DESC:FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003

COMPLETE SPECIFICATION
(See section 10 and rule 13)

“PROCESS FOR PREPARATION OF BETRIXABAN MALEATE”
Glenmark Life Sciences Limited;
an Indian Company, registered under the Indian company’s Act 1957 and having its registered office at
Glenmark House,
HDO- Corporate Bldg, Wing-A,
B. D. Sawant Marg, Chakala,
Andheri (East), Mumbai- 400 099

The following specification particularly describes the invention and the manner in which it is to be performed

Field of the invention
The present invention relates to process for the preparation of crystalline betrixaban maleate and crystalline betrixaban.
Background of the invention
Betrixaban maleate which is chemically known as N-(5-chloropyridin-2-yl)-2[4-(N,N-dimethylcarbamimidoyl)-benzoylamino]-5-methoxybenzamide maleate, is represented by chemical formula I.
I
Betrixaban maleate is indicated for the extended duration prophylaxis of venous thromboembolism in acute medically ill patients.
Summary of the invention
In one embodiment, the present invention provides a process for the preparation of betrixaban maleate, a compound of formula I comprising:
I
a) contacting betrixaban, a compound of formula II, with maleic acid in a solvent mixture of methanol and water to obtain a reaction mixture;
II
b) heating the reaction mixture of step a) to a temperature of 45°C to 65°C to obtain a solution;
c) cooling the solution of step b) to a temperature of 20°C to 35°C;
d) adding water to the solution of step c) to precipitate betrixaban maleate;
e) cooling the solution containing precipitated betrixaban maleate to a temperature below 20°C; and
f) isolating betrixaban maleate.
In one embodiment, the present invention provides crystalline betrixaban characterized by X-ray Diffraction (XRD) spectrum having peak reflections at about 11.6, 14.5, 18.8, 22.5 and 25±0.2 degrees 2 theta.
In one embodiment, the present invention provides a process for the preparation of crystalline betrixaban characterized by X-ray Diffraction (XRD) spectrum having peak reflections at about 11.6, 14.5, 18.8, 22.5 and 25±0.2 degrees 2 theta comprising isolating betrixaban from a mixture of dimethyl sulfoxide and a solvent selected from the group consisting of C1-4 alcohols, esters, ethers, amides or mixtures thereof.
In one embodiment, the present invention provides crystalline betrixaban maleate characterized by X-ray Diffraction (XRD) spectrum having peak reflections at about 3.7, 7.0, 7.5, 11.1 and 19.1±0.2 degrees 2 theta.
In one embodiment, the present invention provides crystalline betrixaban maleate characterized by X-ray Diffraction (XRD) spectrum having peak reflections at about 12.3, 18.9, 24.6, 25.1, and 28.8 ± 0.2 degrees 2 theta.
In one embodiment, the present invention provides a process for the preparation of crystalline betrixaban maleate a compound of formula I, characterized by X-ray Diffraction (XRD) spectrum having peak reflections at about 3.7, 7.0, 7.5, 11.1 and 19.1±0.2 degrees 2 theta comprising isolating crystalline betrixaban maleate from a mixture of C1-4 alcohols and ethers.
In one embodiment, the present invention provides a process for the preparation of crystalline betrixaban maleate a compound of formula I, characterized by X-ray Diffraction (XRD) spectrum having peak reflections at about 12.3, 18.9, 24.6, 25.1, and 28.8 ± 0.2 degrees 2 theta comprising isolating crystalline betrixaban maleate from a mixture of C1-4 alcohols and ethers.
Brief description of the drawings
Fig. 1: PXRD pattern of crystalline betrixaban, as obtained in example 6.
Fig 2: DSC pattern of crystalline betrixaban, as obtained in example 6.
Fig 3: TGA of crystalline betrixaban, as obtained in example 6.
Fig 4: PXRD pattern of crystalline betrixaban maleate, as obtained in example 7.
Fig 5: DSC pattern of crystalline betrixaban maleate, as obtained in example 7.
Fig 6: TGA of crystalline betrixaban maleate, as obtained in example 7.
Fig. 7: PXRD pattern of crystalline betrixaban maleate, as obtained in example 8.
Fig 8: DSC pattern of crystalline betrixaban maleate, as obtained in example 8.
Fig 9: TGA of crystalline betrixaban maleate, as obtained in example 8.
Fig. 10: PXRD pattern of crystalline betrixaban maleate, as obtained in example 9.
Fig 11: TGA of crystalline betrixaban maleate, as obtained in example 9.
