared by a variety of methods. One such method involves use of an intermediate as depicted below, wherein PG is an amine protecting group (herein referred to as amine-protected (1S,2R,4S)-1,2-amino-N,N-dimethylcyclohexane-4-carboxamide)

For example, U.S. Patent No. 7,365,205 discloses Edoxaban, pharmaceutical acceptable salts thereof, as well as a process for the preparation of Edoxaban using this intermediate, wherein the protecting group (PG) is Boc:

U.S. Patent No. 8,686,189 discloses this Boc-protected intermediate as well, along with acid addition salts thereof.

U.S. Patent No. 8,357,808 discloses a process for the preparation of Edoxaban using an oxalate salt of the Boc-protected intermediate:

There is a longstanding need in the field prepare an amine-protected (1S, 2R, 4S)-1,2-amino-N,N-dimethylcyclohexane-4-carboxamide intermediate with high purity. The present invention provides methods for the preparation of a substantially pure camphor sulfonate salt of amine-protected (1S,2R,4S)-1,2-amino-N,N-dimethylcyclohexane-4-carboxamide (represented by formula (X) below).

In particular embodiments, the present invention provides methods for the preparation of a camphor sulfonate salt of a Boc-protected [(1R,2S,5S)-1,2-amino-5-[(dimethylamino)carbonyl] cyclohexane] intermediate ((1S,2R,4S)-1-amino-2-(boc-amino)-N,N-dimethylcyclohexane-4-carboxamide), depicted below, with high purity.

By using the methods provided herein, high yields of amine-protected (1S,2R,4S)-1,2-amino-N,N-dimethylcyclohexane-4-carboxamide camphor sulfonate exhibiting high diastereomeric/enantiomeric purity may be achieved.

SUMMARY OF THE INVENTION
In one aspect, the present invention provides a compound of formula (X), wherein PG is an amine protecting group:

In some embodiments, the amine protecting group is a t-butyloxycarbonyl (Boc) group.
In another aspect, the present invention provides a process for the preparation of formula (X), which may include the steps of:
a) treating formula (VII) with a base in a solvent to obtain formula (VIII)
;
b) converting formula (VIII) to formula (IX)
;
c) reducing the azide of formula (IX); and
d) treating with (1R)-(-)-10-camphorsulfonic acid to obtain formula (X)
,
wherein PG is an amine protecting group.
In some embodiments, the amine protecting group is a t-butyloxycarbonyl (Boc) group.
Within the context of this embodiment, the base may be, for example (but not limited to), sodium hydroxide, potassium hydroxide, and lithium hydroxide. The solvent may be, for example, a ketone solvent, an ester solvent, acetonitrile, or mixtures thereof. Examples of suitable ketone solvents include, but are not limited to, acetone, methyl isobutyl ketone, methyl ethyl ketone, and mixtures thereof. Examples of ester solvents include, but are not limited to, ethyl acetate, isopropyl acetate, and mixtures thereof.
Within the context of the present invention, formula (X) may be further converted to Edoxaban, or a pharmaceutically acceptable salt, a pharmaceutically acceptable solvate, or a combination thereof.
In another aspect, the present invention provides a compound of formula (VIIIa), wherein PG is an amine protecting group
.
In some embodiments, the amine protecting group is a t-butyloxycarbonyl (Boc) group.
In yet another embodiment, the present invention provides a process for the preparation of formula (VIIIa). In one embodiment, formula (VIIIa) may be prepared by a process that includes treating formula (VII) with a base followed by (S)-(alpha)-phenylethylamine in the presence of a solvent
,
wherein PG is an amine-protecting group.
Within the context of this embodiment, the base may be, for example (but not limited to), sodium hydroxide, potassium hydroxide, and lithium hydroxide. The solvent may be, for example, a ketone solvent, an ester solvent, acetonitrile, or mixtures thereof. Examples of suitable ketone solvents include, but are not limited to, acetone, methyl isobutyl ketone, methyl ethyl ketone, and mixtures thereof. Examples of ester solvents include, but are not limited to, ethyl acetate, isopropyl acetate, and mixtures thereof.
Formula (VIIIa) may be further converted to formula (IX).

