FORM 2
THE PATENTS ACT, 1970
(39 OF 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10; rule 13)
1. Title of the invention – An improved process for preparation of Betrixaban Maleate.
2. Applicant(s)
(a) NAME :
(b) NATIONALITY:
(c) ADDRESS : ALEMBIC PHARMACEUTICALS LIMITED
An Indian Company.
Alembic Research Centre, Alembic Road, Vadodara-390 003, Gujarat, India
3. PREAMBLE TO THE DESCRIPTION
The following specification describes the invention and the manner in which is to be performed:

RELATED APPLICATION
This application claims the benefit of priority of our Indian patent application numbers IN 201921019360 filed on 15th May 2019 which are incorporated herein by reference.
FIELD OF THE INVENTION
The present application provides an improved process for preparation of Betrixaban Maleate.
BACKGROUND OF THE INVENTION
Betrixaban maleate is chemically known as N-(5-chloropyridin-2-yl)-2-[4-(N,N- dimethylcarbamimidoyl)-benzoylamino]-5-methoxybenzamide maleate and has the structure shown in Formula I.

Betrixaban is a factor Xa inhibitor, marketed in the US under the brand name BEVYXXA. BEVYXXA® contains Betrixaban in the form of its maleate salt. BEVYXXA® 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.
Betrixaban and pharmaceutically acceptable salts thereof are disclosed in the U.S. Patent No. 6,376,515.

U.S. Patent No. 7,598,276 discloses Betrixaban maleate crystalline form-I and processes for the preparation thereof.
DETAILED DESCRIPTION OF THE INVENTION
Provided herein is an improved process for preparation of Betrixaban Maleate.
Provided herein is a process for preparation of Betrixaban maleate Form-I.
Still further, provided herein is a process for preparation of Betrixaban
maleate Form-I comprising mixing Betrixaban and maleic acid in suitable solvent
system and isolating Betrixaban maleate Form-I by filtration. Wherein the suitable
solvent system contains single solvent or mixture of solvents such as only water,
DMSO:water, MDC:methanol, acetone:water, ethyl acetate:water and
acetonitrile:water and like; preferably only in water. The quantity of maleic acid used may vary from 1 mole to 10 mole equivalents with respect to Betrixaban, preferably about 2 to 3 mole equivalents with respect to Betrixaban. The reaction mass is stirred for 3 to 20 hours.
Still further, provided herein is a process for purification of Betrixaban maleate comprising stirring Betrixaban maleate in suitable solvent and isolating Betrixaban maleate Form-I . Wherein the suitable solvent comprises ethanol, methanol, NMP, DMSO, DMAc, acetonitrile, toluene, ethyl acetate, IPA, Isopropyl acetate, water, acetone, MTBE, cyclohexane, methyl acetate, isobutyl acetate, water, acetic acid, veratrole, propionitrile and methylethyl ketone or like.
The term "purification or preparation of Form -I" refers to any method known to a person skilled in the art such as purification from single solvent or combination of solvents by dissolving the compound optionally at elevated temperature and precipitating the compound by cooling the solution or removing

solvent from the solution or both. It further includes methods such as solvent/antisolvent or precipitation.
Betrixaban maleate form-I is isolated from reaction mass by conventional isolation procedure such as filtration, centrifugation, washing the wet cake and drying or by evaporation of solvent.
In one embodiment, the present invention provides a process for the
purification of N-(5-chloropyridin-2-yl)-2-(4-cyano-benzoylamino)-5-methoxy
benzamide, a compound of Formula II comprising providing a solution of a compound of Formula II in solvent such as DMSO (dimethyl sulfoxide), DMF (dimethyl formamide) and DMAc (dimethyl acetamide) and like; preferably DMSO and addition of anti-solvent such as methanol, ethanol, propanol, isopropanol (IPA) and like; preferably isopropanol.
In one embodiment, the present invention provides a process for the preparation of compound of Betrixaban maleate, a compound of Formula I as represented schematically in scheme 1 as shown below.


The invention is further exemplified by the following non-limiting examples, which are illustrative representing the preferred modes of carrying out the invention. The invention's scope is not limited to these specific embodiments only but should be read in conjunction with what is disclosed anywhere else in the specification together with those information and knowledge which are within the general understanding of the person skilled in the art.
Examples
Example 1: Process for preparation of N-(5-chloropyridine-2- yl)-5-methoxy-2-nitrobenzamide.
To 5-methoxy-2-nitrobenzoic acid (100g) in acetonitrile (300 ml), 5-chloropyridin-2-amine (65.20g) was added at 27-30 ºC u/nitrogen atmosphere. Pyridine (100.30 g) was charged in to the reaction mixture at 27-30 ºC and stirred. The obtained reaction mixture was cooled to 12-15 ºC followed by slow addition of phosphorus oxychloride (70 g) and stirred. After completion of the reaction, water was added, stirred at 27-30 ºC and obtained solid was filtered and dried in ATD/VTD at 55-60 ºC to get the product. Yield (83%) (HPLC purity 99.9%).
Example 2: Process for preparation of N-(5-chloropyridin-2-yl)-2-(4-cyanobenzoylamino)-5-methoxybenzamide.
To a reaction mixture of N-(5-chloropyridine-2-yl)-5-methoxy-2-nitrobenzamide (100 g) in a mixture of water and ethyl acetate, iron powder (50 g) and acetic acid (2 ml) were added at 27-30 ºC. Reaction mixture was stirred at 72-75 ºC till completion of the reaction. The obtained reaction mixture was filtered and extracted with ethyl acetate. The organic layer was separated and distilled out to afford N-(5-chloropyridine-2- yl)-5-methoxy-2-aminobenzamide.
The obtained residual reaction mass was dissolved in dichloromethane, cooled to 13-16 ºC and followed by addition of triethyl amine (39.46 g) (Reaction mass A). To another reaction vessel, toluene was charged and followed by addition of 4-cyano benzoic acid (50.21 g), dimethylformamide (0.50 ml) and thionyl chloride (46.65 g) at 25-28 ºC u/nitrogen atmosphere. The obtained reaction mass was stirred