Detailed description of the invention
In one embodiment, the present invention provides a process for the preparation of betrixaban maleate, a compound of formula I comprising:
I
a) contacting betrixaban, a compound of formula II, with maleic acid in a solvent mixture of methanol and water to obtain a reaction mixture;
II
b) heating the reaction mixture of step a) to a temperature of 45°C to 65°C to obtain a solution;
c) cooling the solution of step b) to a temperature of 20°C to 35°C;
d) adding water to the solution of step c) to precipitate betrixaban maleate;
e) cooling the solution containing precipitated betrixaban maleate to a temperature below 20°C; and
g) isolating betrixaban maleate.
As used herein, the term “contacting” refers to treating, suspending or slurrying.
In one embodiment, step a) of the above process involves contacting betrixaban with maleic acid in a solvent mixture of methanol and water, wherein betrixaban to solvent mixture weight/volume ratio (g/mL) is 1:5 to 1:20.
In one embodiment, in step a) of the above process, betrixaban to solvent mixture weight/volume ratio (g/mL) is 1:6 to 1:15.
In one embodiment, in step a) of the above process, betrixaban to solvent mixture weight/volume ratio (g/mL) is 1:12.
In one embodiment, the obtained reaction mixture is heated to a temperature of 50°C to 60°C, preferably to about 55°C to 60°C to obtain a solution.
In one embodiment, in step c) of the above process, the solution is cooled to a temperature of about 20°C to 35°C. Preferably, to a temperature of about 25°C to 30°C.
In one embodiment, in step d) of the above process, betrixaban to water weight/volume ratio (g/mL) is 1:2 to 1:12, preferably the ratio is 1:10.
In one embodiment, in step e) of the above process, the solution containing precipitated betrixaban maleate is cooled to a temperature of 0°C to 15°C, preferably, to a temperature of 5°C to 10°C.
In one embodiment, the cooled solution containing precipitated betrixaban maleate is stirred for a period of about 1h to about 10h, preferably, for about 5h, more preferably for about 2h.
In one embodiment, the precipitated betrixaban maleate is isolated from the cooled solution by any method known in the art such as filtration, centrifugation, and the like.
In one embodiment, crystalline betrixaban maleate may be isolated from a mixture of water and solvent such as ketone or ether.
In one embodiment, crystalline betrixaban maleate may be isolated from a mixture of water and acetone.
In one embodiment, crystalline betrixaban maleate may be isolated from a mixture of water and tetrahydrofuran,
In one embodiment, it was surprisingly noted that crystalline betrixaban maleate may be isolated by a convenient process as disclosed herein and avoids the cumbersome process disclosed in art involving repeated partial distillation and addition of water.
In one embodiment, the isolated betrixaban maleate, the compound of formula I, has a purity of at least 99% as measured by HPLC.
In one embodiment, the isolated betrixaban maleate, the compound of formula I, has a purity of at least 99.5% as measured by HPLC.
In one embodiment, the isolated betrixaban maleate, the compound of formula I, has a purity of at least 99.9% as measured by HPLC.
In one embodiment, betrixaban, the compound of formula II, is prepared by a process comprising:
a) reacting 2-nitro-5-methoxy benzoic acid, a compound of formula III with 2-amino-5-chloropyridine, a compound of formula IV to obtain N-(5-chloropyridin-2-yl)-5-methoxy-2-nitrobenzamide, a compound of formula V;

b) optionally, purifying the compound of formula V with C1-4 alcohol to obtain the compound of formula V, with a purity greater than 99%;
c) converting the compound of formula V of step a) or step b) to a compound of formula VI;

d) treating the compound of formula VI with 4-cyanobenzoyl chloride to obtain
a compound of formula VII;

e) optionally, purifying the compound of formula VII with C1-4 alcohol;
f) converting the compound of formula VII of step d) or step e) to betrixaban, the compound of formula II to obtain a reaction mixture; and
g) isolating betrixaban, the compound of formula II.
In one embodiment, step a) of the above process involves reacting a compound of formula III with a compound of formula IV to obtain a compound of formula V.
In one embodiment, the reaction may be carried out in the presence of a suitable solvent selected from the group consisting of alcohols such as methanol, ethanol, propanol, isopropanol, butanol, isobutanol, tert-butanol, cyclohexanol and the like; cyclic or acyclic ethers such as tetrahydrofuran, tetrahydropyran, diethyl ether, methyl-tert-butyl ether, diisopropyl ether and the like; hydrocarbons such as hexane, toluene, cyclohexane, xylene, methylcyclohexane and the like; chlorinated solvents such as methylene dichloride, ethylene dichloride, chloroform, and the like. Preferably the solvent is methylene dichloride.
In one embodiment, it was found that the above reaction when carried out in presence of a nitrile solvent such as acetonitrile, the yield of the product is low and was about 50% and purity was also poor and was about 70%.
In one embodiment, it was surprisingly found that the above reaction when carried out in presence of methylene dichloride, the purity of product was at least 98%.
In one embodiment, the reaction is carried out in the presence of an acid chloride selected from the group consisting of thionyl chloride, phosphorous oxychloride, oxalyl chloride and the like.