Within the context of this embodiment, this conversion may be carried out in a solvent. Examples of suitable solvents include, but are not limited to chlorinated solvents, ketone solvents, ester solvents, toluene, acetonitrile, and mixtures thereof.
Examples of suitable chlorinated solvents include, but are not limited to, methylene dichloride, chloroform, and mixtures thereof. Examples of suitable ketone solvents include, but are not limited to, acetone, methyl isobutyl ketone, methyl ethyl ketone, and mixtures thereof. Examples of ester solvents include, but are not limited to, ethyl acetate, isopropyl acetate, and mixtures thereof.
This conversion may be carried out with a suitable base, for example (though not limited to), triethylamine, diisopropylethylamine, diisopropylamine, or N-methylmorpholine.
Within the context of this embodiment, formula (IX) may be further converted to formula (X) by a process that includes the following steps:
a) reducing the azide of formula (IX); and
b) treating with (1R)-(-)-10-camphorsulfonic acid to obtain formula (X)
,
In some embodiments, using a t-butyloxycarbonyl group as the amine protecting group (PG) is found particularly useful.
Within the context of the present invention, Edoxaban, pharmaceutically acceptable salts, solvates, and solvated salts thereof, prepared by methods disclosed herein may be incorporated into a pharmaceutical dosage form that optionally includes further excipients.
DETAILED DESCRIPTION OF THE INVENTION
In one aspect, the present invention provides formula (X):

