DESC:Field of Invention
The present invention relates to improved processes for preparing N-(5-chloro-2-pyridinyl)-2-{[4-(N,N-dimethylcarbamimidoyl)benzoyl]amino}-5-methoxybenzamide , i.e., Betrixaban or salts thereof as well as to the synthesis of intermediates useful for preparing the same.
Background of the Invention
The present invention is directed to processes for preparing N-(5-chloro-2-pyridinyl)-2-{[4-(N,N-dimethylcarbamimidoyl)benzoyl]amino}-5-methoxybenzamide, i.e., Betrixaban and intermediates thereof. Also the present invention relates to processes for preparing pharmaceutically acceptable salts of Betrixaban.
Betrixaban maleate, a factor Xa inhibitor approved by USFDA in June, 2017 in the form of oral capsules (40mg and 80 mg) under the proprietary name BEVYXXA® has a molecular formula C27H26ClN5O7 and is represented as follows:

Betrixaban is indicated for the prophylaxis of venous thromboembolism (VTE) in adult patients hospitalized for an acute medical illness who are at risk for thromboembolic complications due to moderate or severe restricted mobility and other risk factors for VTE.
Factor Xa, a serine protease, plays an important role in the blood coagulation pathway. Direct inhibition of factor Xa has been considered to be an efficient anticoagulant strategy in the treatment of thrombotic diseases.
U.S. Patent No. 6,376,515 discloses a class of benzamide based compounds as specific factor Xa inhibitors, particularly it discloses the compound Betrixaban under Example 206, represented by a compound of Formula V:

U.S. Patent No. 6,844,367 discloses a process for synthesizing Betrixaban by condensation of 2-amino-N-(5-chloropyridin-2-yl)-5-methoxybenzamide with 4-cyanobenzoyl chloride followed by pinner reaction and further treating the resulting compound with dimethylamine to form betrixaban free base. The process disclosed however involves the use of corrosive chemicals and harsh conditions and has shown to give a low yield with high number of impurities.
U.S. Patent No. 8,394964 discloses a process for the synthesis of Betrixaban, or a salt thereof by condensation of 2-amino-N-(5-chloropyridin-2-yl)-5-methoxybenzamide with 4-(N,N-dimethylcarbamimidoyl)benzoic acid, under reaction conditions comprising N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride to form betrixaban or a salt thereof.
U.S. Patent No. 8,524,907 discloses another process for preparing Betrixaban comprising contacting lithium dimethyl amide with N-(5-chloro-pyridin-2-yl)-2-(4-cyano-benzoyl-amino)-5-methoxybenzamide or a salt thereof, wherein lithium dimethyl amide is prepared by contacting dimethylamine with alkyllithium selected from n-butyllithium, tert-butyllithium, or hexyllithium.
Chinese patent publication No. CN105732490 A describes a process for preparing Betrixaban comprising reacting 5-Methoxy-isatoic anhydride and 2-amino-5-chloropyridine to yield 2-amino-N-(5-chloropyridin-2-yl)-5-methoxybenzamide, treating with 4-cyanobenzoyl chloride, followed by amidine formation in the presence of dimethylamine and n-hexyllithium.
Prior art processes known to date are operationally inconvenient, often requiring multiple steps, multiple purifications, and multiple reaction vessels. Hence, there is a need to develop an improved process for the preparation of betrixaban.
The present invention intends to provide improved user-friendly, industrially scalable, economical processes to synthesize Betrixaban in high yields and with a high degree of chemical purity.
Object of Invention
An object of the invention is to provide improved, industrially scalable, economical processes for the preparation of N-(5-chloro-2-pyridinyl)-2-{[4-(N,N-dimethylcarbamimidoyl)benzoyl]amino}-5-methoxybenzamide, i.e. Betrixaban or salts thereof.
Another object of the invention is to provide novel compounds useful as intermediates for preparing Betrixaban and preparation process thereof.
Summary of the Invention
The present invention is directed to industrially scalable, economical processes for preparing factor Xa inhibitors, preferably benzamide compounds, useful for the treatment of thrombotic diseases. More particularly, the present invention relates to alternative, improved processes for preparation of N-(5-chloro-2-pyridinyl)-2-{[4-(N,N-dimethylcarbamimidoyl)benzoyl]amino}-5-methoxybenzamide (Betrixaban) or pharma -ceutically acceptable salts thereof.
In one embodiment, the present invention provides a process for preparing N-(5-chloro-2-pyridinyl)-2-{[4-(N,N-dimethylcarbamimidoyl)benzoyl]amino}-5-methoxyb -enzamide i.e., Betrixaban represented by a compound of formula V or pharmaceutica -lly acceptable salts thereof, comprising the following steps:
(a) Subjecting compound I to reduction to form compound II;