In one embodiment, the reaction is carried out in the presence of a base selected from the group consisting of triethyl amine, diisopropyl amine, pyridine, sodium carbonate, sodium hydroxide, potassium carbonate and the like.
In one embodiment, the reaction may be carried out in the absence of pyridine.
In one embodiment, step a) involves reaction of compound of formula III with compound of formula IV in methylene dichloride in the presence of phosphorous oxychloride and pyridine for a period of about 30min to 150min. Preferably, the reaction is completed in a period of 120min.
In one embodiment, in step b), the compound of formula V may be optionally purified with C1-4 alcohol to obtain the compound of formula V with a purity greater than 99%. The C1-4 alcohol may be selected from the group consisting of methanol, ethanol, propanol, isopropanol, butanol and mixtures thereof. Preferably, the solvent is methanol.
In one embodiment, the compound of formula V is purified in methanol to obtain a purity of at least 99% by a process comprising slurring the compound of formula V in methanol and stirring for at least 1h and isolating the compound of formula V.
In one embodiment, step c) involves converting compound of formula V to 2-amino-N-(5-chloropyridin-2-yl)-5-methoxy benzamide, a compound of formula VI.
In one embodiment, the compound of formula V is converted to the compound of formula VI by subjecting the nitro group to reduction using a suitable reducing agent.
The reducing agent may be selected from the group consisting of hydrogen in presence of metal catalyst such as Pd/C, Pt/C, Raney Ni or hydrides such as sodium borohydride, potassium borohydride and like. The pressure of hydrogen may vary from 20 to 50 psi.
The reaction may be carried out in the presence of a suitable solvent selected from the group consisting of esters such as ethyl acetate, isopropyl acetate and the like; chlorinated hydrocarbons such as methylene chloride, chloroform and the like; ethers such as tetrahydrofuran, methyl tertiary butyl ether and mixtures thereof.
In one embodiment, the compound of formula VI may be optionally purified in C1-4 alcohol selected from the group consisting of methanol, ethanol, propanol, isopropanol, butanol and mixtures thereof. Preferably, the solvent selected is methanol.
In one embodiment, the compound of formula VI is purified in methanol to obtain a purity of at least 99% by a process comprising slurring the compound of formula VI in methanol, stirring for at least 1h and isolating the compound of formula VI.
In one embodiment, step d) involves treating the compound of formula VI with 4-cyanobenzoyl chloride to obtain N-(5-chloropyridin-2-yl)-2-[(4-cyanobenzoyl) amino]-5-methoxybenzamide, a compound of formula VII.
In one embodiment, 4-cyanobenzoyl chloride is obtained by acylation of 4-cyanobenzoic acid with acid chloride such as thionyl chloride, phosphorus oxychloride and the like. The acylation may be carried out in a solvent selected from the group consisting of ethers such as diisopropyl ether, tetrahydrofuran, dioxane and the like; polar aprotic solvents such as dimethyl formamide, dimethyl sulfoxide and the like.
In one embodiment, 4-cyanobenzoic acid was acylated to 4-cyanobenzoyl chloride insitu and reacted with the compound of formula VI. The reaction of 4-cyanobenzoyl chloride with compound of formula VI may be carried out in the presence of a base selected from the group consisting triethylamine, pyridine, N-methyl morpholine. The reaction may be carried out in presence of a suitable solvent selected from the group consisting of ether such as diisopropyl ether, tetrahydrofuran, dioxane and the like; esters such as ethyl acetate, isopropyl acetate and the like; chlorinated hydrocarbons such as methylene dichloride, chloroform and the like; alcohols such as methanol, ethanol, isopropanol and the like; hydrocarbons such as toluene, xylene and the like and mixtures thereof.
In one embodiment, in step e), the compound of formula VII may be optionally purified in C1-4 alcohol. The alcohol may be selected from the group consisting of methanol, ethanol, propanol, isopropanol and butanol. Preferably, the compound of formula VII is slurried in methanol for a period of about 1h to obtain a purity of at least 95%.
In one embodiment, in step f), the compound of formula VII is converted to betrixaban, the compound of formula II. The conversion may be carried out by Grignard reaction. The Grignard reagent may be an alkyl magnesium halide wherein the alkyl group may be selected from methyl, ethyl, propyl, isopropyl and the like; the halide may be selected from chloride, bromide or iodide. Preferably, the Grignard reagent is isopropyl magnesium chloride.
The isopropyl magnesium chloride reacts with dimethylamine in a suitable solvent at a temperature of about 0°C to about 30°C to obtain a reaction mixture. The solvent may be selected from the group consisting of ether such as tetrahydrofuran, dioxan, dimethyl ether, diethyl ether, anisole and the like; hydrocarbons such as toluene, xylene, heptane, hexane and the like. The compound of formula VII is added to the above reaction mixture to form the compound of formula II. The reaction may be carried at a temperature of about 0°C to about 30°C, preferably, at about 5-10°C.