Within the context of this invention, “PG” is an amine-protecting group. Examples of suitable amine protecting groups, as well as suitable conditions for protecting and deprotecting, can be found in prior art, such as J. F. W. McOmie, “Protective Groups in Organic Chemistry”, Plenum Press, London and New York 1973; T. W. Greene and P. G. M. Wuts, “Protective Groups in Organic Synthesis”, Third edition, Wiley, New York 1999; “The Peptides"; Volume 3 (editors: E. Gross and J. Meienhofer), Academic Press, London and New York 1981; in “Methoden der organischen Chemie”, Houben-Weyl, 4th edition, Vol. 15/1, Georg Thieme Verlag, Stuttgart 1974; H.-D. Jakubke and H. Jescheit, “Aminosauren, Peptide, Proteine”, Verlag Chemie, Weinheim, Deerfield Beach, and Basel 1982; and Jochen Lehmann, “Chemie der Kohlenhydrate: Monosaccharide und Derivate”, Georg Thieme Verlag, Stuttgart 1974.
Amine protecting groups include, for example, -RP, =RQ, -C(O)R0, -C(O)OR0,–S(O)2R0, and 2-nitrophenylsulfenyl, wherein
RP is a –C(RP1)3, wherein each RP1 is hydrogen or optionally substituted aryl, provided that at least one RP1 is not hydrogen;
RQ is =C(H)-R0; and
R0 is hydrogen, C1-10 alkyl, C2-10 alkenyl, C1-10 haloalkyl, aryl, heteroaryl, arylalkyl, or heteroarylalkyl, wherein each alkyl, aryl, and heteroaryl group is optionally substituted.
“Optionally substituted” as used herein means the reference group is substituted by one or more groups (e.g., 1 to 5, or 1 to 3, or 1 to 2 groups, or 1 group) that are each independently halo, alkyl, alkoxy, nitro, cyano, tri(C1-3alkyl)silyl (e.g., trimethylsilyl).
Particular examples of amine protecting groups include, carbonyls (e.g., methyl carbamate, 9-fluorenylmethyoxycarbonyl (Fmoc), trichloroethoxycarbonyl (Troc), t-butoxycarbonyl (BOC), 2-trimethylsilylethyloxycarbonyl (Teoc), allyloxycarbonyl (Alloc), p-methoxybenzyl carbonyl (Moz), and carboxybenzyl (Cbz)), sulfonyls (e.g., p-toluenesufonyl (Ts), trimethylsilylethanesulfoyl (Ses), t-butylsulfonyl (Bus), 4-methoxyphenylsulfonyl, 4-nitrobenzenesulfonyl (nosyl)), trityl (trt), benzyl (Bn), 3,4-dimethyoxybenzyl (Dmpm), p-methoxybenzyl (PMB), p-methoxyphenyl (PMP), acetyl (Ac), formyl, trifluoroacetyl (Tfa), benzoyl (Bz), or 2-nitrophenylsulfenyl (Nps).
As used herein, the term “alkenyl” means a straight or branched chain hydrocarbon containing from 2 to 10 carbons, unless otherwise specified, and containing at least one carbon-carbon double bond. Representative examples of alkenyl include, but are not limited to, ethenyl, 2-propenyl, 2-methyl-2-propenyl, 3-butenyl, 4-pentenyl, 5-hexenyl, 2-heptenyl, 2-methyl-l-heptenyl, 3-decenyl, and 3, 7-dimethylocta-2,6-dienyl.
The term “alkoxy” as used herein, means an alkyl group, as defined herein, appended to the parent molecular moiety through an oxygen atom. Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, t-butoxy, pentyloxy, and hexyloxy.
The term “alkyl” as used herein, means a straight or branched chain hydrocarbon containing from 1 to 10 carbon atoms, unless otherwise specified. Representative examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, t-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 3-methylhexyl, 2,2-dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl, and n-decyl.
The term “aryl,” as used herein, means a monocyclic (i.e., phenyl), bicyclic, or tricyclic ring fused or bridged system containing at least one phenyl ring. Non-phenyl rings that are part of a bicyclic or tricyclic ring system may be fully or partially saturated, may contain one or more heteroatoms, each selected from N, S, and O, and may be optionally substituted with one or two oxo and/or thio groups. Examples of aryl groups include phenyl, napthyl, anthracenyl, and fluorenyl.
The term “arylalkyl” as used herein, means an aryl group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of arylalkyl include, but are not limited to, benzyl, 2-phenylethyl, 3-phenylpropyl, fluorenylmethyl and 2-naphth-2-ylethyl.
The term “halo” or “halogen” as used herein, means -Cl, -Br, -I, or -F.
The term “haloalkyl” as used herein, means at least one halogen, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of haloalkyl include, but are not limited to, chloromethyl, 2-fluoroethyl, trifluoromethyl, pentafluoroethyl, perfluorononyl, and 2-chloro-3-fluoropentyl.
The term “heteroaryl,” as used herein, means a monocyclic, bicyclic, or tricyclic ring system containing at least one heteroaromatic ring. Any additional rings that are part of a bicyclic or tricyclic ring system may be fully or partially saturated or may be aromatic rings, and each may optionally contain one or more heteroatoms, each selected from N, S, and O. Representative examples of monocyclic and bicyclic heteroaryl include, but are not limited to, furyl, imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, oxazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolyl, pyrrolyl, tetrazolyl, thiadiazolyl, thiazolyl, thienyl, triazolyl, triazinyl, benzimidazolyl, benzofuranyl, benzothienyl, benzoxadiazolyl, benzoxathiadiazolyl, benzothiazolyl, cinnolinyl, dihydroquinolinyl, furopyridinyl, indazolyl, indolyl, isoquinolinyl, naphthyridinyl, quinolinyl, purinyl, and tetrahydroquinolin-yl.
The term “heteroarylalkyl” as used herein, means a heteroaryl, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of heteroarylalkyl include, but are not limited to, furylmethyl, imidazolylmethyl, pyridinylethyl, pyridinylmethyl, pyrimidinylmethyl, and thienylmethyl.
The term “oxo” as used herein means a =O group. The term “thio” as used herein means a =S group.
In some embodiments, use of a t-butyloxycarbonyl (Boc) protecting group is found to be particularly useful as an amine-protecting group.
Another aspect of the present invention provides a process for the preparation of formula (X).
In one embodiment, formula (X) may be prepared by a process that includes the steps of:
a) treating formula (VII) with a base to obtain formula (VIII)


b) converting formula (VIII) to formula (IX)

c) reducing the azide of formula (IX); and
d) treating with (1R)-(-)-10-camphorsulfonic acid to obtain formula (X).

According to this embodiment, formula (VIII) may formed by treating formula (VII) with a base. Examples of suitable bases include sodium hydroxide, potassium hydroxide, and lithium hydroxide.
This reaction may be carried out in a suitable solvent, for example, an organic solvent. Examples of suitable organic solvents include, but are not limited to, acetonitrile, ketones, esters, or mixtures thereof. Examples of suitable ketones include, but are not limited to, acetone, methyl isobutyl ketone (MIBK), methyl ethyl ketone (MEK), and mixtures thereof. Examples of suitable esters include, but are not limited to, ethyl acetate, isopropyl acetate, and mixtures thereof.
Next, formula (VIII) may be converted to formula (IX). This may be carried out using a “direct conversion” or a “two-step conversion.”
Direct Conversion