Wherein R is hydrogen or a C1-C4 alkyl, C2-C4 alkenyl, unsubstituted or substituted phenyl group with nitro, alkyl, alkoxy or halogen,
(b) Contacting compound II with 4-cyanobenzoyl chloride to form compound III;

(c) Converting compound III by reacting with a suitable reagent to form compound IV;

(d) Coupling compound IV with 2-amino-5-chloropyridine under reaction conditions to form betrixaban free base;

(e) Optionally converting betrixaban free base into pharmaceutically acceptable salts.
In a second embodiment, the improved processes of present invention for preparing Betrixaban or pharmaceutically acceptable salts thereof, provides a novel compound useful as an intermediate represented by formula IV,

Wherein R is defined as hereinbefore.
In a third embodiment, the present invention provides one process for preparing compound IV, comprising reacting compound III with alcoholic hydrochloric acid, followed by treating with dimethylamine, wherein compound III undergoes pinner reaction to form an amidine compound IV;

In a fourth embodiment, the present invention provides a second process for preparing compound IV, comprising reacting compound III with an amine in Grignard reagent under reaction conditions to form compound IV;

In a fifth embodiment, the present invention provides a third process for preparing compound IV, comprising reacting compound III with lithium dimethyl amide under reaction conditions to form compound IV;
.
Detailed Description of the Invention
The present invention is directed to industrially viable processes for preparing Betrixaban or pharmaceutically acceptable salts thereof and intermediates thereof.
In an embodiment, the process of present invention for preparing Betrixaban, represented by a compound of formula V, comprises coupling a compound of formula IV with 2-amino-5-chloropyridine under reaction conditions,

Wherein in compound of formula IV, R is hydrogen, C1-C4 alkyl, C2-C4 alkenyl, unsubstituted or substituted phenyl group with nitro, alkyl, alkoxy or halogen.
In the present context, the reaction conditions comprise use of coupling reagent. Examples of coupling reagent include without limitation, phosphorous oxychloride (POCl3), carbonyldiimidazole (CDI), carbodiimides such as N,N’-dicyclohexylcarbodiimide (DCC), N,N’-diisopropylcarbodiimide (DIC), N-(3-dimethylaminopropyl)-N’-ethylcarbodiimide (EDC).The carbodiimides may be used in conjunction with additives such as dimethylaminopyridine (DMAP) or 1-hydroxybenzo -triazole (HOBt). Other amide coupling reagents include N-[(dimethylamino)-1H-1,2,3-triazolo[4,5-b]pyridine-1-ylmethylene]-N-methylmethanaminium hexafluorophosphate N-oxide (HATU), N-[(1H-benzotriazol-1-yl)(dimethylamino)methylene]-N-methylmetha -naminiumhexafluorophosphate N-oxide (HBTU), O-(Benzotriazol-1-yl)-N,N,N',N'-tetramethyluroniumtetrafluoroborate(TBTU) and benzotriazol-1-yl-N-oxy-tris(pyrrolid-ino)phosphoniumhexafluorophosphate (PyBOP).
The reaction conditions may include a solvent selected from acetonitrile, dichloromethane, dimethylformamide, ethyl acetate, tetrahydrofuran, or mixtures thereof, and may also include an organic base such as pyridine, diisopropylamine, diisopropylethylamine (DIEA), dimethylaminopyridine (DMAP) or mixtures thereof. The reaction may be carried out at a temperature of about 10°C to room temperature.
In one embodiment, where R is hydrogen, the reaction proceeds by coupling compound IV i.e., 2-(4-amidinobenzamido)-5-methoxybenzoic acid with 2-amino-5-chloropyridine under reaction conditions to form betrixaban free base.
In another embodiment, where R is a group other than hydrogen, the reaction proceeds by first subjecting the compound IV to hydrolysis, followed by coupling with 2-amino-5-chloropyridine under reaction conditions to form betrixaban free base.
In the present context, hydrolysis may be carried out in the presence of a base such as lithium hydroxide, sodium hydroxide, potassium hydroxide, or water; or in presence of an acid such as hydrochloric acid, trifluoroacetic acid and the like.
In another embodiment, the processes of present invention for preparing compound IV comprises reacting compound III with a suitable reagent under reaction conditions to form compound IV.
In an embodiment, the reaction conditions comprise standard pinner reaction conditions, wherein compound III is reacted with an alcohol such as methanol or ethanol, in presence of an acid, such as HCl to form an intermediate IIIa, which is further treated with dialkylamine to form compound IV. The reaction may be carried out at a temperature of about 0°C to 10°C using solvents selected from acetonitrile, dichloromethane, dimethylformamide, ethyl acetate, tetrahydrofuran, or mixtures thereof.