In one embodiment, in step g), betrixaban, the compound of formula II is isolated from the reaction mixture.
In one embodiment, the isolation of betrixaban, the compound of formula II comprises:
i) quenching the reaction mixture of step f) with an acid to obtain a pH of about 8-9;
ii) distilling the reaction mixture to obtain a solid;
iii) adding water to the above solid to obtain a slurry; and
iv) filtering the slurry to isolate betrixaban, the compound of formula II.
In one embodiment, in step i), the reaction mixture containing betrixaban is quenched with an acid to obtain pH of about 8-9. The acid may be selected from group consisting of hydrochloric acid, sulfuric acid, trifluroacetic acid, acetic acid and the like.
In one embodiment, in step ii), the reaction mixture is distilled to obtain a solid. The distillation involves partial or complete removal of the solvent.
In one embodiment, in step iii), water is added to obtain a slurry. The addition of water is carried out at a temperature of about 25-30°C.
In one embodiment, the present invention provides crystalline betrixaban characterized by X-ray Diffraction (XRD) spectrum having peak reflections at about 11.6, 14.5, 18.8, 22.5 and 25±0.2 degrees 2 theta.
In one embodiment, the present invention provides crystalline betrixaban having PXRD pattern, which is substantially in accordance with Fig. 1.
In one embodiment, the crystalline betrixaban is characterized by differential scanning calorimetric (DSC) thermogram having an endothermic peak at about 235.3 and 263.7°C.
In one embodiment, the present invention provides crystalline betrixaban characterized by differential scanning calorimetric (DSC) thermogram, which is substantially in accodance with Fig. 2.
In one embodiment, the present invention provides crystalline betrixaban characterized by thermogravimetric analysis (TGA) thermogram, showing a weight loss of about 0.49 % at 100ºC determined over the temperature range of 0ºC to 350ºC and heating rate of 10oC/min.
In one embodiment, the present invention provides crystalline betrixaban characterized by thermogravimetric analysis (TGA) thermogram, which is substantially in accordance with Fig.3.
In one embodiment, the present invention provides a process for the preparation of crystalline betrixaban comprising isolating betrixaban from a mixture of dimethyl sulfoxide and a solvent selected from the group consisting of C1-4 alcohol, esters, ethers, amide or mixtures thereof.
In one embodiment, the present invention provides a process for the preparation of crystalline betrixaban comprising:
a) contacting betrixaban with dimethyl sulfoxide and optionally adding a solvent selected from the group consisting of alcohol, ester, ether, amide or mixtures thereof to obtain a mixture;
b) heating the mixture of step a) to obtain a solution;
c) optionally, adding an anti-solvent to above solution of step b) to obtain a reaction mixture; and
d) crystallizing betrixaban from the above step b) or step c).
The solvent in step a) may be selected from the group consisting of alcohol such as methanol, ethanol, isopropanol and the like; ether such as diisoproyl ether, diethyl ether, methyl tertiary butyl ether; ester such as ethyl acetate, isopropyl acetate and the like; amide such as dimethylformamide, dimethylacetamide.
In one embodiment, in step a) of the above process, betrixaban is suspended in dimethyl sulfoxide to obtain a mixture.
In one embodiment, in step b) of the above process, the mixture containing betrixaban and dimethyl sulfoxide is heated to obtain a solution. The mixture may be heated to a temperature of about 40-75°C.
In one embodiment, in step c) of the above process, ethyl acetate is added as an anti- solvent to obtain a reaction mixture. The addition may be carried out at a temperature of about 50-60°C.
In one embodiment, in step a) of the above process, betrixaban is suspended in a mixture of dimethyl sulfoxide and ethanol to obtain a mixture.
In one embodiment, in step b) of the above process, the mixture containing betrixaban, ethanol and dimethyl sulfoxide is heated to obtain a solution. The mixture may be heated to a temperature of about 60-70°C. The solution is maintained for about 30min to 120min preferably, for about 60min.
In one embodiment, in step d) of the above process, betrixaban is crystallized from the reaction by cooling the reaction mixture to a temperature of about 20-35°C. The reaction mixture is maintained for a period of about 30min to about 180min. Betrixaban is isolated from the reaction mixture by known method such as filtration, centrifugation
In one embodiment, crystalline betrixaban is isolated from a mixture of dimethylsulfoxide and ethylacetate.
In one embodiment, crystalline betrixaban is isolated from a mixture of dimethylsulfoxide and ethanol.
In one embodiment, the isolated betrixaban maleate has a purity = 99% as measured by HPLC (high performance liquid chromatography).
In one embodiment, the isolated betrixaban maleate has a purity = 99.7% as measured by HPLC.