In one embodiment, formula (VIII) may be converted directly to formula (IX) by treating formula (VIII) with a base. Examples of suitable bases include, but are not limited to, triethylamine, diisopropylethylamine, diisopropylamine, and N-methylmorpholine. This reaction may be carried out in a suitable solvent. Example of suitable solvents include, but are not limited to, chlorinated solvents, ketone solvents, ester solvents, toluene, acetonitrile, or mixtures thereof. Examples of suitable chlorinated solvents include, but are not limited to, methylene dichloride, chloroform, and mixtures thereof. Examples of suitable ketone solvents include, but are not limited to, acetone, methyl isobutyl ketone (MIBK), methyl ethyl ketone (MEK), and mixtures thereof. Examples of suitable ester solvents include, but are not limited to, ethyl acetate, isopropyl acetate, and mixtures thereof.
Two-Step Conversion

In one embodiment, formula (VIII) may be converted to formula (IX) by first converting formula (VIII) to formula (VIIIa). This may be carried out by treating formula (VIII) with (S)-(alpha)-phenylethylamine. This may be carried out in a suitable solvent, for example (but not limited to), acetonitrile, a ketone solvent, an ester solvent, or mixtures thereof. Examples of suitable ketones include but are not limited to, acetone, methyl isobutyl ketone (MIBK), methyl ethyl ketone (MEK), and mixtures thereof. Examples of suitable esters include, but are not limited to, ethyl acetate, isopropyl acetate, and mixtures thereof.
Next, formula (VIIIa) may be converted to formula (IX). This may be performed using a base. Examples of suitable bases include, but are not limited to, triethylamine, diisopropylethylamine, diisopropylamine, and N-methylmorpholine. This reaction may be carried out in a solvent. Suitable solvents include, but are not limited to, acetonitrile, toluene, chlorinated solvents (e.g., methylene dichloride, chloroform, and mixtures thereof), ketones (e.g., acetone, methyl isobutyl ketone (MIBK), methyl ethyl ketone (MEK), and mixtures thereof), esters (e.g., ethyl acetate, isopropyl acetate, and mixtures thereof), and mixtures thereof.
Formula (IX) may then be reduced. Reduction may be carried out by methods well known in the art. For example, this reduction may be achieved by hydrogenation according to methods and reaction conditions well known to one of skill in the art. For example, hydrogenation may be carried out by bubbling hydrogen into the reaction mixture containing palladium on carbon (Pd/C) in an alcoholic solvent such as methanol, ethanol, isopropanol, or mixtures thereof.
Subsequent treatment with a (1R)-(-)-10-camphorsulfonic acid in a suitable organic solvent may then generate formula (X). Examples of suitable organic solvents include, but are not limited to, acetonitrile, ketones, esters, and mixtures thereof. Examples of suitable ketones include, but are not limited to, acetone, methyl isobutyl ketone (MIBK), methyl ethyl ketone (MEK), and mixtures thereof. Examples of suitable esters include, but are not limited to, ethyl acetate, isopropyl acetate, and mixtures thereof.

Within the context of the present invention, formula (X) may be converted to Edoxaban, salts, solvates, or solvated salts thereof. For example, formula (X) may be condensed with ethyl 2-[5-chloropyridin-2-ylamino]-2-oxoacetate to get formula XI. Upon condensation with 5-methyl-4,5,6,7-tetrahydrothiazolo-[5,4-c]pyridine-2-carboxylic acid hydrochloride, formula XI may be converted to Edoxaban free base. Edoxaban tosylate monohydrate may then be formed by treating Edoxaban free base with p-toluenesulfonic acid. This set of reactions is depicted as Scheme I below:

Scheme I
Within the context of the present invention, formula (VII) may be prepared by prior art methods, for example, by a series of reactions depicted in Scheme 2 below:

Scheme 2
Within the context of this invention, “ PG' ” in formula VI is a hydroxy protecting group.
Examples of suitable hydroxy protecting groups, as well as suitable conditions for protecting and deprotecting, can be found in prior art, such as J. F. W. McOmie, “Protective Groups in Organic Chemistry”, Plenum Press, London and New York 1973; T. W. Greene and P. G. M. Wuts, “Protective Groups in Organic Synthesis”, Third edition, Wiley, New York 1999; “The Peptides"; Volume 3 (editors: E. Gross and J. Meienhofer), Academic Press, London and New York 1981; in “Methoden der organischen Chemie”, Houben-Weyl, 4th edition, Vol. 15/1, Georg Thieme Verlag, Stuttgart 1974; H.-D. Jakubke and H. Jescheit, “Aminosauren, Peptide, Proteine”, Verlag Chemie, Weinheim, Deerfield Beach, and Basel 1982; and Jochen Lehmann, “Chemie der Kohlenhydrate: Monosaccharide und Derivate”, Georg Thieme Verlag, Stuttgart 1974. In some embodiments, mesylate is used as a hydroxy protecting group.
In addition to converting Edoxaban free base to the Edoxaban tosylate monohydrate, Edoxaban may be converted to a number of other pharmaceutically acceptable salts, which are well-known in the art. Methods for converting compounds into their acid salt forms are also well known in the art, and may be carried out, for example, by reacting a free base moiety on Edoxaban with a suitable reagent.
Examples of suitable acids include, for example, inorganic acids or organic acids. Examples of suitable inorganic acids include hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid. Suitable organic acids include, for example, acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, and malonic acid. A pharmaceutically acceptable salt may alternatively be prepared by other methods well known in the art, for example, ion exchange. Additional examples of suitable salts include, for example, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, (R,S)-malate, (S)-malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, phthalate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, and valerate salts.
In particularly useful embodiments of the present invention, Edoxaban or salts, solvates, or solvated salts thereof may be prepared using formula VIII by way of Scheme 3 below, where the amine-protecting group, introduced in formula V, is a t-butyloxycarbonyl (Boc) and the hydroxy protecting group, introduced in formula VI, is a mesylate (Ms) group:

Scheme 3
In another aspect, the present invention provides formula (VIIIa), which, as depicted above, may be useful for the preparation of formula IX.

When prepared by methods disclosed herein, formula (X) may be prepared with high purity. In some embodiments, when prepared by the methods disclosed herein, formula (X) may display a purity of more than 99% and enantiomeric excess (ee) of greater than 99.5%. Preparation of the formula (X) intermediate with high purity and yield may, in some embodiments, result in increased purity and yield of subsequent intermediate (e.g., formula (XI)) and increased purity and yield of the final Edoxaban and pharmaceutically acceptable salts, solvates, or solvated salts thereof. For example, the table below provides yield and purity measurements for formula (X), wherein the PG=Boc along with each successive intermediate, as well as the final product prepared by embodiments of methods disclosed herein.
Compound Yield (%) Purity by HPLC
Formula (X), where PG=Boc 72 % 99.2%;
(ee): 99.9%
Formula (XI), where PG=Boc 77% > 99%
Edoxaban 85% > 99%
Edoxaban Tosylate Monohydrate (Formula I) 75% 99.7%

HPLC Method:

Column : X Bridge BEH C18, 100x4.6mm, 2.5 µm
Detector : UV at 290 nm
Flow rate : 0.8 mL/minute
Injection volume : 10 µL
Column oven temp. : 30 °C
Acquisition time : 30 minutes
Run time : 40 minutes
Diluent : Acetonitrile : Water (1:1 v/v)

Buffer Preparation:

Dissolve 1.54 Ammonium Acetate into 1000 mL of water and adjust the pH to 5.00 0.05 with dilute Acetic acid solution. Filter through 0.22 µm membrane and degas.

Mobile phase-A: Buffer

Mobile phase-B: Transfer about 800 mL of Acetonitrile by using a 1000 mL measuring cylinder and 200 mL of Methanol by using a 250 mL (or) 500 mL measuring cylinder into a mobile phase bottle, mix thoroughly to form a uniform mixture of Acetonitrile : Methanol (80:20) v/v and degassed.