In preferred embodiments, compound III is treated with methanolic HCl, followed by addition of dimethylamine in tetrahydrofuran to form compound IV.
In another embodiment, compound III is reacted with a dialkylamine in Grignard reagent to form compound IV, wherein dialkylamine is selected from dimethylamine, diethylamine, dipropylamine, diisopropylamine, and methyl ethyl amine. Grignard reagent (RMgX) is selected from methylmagnesium chloride, methylmagnesium bromide, isopropylmagnesium chloride, isopropylmagnesium bromide.

The reaction conditions comprise use of a solvent selected from tetrahydrofuran, diethyl ether, dioxane, hexane, methyl tert-butyl ether, heptane, cyclohexane or mixtures thereof. The reaction may be carried out a temperature of about -15°C to 25°C. In preferred embodiments, compound III is reacted with a solution of dimethylamine in isopropyl magnesium bromide to form compound IV.
In another embodiment, compound III is reacted with lithium dimethylamide under reaction conditions to form compound IV, wherein lithium dimethylamide is formed by reacting dimethylamine with an alkyl lithium. The reaction may be carried out using solvents selected from tetrahydrofuran, diethyl ether, dimethoxymethane, dioxane, hexane, methyl tert-butyl ether, heptane, cyclohexane, and mixtures thereof. In preferred embodiments, alkyl lithium is selected from n-butyllithium, tert-butyllithium, or hexyllithium.

In yet another embodiment, the process of the present invention for preparing compound III comprises contacting compound II with 4-cyanobenzoyl chloride under reaction conditions, wherein R is defined as hereinbefore.

In the present context, the reaction conditions comprise use of triethylamine, pyridine, sodium carbonate, sodium hydrogen carbonate, and solvents selected from dichloromethane, chloroform, tetrahydrofuran and the like. In an embodiment, 4-cyanobenzoyl chloride may be prepared according to methods known in the art.
According to the present invention, 4-cyanobenzoyl chloride may be prepared by treating the corresponding acid with a chlorinating agent such as thionyl chloride in suitable solvent selected from tetrahydofuran, dichloromethane, dioxane, toluene and the like.
In a further embodiment, the process of present invention for preparing compound II comprises subjecting compound I to reduction under reaction conditions,

Wherein R is defined as hereinbefore.
In some embodiments, compound I (where R = H) may be subjected to reduction first followed by protecting the carboxyl group by esterification to form compound II (where R ? H).
In some other embodiments, the compound I (where R = H) may be subjected to esterification first, followed by reducing nitro group using suitable reducing agent to form compound II (where R ? H).
In present context, reduction may be carried out using reducing agents selected from Fe/NH4Cl, Zn/NH4Cl, Fe/HCl, Zn/HCl, SnCl2, Raney Ni/H2 and Pd/C/H2. In preferred embodiments, reduction is carried out by hydrogenation using 5% Pd/C. The reaction may be carried out at room temperature, and using solvent selected from dichloromethane, ethanol, methanol, ethyl acetate, tetrahydrofuran.
In preferred embodiments, esterification may be carried out using methanol or ethanol.
In another embodiment, the process of the present invention for preparing N-(5-chloro-2-pyridinyl)-2-{[4-(N,N-dimethylcarbamimidoyl)benzoyl]amino}-5-methoxy benzamide i.e., Betrixaban results into a novel compound, useful as an intermediate, represented by a compound of formula IV,