In one embodiment, the isolated betrixaban maleate has a purity = 99.9% as measured by HPLC.
In one embodiment, the isolated betrixaban maleate is having less than 0.1% w/w of any of the impurity A, impurity B, impurity C, impurity D relative to the amount of betrixaban maleate, as measured by HPLC.

In one embodiment, the present invention provides crystalline betrixaban maleate characterized by X-ray Diffraction (XRD) spectrum having peak reflections at about 3.7, 7.0, 7.5, 11.1 and 19.1±0.2 degrees 2 theta.
In one embodiment, the present invention provides crystalline betrixaban maleate having PXRD pattern, which is substantially in accordance with Fig. 7.
In one embodiment, the present invention provides crystalline betrixaban maleate characterized by differential scanning calorimetric (DSC) thermogram having an endothermic peak at about 175.11°C and 242.01°C.
In one embodiment, the present invention provides crystalline betrixaban maleate characterized by differential scanning calorimetric (DSC) thermogram, which is substantially in accordance with Fig. 8.
In one embodiment, the present invention provides crystalline betrixaban maleate characterized by thermogravimetric analysis (TGA) thermogram, which is substantially in accordance with Fig. 9.
In one embodiment, the present invention provides crystalline betrixaban maleate characterized by X-ray Diffraction (XRD) spectrum having peak reflections at about 12.3, 18.9, 24.6, 25.1, and 28.8 ± 0.2 degrees 2 theta.
In one embodiment, the present invention provides crystalline betrixaban maleate having PXRD pattern, which is substantially in accordance with Fig. 10.
In one embodiment, the present invention provides crystalline betrixaban maleate characterized by thermogravimetric analysis (TGA) thermogram which is substantially in accordance with Fig. 11.
In one embodiment, the present invention provides crystalline betrixaban maleate prepared by a process comprising isolating betrixaban maleate from a mixture of C1-4 alcohols and ethers. The C1-4 alcohols may be selected from the group consisting of methanol, ethanol, isopropanol, butanol and the like; ethers may be selected from cyclic or acylic ethers such as diethyl ether, diisopropyl ether, methyl tertiary butyl ether, tetrahydropyran, tetrahydrofuran, dioxane and the like.
In one embodiment, the present invention provides crystalline betrixaban maleate characterized by X-ray Diffraction (XRD) spectrum having peak reflections at about 3.7, 7.0, 7.5, 11.1 and 19.1±0.2 degrees 2 theta, isolated by a process comprising:
a) heating a mixture of betrixaban and maleic in methanol to obtain a solution;
b) cooling the solution of step a) to a temperature of about 0°C to about 10°C;
c) adding methyl tertiary butyl ether at a temperature of about 0°C to about 10°C to the solution of step b) to obtain a reaction mixture;
d) stirring the reaction mixture of step c) for a period of 45min to 75min; and
e) isolating crystalline betrixaban maleate .
In one embodiment, step a) involves heating a mixture of betrixaban and maleic in methanol to a temperature of about 40-60°C to obtain a solution. The solution is maintained for a period of about 25 min to 45 min, preferably, for about 30 min.
In one embodiment, step b) involves cooling the solution to temperature of about 0°C to about 10 °C. Preferably, the solution is cooled to a temperature of about 0-5°C.
In one embodiment, step c) involves adding methyl tertiary butyl ether at a temperature of about 0°C to 5°C.
In one embodiment, step d) involves stirring the reaction mixture for period of about 30min to 70min. Preferably, the reaction is maintained for a period of 60min.
In one embodiment, step e) involves isolating the crystallized betrixaban maleate by methods known in the art such as filtration, centrifugation and the like.
In one embodiment, the present invention provides crystalline betrixaban maleate characterized by X-ray Diffraction (XRD) spectrum having peak reflections at about 12.3, 18.9, 24.6, 25.1, and 28.8 ± 0.2 degrees 2 theta isolated by a process comprising;
a) heating a mixture of betrixaban and maleic in methanol to obtain a solution;
b) cooling the solution of step a) to a temperature of 25°C to 30°C;
c) adding methyl tertiary butyl ether at a temperature of 25°C to 30°C to step b) to obtain a reaction mixture;
d) stirring the reaction mixture of step c) for a period of 80min to 180min; and
e) isolating crystalline betrixaban maleate.
In one embodiment, step a) involves heating a mixture of betrixaban and maleic in methanol to a temperature of about 40-60°C to obtain a solution. The solution is maintained for a period of about 25min to 45min, preferably, for about 30 min.
In one embodiment, step d) involves stirring the reaction mixture for a period of about 60min to 120min. Preferably, the reaction is maintained for a period of 120 minutes.
In one embodiment, the present invention provides pharmaceutical compositions comprising betrixaban maleate obtained by processes herein described, having a D90 particle size of less than about 250 microns, preferably less than about 150 microns, more preferably less than about 50 microns, still more preferably less than about 20 microns, still more preferably less than about 15 microns and most preferably less than about 10 microns.