The Edoxaban and pharmaceutical salts, solvates, or solvated salts thereof disclosed herein and prepared by the disclosed methods may be used to formulate an oral dosage form, such as a tablet or a capsule. When administered to patients, the Edoxaban or pharmaceutical salts thereof of the present invention may be useful to reduce the risk of stroke and systemic embolism in patients with non-valvular atrial fibrillation, in the treatment of deep vein thrombosis, pulmonary embolism, or any combination thereof.
The Edoxaban and pharmaceutical salts, solvates, or solvated salts thereof (e.g., Edoxaban tosylate monohydrate) as disclosed and prepared herein may be formulated into a tablet which may contain inactive ingredients such as mannitol, pregelatinized starch, crospovidone, hydroxypropyl cellulose, magnesium stearate, talc, carnauba wax, or mixtures thereof. The tablet may, in some embodiments, be coated with a film that includes additional excipients, artificial colors, and flavors. For example, a coating may contain hypromellose, titanium dioxide, talc, polyethylene glycol 8000, iron oxide yellow, iron oxide red, and mixtures thereof. One of skill in the art will be familiar with a variety of excipients and formulations that may be used to prepare desirable dosage forms with desired release characteristics and pharmacokinetic properties without undue experimentation.
In some embodiments, the tablets may contain Edoxaban, pharmaceutical salts, solvates, or solvated salts thereof at an effective amount of between 15 mg and 60 mg. In particularly useful embodiments, the tablets have 15 mg, 30 mg, or 60 mg of effective Edoxaban. Within the context of this invention, an effective amount refers to the amount of active Edoxaban included within the dosage form. In some embodiments when a salt of Edoxaban is used, the salt may be included in the dosage form at a higher weight to achieve the nominal effective concentration. For example, 20.2 mg of Edoxaban tosylate monohydrate may be included in a dosage form, resulting in a dosage form with an effective amount of 15 mg Edoxaban.
Certain specific aspects and embodiments of the present application will be explained in greater detail with reference to the following examples, which are provided only for purposes of illustration and should not be construed as limiting the scope of the disclosure in any manner. In view of the above description and the examples below, one of ordinary skill in the art will be able to practice the invention as claimed without undue experimentation. The foregoing will be better understood with reference to the following examples that detail certain procedures for the preparation of molecules according to the present invention.
All references made to these examples are for the purposes of illustration. The following examples should not be considered exhaustive, but merely illustrative of only a few of the many aspects and embodiments contemplated by the present disclosure.
EXAMPLES:

Example 1: Preparation of formula (II):

(S)-(-)-3-cyclohexenecarboxylic acid (100 g, 0.793 moles) was added to N-bromosuccinimide (145.3 g, 0.816 moles) and sodium hydroxide (0.5 g, 0.012 moles) in ethyl acetate (200 ml) at room temperature and was stirred for 3 hours. Then reaction mass was distilled under reduced pressure, water (500 ml) was added, and the reaction mass was heated to 75 °C. The obtained mixture was then filtered to obtain a solid which was dried under atmospheric pressure at 50 °C to get formula (II) as an off white solid (140 g, yield: 86%).
Example 2: Preparation of formula (III):

Formula (II) (10 g) was dissolved in ethanol (50 ml). Potassium carbonate (6.59 g) was added to this solution at 75 °C. The mixture was heated to maintain the temperature at 75 °C for 2 hours and then allowed to cool to room temperature. The precipitate was filtered off and the filtrate was concentrated under reduced pressure. A mixture of ethyl acetate (80 ml) and water (20 ml) was added to the obtained residue and the aqueous and organic layers were separated. The organic layer was then dried over anhydrous sodium sulfate (5 g) and the solvent was distilled off under reduced pressure to obtain formula (III) as a pale yellow oil (5.5 g).
Example 3: Preparation of formula (IV):

A mixture formula (III) (5.0 g), ethanol (25 ml), and ammonia (25 ml) was stirred at 45 °C for 24 hours. The reaction mass was distilled under reduced pressure to obtain formula (IV) as an oily mass (6.0 g).

Example 4: Preparation of formula (V):

Boc-anhydride was added to a mixture of formula (IV) (5 g) in water (40 ml) cooled with ice. The reaction mass was stirred at room temperature for 2 hours. After completion of the reaction, ethyl acetate was added. The organic layer was separated from the aqueous layer then distilled under reduced pressure to remove the solvent and obtain an oily mass. The obtained oily mass was crystalized with hexanes to obtain formula (V) as a solid (4 g).
Example 5: Preparation of formula (VI):

Triethylamine (5.84 g) and methane sulfonyl chloride (4.28 g) were simultaneously added to a stirred solution of formula (V) (10 g) in acetone (50 ml) at 15-20 °C. The temperature of the reaction mixture was maintained for 90 mins. After completion of the reaction, water (25 ml) was added to the reaction mixture. Then, the mixture was filtered to obtain a precipitate which was dried under reduced pressure to get formula (VI) as an off-white solid (10.5 g).
Example 6: Preparation of formula (VII):