at 80-82 ºC. After completion of reaction, reaction ass was cooled to 13-16 ºC u/nitrogen atmosphere (Reaction mass B)
Reaction mass B was added to reaction mass A and stirred at 25-28 ºC till completion of reaction. To the obtained reaction mass water was added, stirred, filtered to obtain solid and dried. The obtained solid was dissolved in DMSO and stirred at 80-85 ºC followed by addition of isopropyl alcohol. The reaction mixture was stirred at 80-85 ºC, cooled to 25-28 ºC and filtered washed with isopropyl alcohol. Obtained solid was dried in ATD/VTD, to afford the product. Yield (68 %) (HPLC purity -99.0%).
Example 3: Process for preparation of N-(5-chloropyridine-2- yl)-5-methoxy-2-aminobenzamide.
To a reaction mixture of N-(5-chloropyridine-2-yl)-5-methoxy-2-nitrobenzamide
(10g) in a mixture of water and ethyl acetate, NH4Cl (5.22g) and iron powder
(5.80g) were added at 20-35°C. Reaction mixture was stirred at 60-80°C till
completion of the reaction. Reaction mixture was filtered and washed with ethyl
acetate. Layers in the filtrate were separated and organic layer was distilled out
completely to afford N-(5-chloropyridine-2- yl)-5-methoxy-2-aminobenzamide.
Yield (85%) (HPLC purity-98.0%).
Example 4: Process for preparation of N-(5-chloropyridine-2- yl)-5-methoxy-2-aminobenzamide.
To a reaction mixture of N-(5-chloropyridine-2- yl)-5-methoxy-2-nitrobenzamide (10g) in ethyl acetate, 10% pd /c (0.5g) was added in hydrogenation reactor. Hydrogen gas was purged at 2-6 kg/cm2 at room temperature. After completion of the reaction, reaction mixture was filtered and washed with ethyl acetate (50ml). Solvent was distilled out to get the product. Yield (85%) (HPLC purity-98.0%).
Example 5: Process for preparation of Betrixaban.
To a reaction vessel, THF (850 ml) was charged and cooled to -7 to -10 ºC followed by addition of N-(5-chloropyridin-2-yl)-2-(4-cyanobenzoylamino)-5-methoxybenzamide (100 g), solution of dimethyl amine in THF (200 ml) and isopropyl magnesium chloride (2M solution in THF) at -7 to -10 ºC. Reaction

mixture was stirred at 5-10 ºC till completion of the reaction. Acetic acid (147-48 g) was added to the reaction mixture at -7 to -10 ºC followed by addition of water (1500 ml) at 25-30 ºC and stirred. Both layers were separated and aqueous layer was extracted with THF and separated to obtain organic layer. Both organic layer were combined and treated with sodium chloride solution. Organic layer was separated and distilled. Obtained residue was dissolved in ethyl acetate (100 ml) and distilled. DMSO (300 ml) was charged to the residue and temperature was raised at 63-65 ºC. Ethyl acetate (900ml) was added to reaction mass cooled to room temperature and stirred. Obtained solid was filtered & washed with ethyl acetate, dried in VTD at 55-58 ºC to afford Betrixaban. Yield (54%).
Example 6: Process for preparation of Betrixaban Maleate
To the solution of maleic acid (38. 52 g) in water (160 ml), acetone (420 ml) and Betrixaban (100g) were charged at 27-30 ºC. Reaction mass was stirred at 35-37 ºC for 20-30 minutes and treated with activated carbon. Obtained reaction mass was filtered and filtrate was distilled to reduce volume. Water (1000 ml) was added to obtained reaction mass and stirred for around 12 hours at 27-30 ºC and for around 1 hour at 35-37 ºC. Reaction mass was filtered and obtained solid was dried in ATD/VTD at 45-50 ºC, to afford Betrixaban maleate Form –I.
Example 7: Process for preparation of Betrixaban Maleate
To the solution of maleic acid (51.5g) in water (1500 ml) at 20-30°C, Betrixaban (100g) was charged and stirred it 14-24 hrs at 20-30 0C. Solid was filtered & washed with water. Dried in ATD/VTD at 35-45°C, to afford Betrixaban maleate Form –I.

We claim:
1. A process for the preparation of Betrixaban maleate, a compound of Formula I
comprising:
a) providing a solution of maleic acid in a suitable solvent or mixture thereof;
b) adding Betrixaban to solution of step (a); and
c) isolating Betrixaban maleate.

2. The process as claimed in claim 1, wherein the solvent in step (a) water.
3. A process for the purification of N-(5-chloropyridin-2-yl)-2-(4-cyano benzoylamino)-5-methoxybenzamide, a compound of Formula II comprising:

a) providing a solution of compound of Formula II in a DMSO ;
b) heating the reaction mixture of step a) to a temperature of 65˚C to 85˚C to obtain a solution;
c) addition of isopropyl alcohol to the reaction mixture of step b);
d) cooling the solution of step c) to a room temperature;
d) isolating a compound of Formula II.