In one embodiment, the present invention provides pharmaceutical compositions comprising betrixaban maleate obtained by the processes herein described, having a D50 particle size of less than about 250 microns, preferably less than about 150 microns, more preferably less than about 50 microns, still more preferably less than about 20 microns, still more preferably less than about 15 microns and most preferably less than about 10 microns.
The particle size disclosed here can be obtained by, for example, any milling, grinding, micronizing or other particle size reduction method known in the art to bring the solid state betrixaban maleate into any of the foregoing desired particle size range.
The examples that follow are provided to enable one skilled in the art to practice the invention and are merely illustrative of the invention. The examples should not be
read as limiting the scope of the invention.

Examples:
Example 1: Preparation of 2-amino-N-(5-chloropyridin-2-yl)-5-methoxy-2- nitrobenzamide [V]: 5-methoxy-2-nitrobenzoic acid (5.0g) and 5-chloropyridin-2-amine (3.89g) was added to methylene dichloride (50mL) to obtain a reaction mixture. To this reaction mixture was added pyridine (6.0mL). The reaction mixture was cooled to 5-10°C and to this added phosphorous oxychloride (4.65gm) dropwise. Temperature was raised to 25-30°C and stirred for 2 hours. On completion, the reaction mass was quenched with water. The organic layer washed with water then with 10% NaCl solution. Organic layer was distilled to get solid. HPLC purity: 98.44%, Content of 5-methoxy-2-nitrobenzoic acid: 0.51%.The solid was slurried in methanol (25mL), stirred for 1h, filtered, tray dried for 12 hours at 40-45°C. HPLC purity: 99.34%;content of III:0.02%
Example 2: Preparation of 2-amino-N-(5-chloropyridin-2-yl)-5-methoxy benzamide [VI]:To a solution of 2-amino-N-(5-chloropyridin-2-yl)-5-methoxy-2- nitrobenzamide (50g) in ethyl acetate (1500mL), was added Platinum on carbon (2.5g) in one portion. The reaction mixture was stirred in autoclave flushed with hydrogen gas for 12 hr at 25-30°C under 30 psi pressure. On completion, reaction mixture was filtered over hyflo bed. The organic layer was distilled to afford product. HPLC purity: 97.6%. To this product was added methanol (200mL) and stirred for 60 min, filtered and dried in VTD at 40-45°C for 12 hours to get 35.0gm HPLC purity: 99.21%.
Example 3: Preparation of N-(5-chloropyridin-2-yl)-2-[(4-cyanobenzoyl) amino]-5-methoxybenzamide [VII]: To a solution of 4-cyanobenzoic acid (12.73g), tetrahydrofuran (200mL) was added dimethyl formamide (2.0mL) followed by thionyl chloride (20.44g) slowly. The resulting solution was heated to 60-65°C for 2.0 hr. On consumption of 4-cyanobenzoic acid, reaction mixture was cooled to 25-30°C and to this was added pyridine (2.0mL) and stirred for 15min. To this reaction mixture a solution of 2-amino-N-(5-chloropyridin-2-yl)-5-methoxybenzamide (20g) in THF (200mL) was added at 25-30°C and stirred for 12h. On completion, the reaction mixture was quenched with 10% aq. Na2CO3, stirred for 5-6h at 25-30°C. The solid was filtered and air dried in tray dryer for 12h at 45-50°C. This was suspended in methanol (200mL), heated to 55-60°C, stirred for 60 min. The slurry was cooled to 25-30°C, filtered, dried in tray dryer at 45-50°C. Yield: 20g, 68%. HPLC purity: 97.72%
Example 4: Preparation of betrixaban[II]: To a solution of dimethylamine (80mL, 2M in THF) at 5-10°C, was added isopropyl magnesium chloride solution (90mL). The reaction mixture was maintained for 30min at 5-10°C and then added a soln of N-(5-chloropyridin-2-yl)-2-[(4-cyanobenzoyl)amino]-5-methoxybenzamide (10g) in tetrahydrofuran (THF,300mL). The reaction mixture was stirred for 2 hour at 5-10°C. On completion, reaction mixture was quenched with 20% aq. HCl to obtain a pH of about 8-9. The THF layer was distilled under reduced pressure to obtain solid, then cooled to 25-30°C.Water (200 mL) was added to obtain a slurry. This was stirred for 60 min at 25-30°C. The solid was filtered, dried in tray dryer at 40-45°C for 12h. The solid was dissolved in mixture of methylene dichloride and methanol and stirred for 60 min at 25-30°C. This was filtered, filtrate was distilled to get solid. To this solid was added THF (100mL) and stirred for 60 min at 25-30°C. The solid was washed with THF, dried in tray dryer at 40-45°C to get 8g product, HPLC purity: 98.08%, yield; 75%.