Sodium azide (8.87 g, 0.054 moles) and benzyltriethylammonium chloride was added to a solution of formula (VI) (10g, 0.027 moles) in N, N-dimethyl formamide (20 ml) and stirred at 55-60 °C for 48 hours. After completion of the reaction, the reaction mixture was cooled the reaction to room temperature and water (40 ml) was added and stirred for 4 hours. The mixture was filtered to obtain a precipitate which was washed with water then dried under reduced pressure to obtain formula (VII) as a solid (6.5 g, yield: 76%).
Example 7: Preparation of formula (VIII):

A solution of lithium hydroxide (3.226 g) dissolved in water (20 ml) was added to a stirred solution of formula (VII) (20 g) and water (100 ml) at room temperature. Then, the reaction mixture was stirred for 18 hours at the same temperature. After completion of reaction, the pH of the solution was adjusted to 4.0-4.5 by using aqueous citric acid solution. A precipitate formed and the mixture was filtered to isolate the solid, which was then dried under reduced pressure to get Formula (VIII) as a solid (16 g).
Example 8:
a. Direct conversion of formula (VIII) to formula (IX):

Triethylamine (74.83 g, 0.738 moles) was added to a solution of formula (VIII) (70 g, 0.246 moles) in methylene dichloride (350 ml) and the solution was cooled to -5 to -10 °C. Pivaloyl chloride (29.66 g, 0.246 moles) was then slowly added dropwise and the reaction was maintained at the same temperature for 90 minutes. Dimethylamine hydrochloride (24.07 g, 0.295 moles) was then added lot wise and the reaction mixture was maintained for 4 hours. After completion of the reaction, water (350 ml) was added and the layers were separated. The organic layer was subjected to distillation under reduced pressure to remove organic solvent to obtain an oily mass. Isopropyl ether (350 ml) was added to the oily mass and the mixture was stirred for 4 hours at room temperature then cooled to 5-10 °C. The mixture was then filtered to isolate a solid which was dried under reduced pressure to get formula (IX) as a solid (60 g, yield: 78.2%).
b. Two-step conversion of formula (VIII) to formula (IX).
Conversion of formula (VIII) to formula (VIIIa):

A solution of (S)-(alpha)-phenylethylamine (6.14 g; 0.05 moles) dissolved in acetone (160 ml) was added to a stirred solution of formula (VIII) (16g, 0.056 moles) in acetone (48 ml) at room temperature. The reaction mixture was stirred for 16 hours, filtered, and the obtained solid was dried under reduced pressure to get Formula (VIIIa) (16 g).
Conversion of formula (VIIIa) to formula (IX):

Triethylamine (52.34 g, 0.518 moles) was added to a solution of formula (VIIIa) (70 g, 0.172 moles) in methylene dichloride (350 ml) and the solution was cooled to -5 to -10 °C. Pivaloyl chloride (24.87 g, 0.206 moles) was slowly added dropwise and the reaction mass was maintained at the same temperature for 90 minutes. Dimethylamine hydrochloride (16.90 g, 0.206 moles) was then added lot wise and the reaction mass was maintained at the same temperature for 4 hours. After completion of the reaction, water (350 ml) was added and the organic and aqueous layers were separated. The organic layer was distilled under reduced pressure to remove the solvent and obtain an oily mass. Isopropyl ether (350 ml) was added to the oily mass and the mixture was stirred for 4 hours at room temperature then cooled to 5-10 °C to form a solid. The mixture was filtered to isolate a solid which was dried under reduced pressure to get formula (IX) as a solid (40 g, yield: 74.4%).
Example 9: Preparation of formula (X):

10% Pd/C (0.75g, 5% loading) was added to a solution of formula (IX) (15 g, 0.048 moles) in methanol (120 ml) purged with hydrogen gas (3 kg/cm3) and stirred for 8 hours at room temperature. After completion of the reaction, the reaction mass was filtered through Hyflo and the filtrate was concentrated under reduced pressure to get an oily mass. The oily mass was then dissolved in acetone (150 ml) and a solution of (1R)-camphorsulfonic acid (9.5 g, 0.040 moles) in acetone (45 ml) was added slowly at room temperature. The reaction mass was then stirred for 15 hours. The reaction mass was filtered and the obtained solid was dried under reduced pressure at 50 °C for 4 hours to get formula (X) as white solid (18.0 g, yield: 72%; HPLC Purity: 99.7%; ee: 99.9%).