Wherein R is hydrogen, C1-C4 alkyl, C2-C4 alkenyl, unsubstituted or substituted phenyl with nitro, alkyl, alkoxy or halogen. In preferred embodiments, R is methyl, ethyl, tert-butyl, and benzyl.
In one embodiment, the compounds/intermediates from the processes of the present invention may be formed as free acid/base or salts thereof.
In another embodiment, the processes of the present invention may be optionally carried out in a single pot, without the isolation of the intermediates or salts thereof. Alternatively, the intermediates or their salts formed may be isolated and used in subsequent reactions.
In yet another embodiment, the present invention provides processes for preparing pharmaceutically acceptable salts of Betrixaban, wherein the salts include acid addition salts or base addition salts. Examples of acid addition salts include salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, and organic acids such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicyclic acid and the like.
Examples of base addition salts include salts formed from inorganic bases such as sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like.
In an embodiment, the process of present invention for preparing Betrixaban salts comprises: a) dissolving betrixaban free base in a suitable solvent; b) adding free acid or a base to the above solution; c) isolating the precipitated salt, and d) optionally drying the resulting salt.
In an embodiment, the process of present invention for preparing Betrixaban may be represented in Scheme-1.

In another embodiment, the process of present invention for preparing Betrixaban may be represented in Scheme-2.
Further the process for preparing Betrixaban and intermediates thereof according to the present invention are illustrated in the following examples. The following specific and non-limiting examples are to be construed as merely illustrative, and do not limit the present disclosure in any way whatsoever.
Examples:
Example 1: Preparation of 2-amino-5-methoxybenzoic acid
In an autoclave vessel, was charged 5-methoxy-2-nitrobenzoic acid (20 g), methanol (200 ml) and 5% Pd-C (2 g) and pressurized with hydrogen to 6.0 kg/cm2. Maintained the reaction mass (RM) at room temperature (RT) for 5 hrs. The reaction was monitored by TLC. After completion of reaction, the RM was unloaded and filtered through hyflow, followed by washing with methanol (2 vol). The solvent was distilled off completely to yield the title compound as a white solid.
Example 2: Preparation of methyl 2-amino-5-methoxybenzoate
Compound (15 g) obtained from Example 1 was dissolved in methanol (5 vol) and cooled to 0-5°C. Thionyl chloride (21.35 g) was added dropwise at same temperature. Slowly the temperature was raised to RT and the reaction mixture was heated to reflux for 12 hrs. The reaction mixture was concentrated in vacuo. The crude material was dissolved in dichloromethane (5 vol), washed with 1 N NaOH (3 vol) and stirred for 10 mins. The organic layer was washed with water (3 vol) and dried with Na2SO4. The solvent was distilled completely, to give the crude compound.
Example 3: Preparation of methyl 2-(4-cyanobenzamido)-5-methoxybenzoate (III): In a clean and dry RBF, was charged 4-cyanobenzoic acid (13.4 g) and thionyl chloride (30 ml), stirred for 60 mins at RT. After completion of reaction, the solvent was distilled off completely to give a crude compound (4-cyanobenzoyl chloride). In another RBF, compound (15 g) obtained from Example 2 was dissolved in tetrahydrofuran (75 ml). Triethylamine (8.86 g) was added and the RM was cooled to -5° to 0°C.To the above RM, was added a solution of 4-cyanobenzoyl chloride in tetrahydrofuran (30 ml). The temperature was slowly raised to RT, stirred for 3-4 hrs. The progress of reaction was monitored by TLC. After completion of reaction, the RM was filtered and washed with chilled tetrahydrofuran (0.5 vol), followed by drying the solid to yield the title compound.
Example 4: Preparation of compound (IV) (where R = Me)
Method 1: In a clean and dry RBF under nitrogen atmosphere, was charged 2.0 M dimethylamine solution in tetrahydrofuran (96 ml), cooled to -65°C to -70°C. Slowly added 2.3 M n-hexyl lithium in hexane (105 ml) at same temperature and stirred for 10 mins. To the above RM, was added a solution of compound III (10 g) from Example 3 in tetrahydrofuran (100 ml), stirred for 2-3 hours at same temperature. After completion of reaction, added sodium carbonate and sodium bicarbonate (1:1) mixture. Charged ethyl acetate (5 vol), and the aqueous layer was extracted twice with ethyl acetate. Dried with sodium sulfate and solvent was distilled completely under vacuum to give the compound IV (where R = Me)