Example 5: Purification of betrixaban: A suspension of betrixaban (150g), dimethylsulfoxide (750mL) was heated to 50-55°C to get solution. The solution was stirred at 50-55°C for 15-30 min. To this clear solution ethyl acetate (1500mL) was added and cooled the reaction mass to 25-30°C and maintained for 2h. The product was filtered, washed with ethyl acetate and dried in vacuum tray dryer at 40-45°C for 12h to get 115.0g betrixaban. Yield: 80%, HPLC purity: 99.75%
Example 6: Purification of betrixaban: A suspension of betrixaban (5g), dimethylsulfoxide (750mL) and ethanol was heated to 60-65°C to get solution. The solution was stirred at 60-65°C for 60 min. The reaction mass was cooled to 25-30°C and maintained for 2h. The product was filtered, washed with ethanol and dried in vacuum tray dryer at 40-45°C for 12 h to get 4g betrixaban.Yield:80% HPLC purity: 99.85%; DSC: Endotherm at 234.60°C and 262.45°C; TGA: 0.60% XRPD peaks of betrixaban:
Pos. [°2Th.] d-spacing [Å] Rel. Int. [%] Pos. [°2Th.] d-spacing [Å] Rel.Int. [%]
9.32 9.4 14.26 19.71 4.50 5.93
10.06 8.78 2.36 19.97 4.44 2.99
11.62 7.61 19.85 20.21 4.39 3.54
12.11 7.30 27.31 20.83 4.26 3.06
12.53 7.06 2.58 22.16 4.01 3.10
13.78 6.42 63.57 22.55 3.94 14.22
14.44 6.12 100.00 22.81 3.89 24.89
16.32 5.43 32.71 23.46 3.79 22.46
17.02 5.20 4.62 23.73 3.74 58.57
17.81 4.97 2.18 24.37 3.65 54.82
18.27 4.85 5.15 24.97 3.56 82.39
18.80 4.71 76.19 26.12 3.41 9.04
Example 7: Preparation of betrixaban maleate: A mixture of betrixaban (7.0g), maleic acid (3.95g), methanol (35.0mL) and water (49mL) was heated to about 55-60°C to get solution. The reaction mass was filtered to remove undissolved particles and washed with methanol (28.0mL). The filtrate was cooled to about 25-30°C and water was (70.0mL) added to precipitate betrixaban maleate. The reaction mass stirred for 2h at 25-30°C. The reaction mass was further cooled to about 5-10°C and maintained for about 2.0h, then filtered, washed with water and dried in vacuum tray dryer at 40-45°C for 12h to get 5.6gm product, HPLC purity:99.77% .XRPD peaks:
Pos. [°2Th.] d-spacing [Å] Rel. Int. [%] Pos. [°2Th.] d-spacing [Å] Rel.Int. [%]
4.94 17.87 100.00 18.63 4.76 33.43
9.82 9.0 77.02 19.64 4.51 5.69
11.39 7.76 2.63 20.12 4.41 16.69
11.86 7.45 10.84 20.93 4.24 22.58
13.17 6.71 1.72 21.76 4.08 16.93
13.87 6.38 49.70 22.02 4.03 8.33
14.23 6.22 39.11 22.47 3.95 7.02
14.72 6.01 11.28 22.67 3.92 15.16
14.83 5.97 7.93 22.83 3.89 16.47
15.37 5.762 23.09 24.18 3.67 20.90
16.56 5.35 2.03 24.60 3.61 7.60
17.06 5.19 1.40 25.12 3.54 9.61
17.61 5.03 26.64 25.56 3.48 2.48
17.88 4.95 21.11 26.41 3.37 55.60
18.44 4.81 15.37 26.70 3.33 18.53
DSC: Endotherm at 196.11°C, TGA: 0.09% (Anhydrous form)
Example 8: Preparation of betrixaban maleate: A mixture of betrixaban (4.0g), maleic acid (2.26g) and methanol (20mL) was heated to 50-55°C to get solution. The solution was stirred for about 30 min at about 50-55°C. The solution was further cooled to about 0-5°C and to this methyl tertiary butyl ether was added (40mL) to obtain a reaction mixture. The reaction mixture was stirred at about 0-5°C for 60 mins. The product was filtered and dried in vacuum tray dryer at 40-45°C for 12h to obtain 3.6g of product, HPLC purity: 98.8%.; DSC: endothermic peak : 175.0°C, TGA: 3.77% weight loss at 100°C; % crystallinity:47.61%; XRPD peaks of betrixaban maleate:
Pos. [°2Th.] d-spacing [Å] Rel. Int. [%] Pos. [°2Th.] d-spacing [Å] Rel.Int. [%]
3.73 23.66 11.62 16.02 5.52 73.21
5.24 16.85 67.23 16.79 5.27 73.21
5.59 15.79 42.57 17.39 5.09 60.65
7.01 12.59 28.45 18.64 4.75 55.98
7.43 11.88 45.28 19.18 4.62 100
9.29 9.51 31.21 23.04 3.85 7.86
10.41 8.49 12.24 24.23 3.67 8.85
11.15 7.93 35.15 26.05 3.42 29.35
12.90 6.85 43.01 26.95 3.30 32.17
15.20 5.82 24.82 28.22 3.16 28.53