Example 10: Preparation of formula (XI):

Triethylamine (16.86 ml, 0.049 moles) was added to a solution of formula (X) (10.0g, 0.019 moles) in acetonitrile (55 ml) at 60 °C. Ethyl 2-[5-chloropyridin-2-ylamino]-2-oxoacetate (5.3 g, 0.023 moles) was then added at same temperature and reaction mass was maintained for 6 hours. After 6 hours, the reaction mixture temperature was allowed to decrease to room temperature and then was stirred for 16 hours. The reaction mixture was further cooled to 5-10 °C and stirred for 90 minutes to obtain formula (XI) as a white precipitate. (7.0 g, yield: 77%, HPLC Purity: >99%).
Example 11: Preparation of Edoxaban:

A solution of formula (XI) (7.0 g, 0.014 moles) in methylene dichloride (56 ml) and methane sulfonic acid (4.85 ml, 0.074 moles) was stirred for 2 hours at room temperature. After completion of the reaction, triethylamine (15.63 ml, 0.112 moles), 5-methyl-4,5,6,7-tetrahydrothiazolo-[5,4-c] pyridine-2-carboxylic acid hydrochloride (3.86 g, 0.0164 moles), N-(3-dimethylaminopropyl)-N’-ethylcarbodiimide hydrochloride (3.44 g, 0.017 moles), and 1-hydroxybenzotriazole (2.43 g, 0.0158 moles) was added while the reaction mixture was cooled with ice. The reaction mixture was stirred for 18 hours at room temperature after which water (35 ml) and methylene dichloride (70 ml) was added. The layers were separated the layers and organic layer was concentrated under reduced pressure to get Edoxaban as a solid (7.0 g, yield: 85%, HPLC Purity: >99%).
Example 12: Preparation of Edoxaban Tosylate (Formula 1):

P-toluenesulfonic acid (1.73 g) was added to a stirred solution of Edoxaban (5.0 g), methylene dichloride (5 ml), and ethanol (85 ml). The mixture was distilled under atmospheric pressure and water (12.5 ml) was added and the mixture was heated to 70-75 °C to obtain a clear solution. The reaction mixture was cooled to room temperature and stirred for 16 hours. The solution was filtered to obtain a white precipitate, which was washed with ethanol (5 ml) then dried under reduced pressure at room temperature to obtain Formula 1 (5.0 g, yield: 75%, HPLC Purity: 99.7%).
,CLAIMS:We claim:
1. A compound of formula (X)

wherein PG is an amine protecting group.
2. A process for the preparation of formula (X), comprising the steps of:
a.) treating formula (VII) with a base in a solvent to obtain formula (VIII)
;
b.) converting formula (VIII) to formula (IX)
;
c.) reducing the azide of formula (IX) and treating with (1R)-(-)-10-camphorsulfonic acid to obtain formula (X)
,
wherein PG is an amine protecting group.

3. A compound of formula (VIIIa)

wherein PG is an amine protecting group

4. A process for the preparation of formula (VIIIa), comprising treating compound of formula (VII) with a base followed by (S)-(alpha)-phenylethylamine in the presence of a solvent.
,
wherein PG is an amine-protecting group.
5. The process according to claim 5, further comprising the step of:
a.) converting formula (VIIIa) to formula (IX)
,
b.) reducing the azide of formula (IX) and treating with (1R)-(-)-10-camphorsulfonic acid to obtain formula (X)
,
wherein PG is an amine protecting group.

6. The compound of preceding claims 1 to 5, wherein the amine protecting group is a t-butyloxycarbonyl (Boc) group.
7. The process of claim 2 or 4,, wherein the base is selected from the group consisting of sodium hydroxide, potassium hydroxide, and lithium hydroxide.
8. The process of claim 2 or 4, wherein the solvent is selected from the group consisting of ketone solvents, ester solvents, acetonitrile, and mixtures thereof.
9. The process of claim 2 or 5, further comprises converting compound of formula (X) to Edoxaban or it’s pharmaceutically acceptable salts, solvate, or a combination thereof.

10. A pharmaceutical composition comprising Edoxaban or its pharmaceutically acceptable salts, prepared by the process of claim 2, or claim 5.