Method 2: In a clean and dry RBF, was charged compound III (10 g) obtained from Example 3 and ethanolic HCl (100 ml) at 5-10°C, stirred for 2-4 hours at same temperature. After completion of reaction, the solvent was distilled off completely and charged ethanol (50 ml), then cooled to 0-5°C. Slowly 2.0 M dimethylamine solution in tetrahydrofuran (96 ml) was added at same temperature and stirred for 30 hrs. After completion of reaction, distilled the total solvent to give compound IV (where R = Me)
Method 3: To 2.0 M dimethylamine solution in tetrahydrofuran (80.6 ml), was added a solution of 2.0 M isopropyl magnesium chloride in tetrahydrofuran (80.6 ml) dropwise and stirred for 2 hours. Slowly the RM was cooled to -10°C to -5°C and added compound III (10 g) from Example 3 under nitrogen atmosphere at same temperature and stirred for 3 hrs. After completion of reaction, RM was quenched with 10% ammonium chloride solution. Then temperature raised to 20-25°C and stirred for 1 hour. The RM was filtered, followed by washing with dichloromethane (5 vol). The aqueous and organic layer were separated. The organic layer was washed with water followed by brine solution. Organic layer was concentrated to remove the solvent, to get compound IV.
Example 5: Preparation of Compound IVa (2-(4-amidinobenzamido)-5-methoxy benzoic acid): To a solution of compound IV (6.0 g) in tetrahydrofuran (18 ml) obtained from Example 4, was added aq. Lithium hydroxide solution (12 ml) and stirred at RT for 15 hrs. After completion of reaction, water (25 ml) and ethyl acetate (25 ml) were charged into RM and stirred for 15 mins. Aq and organic layers were separated and the pH was adjusted to 3-4 using 6N HCl. the RM was stirred for 15 mins and the solid was filtered, followed by washing with n-hexane to give the title compound.
Example 6: Preparation of Betrixaban (V)
Method 1: To a solution of compound IVa (2 g) in acetonitrile (20 ml), was charged 2-amino-5-chloropyridine (2.1 g) and cooled to 15-20°C. Slowly added pyridine (2.8 g) to RM at same temperature and stirred for 30 minutes. Then thionyl chloride (2.16 g) was added to RM at same temperature, stirred for 3-4 hours. After completion of reaction, water was charged to RM and stirred for 15 minutes. Filtered the product and washed with water (5 vol), followed by purification with acetonitrile (3 vol), drying to yield Betrixaban free base.
Method 2: To a solution of compound IVa (1 g) in tetrahydrofuran (10 ml), was charged carbonyldiimidazole (560 mg) and cooled to 10-15°C. Slowly added 2-amino-5-chloropyridine (1.05 g) in tetrahydrofuran and stirred for 10 hrs. After completion of reaction, charge water (5vol) and ethyl acetate (5vol) to the reaction mass. The organic and aqueous layers were separated. Organic layer washed with water and dried with sodium sulfate. Then the solvent was distilled completely under vacuum, followed by purification with acetonitrile (3 vol), and drying to yield Betrixaban free base.
Although the foregoing invention has been described in some detail by way of illustration and example for purposes of clarity of understanding, a person skilled in the art will appreciate that certain changes and modifications may be practiced within the scope of the invention described.
Without being limited by theory, the processes according to the present invention may be advantageously used to prepare the complex compounds like Betrixaban. The proposed routes of the drug described in schemes 1 and 2 are such that it prevents the disadvantages of the prior art.
The proposed processes according to schemes 1 and 2 of the present invention are convenient to use by the end users and eliminates impurities.
The foregoing embodiments and advantages are merely exemplary and are not to be construed as limiting the scope of the present invention. The description of the exemplary embodiments of the present invention is intended to be illustrative and not to limit the scope of the invention. Various modifications, alterations and variations, which are apparent to a person skilled in the art, are intended to fall within the scope of the invention.
,CLAIMS:We Claim,

1. An improved processes for the preparation of N-(5-chloropyridin-2-yl)-2­[4-(N,N-dimethylcarbamimidoyl)-benzoylamino]-5-methoxybenzamide, represented by a compound of formula V or salts thereof, comprising:
(a) Reacting a compound of formula III with dialkylamine and a suitable reagent to a form a compound of formula IV;

Wherein R is hydrogen, C1-C4 alkyl, C2-C4 alkenyl, unsubstituted or substituted phenyl group with nitro, alkyl, alkoxy or halogen,
(b) Coupling the compound of formula IV with 2-amino-5-chloropyridine to form compound V;