Example 9: Preparation of betrixaban maleate: A mixture of betrixaban (4.0g), maleic acid (2.26g) and methanol (20mL) was heated to about 50-55°C to get solution. The solution was stirred for 30 min at 50-55°C, further cooled to 25-30°C and to this methyl tertiary butyl ether was added (40mL) to obtain a reaction mixture. This was stirred at about 25-30°C for 120min. The product was filtered and dried in vacuum tray dryer at about 40-45°C for 12h to obtain 3.65g of product, HPLC purity: 98.8%; TGA: 2.24% weight loss at 100°C, %crystallinity: 49.03%; betrixaban maleate XRPD peaks:
Pos. [°2Th.] d-spacing [Å] Rel. Int. [%] Pos. [°2Th.] d-spacing [Å] Rel.Int. [%]
2.17 40.63 5.22 16.06 5.51 38.91
3.71 23.77 6.78 16.83 5.26 70.78
5.28 16.72 38.13 17.4 5.09 72.93
5.63 15.68 28.44 18.94 4.68 100
7.38 11.96 58.28 19.22 4.61 83.18
9.29 9.51 43.35 21.5 4.13 10.05
11.22 7.88 49.36 23.95 3.71 42.97
12.24 7.22 22.77 24.57 3.62 49.9
12.95 6.83 34.18 25.15 3.54 40.21
13.93 6.35 26.91 26.6 3.35 54.85
14.58 6.04 21.80 27.00 3.3 45.05
15.24 5.81 22.82 28.8 3.09 61.42
,CLAIMS:We claim:
1] A process for the preparation of betrixaban maleate, a compound of formula I comprising:
I
a) contacting betrixaban, a compound of formula II, with maleic acid in a solvent mixture of methanol and water to obtain a reaction mixture;
II
b) heating the reaction mixture of step a) to a temperature of 45°C to 65°C to obtain a solution;
c) cooling the solution of step b) to a temperature of 20°C to 35°C;
d) adding water to the solution of step c) to precipitate betrixaban maleate;
e) cooling the solution containing precipitated betrixaban maleate to a temperature below 20°C; and
h) isolating betrixaban maleate.
2] The process as claimed in claim 1, wherein in step a) betrixaban to solvent mixture weight/volume ratio (g/mL) is 1:5 to 1:20.
3] The process as claimed in claim 1, wherein in step b), betrixaban, the compound of formula II and maleic acid in a mixture of methanol and water is heated to a temperature of 50°C to 60°C.
And in step c), the solution obtained in step ‘b’ is cooled to a temperature of 25°C to 30°C.
4] The process as claimed in claim 1, wherein in step d), betrixaban to water weight/volume ratio (g/mL) is 1:2 to 1:12.
5] The process as claimed in claim 1, wherein in step e), the solution containing precipitated betrixaban maleate is cooled to a temperature of 0°C to 15°C.
6] The process as claimed in claim 1, wherein the isolated betrixaban maleate has a purity of about 99% as measured by HPLC.
7] The process as claimed in claim 1, wherein betrixaban, the compound of formula II, is prepared by a process comprising:
a) reacting 2-nitro-5-methoxy benzoic acid, a compound of formula III with 2-amino-5-chloropyridine, a compound of formula IV to obtain N-(5-chloropyridin-2-yl)-5-methoxy-2-nitrobenzamide, a compound of formula V ;

b) optionally, the compound of formula V is purified with C1-4 alcohol to obtain the compound of formula V with a purity greater than 99%;
c) converting the compound of formula V of step a) or step b) to a compound of formula VI;

d) treating the compound of formula VI with 4-cyanobenzoyl chloride to obtain
a compound of formula VII;

e) optionally, purifying the compound of formula VII with C1-4 alcohol;
f) converting the compound of formula VII of step d) or step e) to betrixaban, the compound of formula II to obtain a reaction mixture; and
g) isolating betrixaban, the compound of formula II.
8] The process as claimed in claim 7, wherein the isolation of betrixaban, the compound of formula II comprises:
i) quenching the reaction mixture of step f) with an acid to obtain a pH of about 8-9;
ii) distilling the reaction mixture to obtain a solid;
iii) adding water to the above solid to obtain a slurry; and
iv) filtering the slurry to isolate betrixaban, the compound of formula II.