(c) Optionally contacting the compound of formula V with an acid or base in one or more solvents to form acid or base addition salts thereof.
2. The process as claimed in Claim 1, wherein the suitable reagent in step (a) is an alcohol selected from methanol or ethanol in presence of an acid; Grignard reagent selected from methylmagnesium chloride, methylmagnesium bromide, isopropylmagnesium chloride, or isopropylmagnesium bromide; or an alkyl lithium selected from n-butyllithium, tert-butyllithium, or hexyllithium; the dialkylamine is selected from dimethylamine, diethylamine, dipropylamine, diisopropylamine, or methyl ethyl amine;
Step (b) comprises the use of a coupling reagent selected from phosphorous oxychloride, carbonyldiimidazole, carbodiimides or amide coupling reagents; an organic base selected from pyridine, diisopropylamine, diisopropylethylamine, dimethylaminopyridine or mixtures thereof
In step (c), the acid is an inorganic acid selected from hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid; an organic acid selected from acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, or salicylic acid; a base is selected from sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, or aluminum; solvent is selected from acetonitrile, cyclohexane, dichloromethane, dimethylformamide, diethyl ether, dioxane, ethanol, ethyl acetate, tetrahydrofuran, hexane, heptane, methanol, methyl tert-butyl ether, or mixtures thereof.
3. The process as claimed in Claim 1, optionally comprising:
(a) Subjecting the compound of formula IV to hydrolysis to form compound IVa;

Wherein R is C1-C4 alkyl, C2-C4 alkenyl, unsubstituted or substituted phenyl group with nitro, alkyl, alkoxy or halogen; hydrolysis is performed using a base selected from lithium hydroxide, sodium hydroxide, potassium hydroxide, or water; or an acid selected from hydrochloric acid, trifluoroacetic acid,
(b) Coupling the compound of formula IVa with 2-amino-5-chloropyridine to form compound V;

(c) Optionally contacting the compound of formula V with an acid or base in one or more solvents to form acid or base addition salts thereof.
4. A process for preparing a compound of formula III, comprising:
(a) Reducing a compound of formula I to form a compound of formula II;

(b) Subjecting the compound of formula II to protection to form Compound II;

Wherein R is C1-C4 alkyl, C2-C4 alkenyl, unsubstituted or substituted phenyl with nitro, alkyl, alkoxy or halogen,
(c) Contacting the compound of formula II with 4-cyanobenzoyl chloride to form compound III;

Or contacting a compound of formula II (where R = hydrogen) with 4-cyanobenzoyl chloride to form compound III;

Wherein R is hydrogen, C1-C4 alkyl, C2-C4 alkenyl, unsubstituted or substituted phenyl with nitro, alkyl, alkoxy or halogen.
5. The process as claimed in Claim 4, wherein reduction in step (a) is carried out using a reducing agent selected from Fe/NH4Cl, Zn/NH4Cl, Fe/HCl, Zn/HCl, SnCl2, Raney Ni/H2 and Pd/C/H2; step (c) & (d) comprise the use of base selected from triethylamine, pyridine, sodium carbonate, and sodium hydrogen carbonate.
6. Compound of formula IV;

Wherein R is hydrogen, C1-C4 alkyl, C2-C4 alkenyl, unsubstituted or substituted phenyl with nitro, alkyl, alkoxy or halogen.
7. An improved process for preparing N-(5-chloropyridin-2-yl)-2­[4-(N,N-dimethyl carbamimidoyl)-benzoylamino]-5-methoxybenzamide i.e., Betrixaban or salts thereof, comprising:
(a) Reducing a compound of formula I to form a compound of formula II;

(b) Contacting the compound of formula II with 4-cyanobenzoyl chloride to form compound III;

(c) Reacting the compound of formula III with dialkylamine and a suitable reagent to a form a compound of formula IV;

Wherein the dialkylamine is selected from dimethylamine, diethylamine, dipropylamine, diisopropylamine, or methyl ethyl amine; the suitable reagent is an alcohol selected from methanol or ethanol in presence of an acid; Grignard reagent selected from methylmagnesium chloride, methylmagnesium bromide, isopropylmagnesium chloride, or isopropylmagnesium bromide; or an alkyl lithium selected from n-butyllithium, tert-butyllithium, or hexyllithium,
(d) Coupling the compound of formula IV with 2-amino-5-chloropyridine to form Betrixaban represented by a compound of formula V;
.