DESC:FORM 2

THE PATENTS ACT 1970
(Act 39 of 1970)
and
THE PATENTS RULE 2003
(SECTION 10 and rule 13)
COMPLETE SPECIFICATION
“PROCESS FOR PREPARATION OF BETRIXABAN MALEATE”
Glenmark Pharmaceuticals 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
[0001] The present invention relates to process for the preparation of amorphous betrixaban maleate.
BACKGROUND OF THE INVENTION
[0002] 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
[0003] Betrixaban maleate is indicated for the extended duration prophylaxis of venous thromboembolism in acute medically ill patients.
SUMMARY OF THE INVENTION
[0004] In one embodiment, the present invention provides amorphous betrixaban maleate, a compound of formula I.
I
[0005] In one embodiment, the present invention provides amorphous betrixaban maleate, a compound of formula I, characterized by differential scanning calorimetric (DSC) thermogram having an endothermic peak at about 113.94±2oC.
[0006] In one embodiment, the present invention provides a process for the preparation of amorphous betrixaban maleate, a compound of formula I, comprising:
a) dissolving betrixaban maleate in a solvent or mixture of solvents thereof to provide a solution; and
b) removing the solvent from the solution obtained in (a) to obtain amorphous betrixaban maleate.
[0007] In one embodiment, the present invention provides crystalline betrixaban maleate characterized by X-ray diffraction (XRD) spectrum having peak reflections at about 3.4, 11.4, 19.8, 21.2 and 24.9 ±0.2 degrees 2 theta.
[0008] In one embodiment, the present invention provides a process for the preparation of crystalline betrixaban maleate, a compound of formula I, comprising:
a) contacting betrixaban with a solvent or a mixture of solvents to obtain reaction mixture;
b) adding maleic acid to the reaction mixture of step (a);
c) optionally, heating the above mixture of step (b);
d) filtering the reaction mass;
e) cooling the filtrate; and
f) isolating crystalline betrixaban maleate.
[0009] In one embodiment, the present invention provides a process for the preparation of betrixaban comprising:
a) contacting a compound of formula III
III II with a reagent selected from the group consisting of methyl chloroaluminum N, N-dimethyl amide, tetrakis (dimethylamino) titanium and dimethyl amine/CuCl or mixtures to form compound of formula II;
b) isolating betrixaban, a compound of formula II; and
c) optionally, converting betrixaban to salt, solvate or hydrate thereof.
BRIEF DESCRIPTION OF THE DRAWINGS
[0010]Fig. 1: PXRD pattern of crystalline betrixaban maleate, as obtained in Example 5.
[0011] Fig. 2: DSC pattern of crystalline betrixaban maleate, as obtained in Example 5.
[0012] Fig. 3: TGA of crystalline betrixaban maleate, as obtained in Example 5.
[0013] Fig. 4: PXRD pattern of amorphous betrixaban maleate, as obtained in Example 6.
[0014] Fig. 5: DSC pattern of amorphous betrixaban maleate, as obtained in Example 6.
[0015] Fig. 6: TGA of amorphous betrixaban maleate, as obtained in Example 6.
[0016] Fig. 7: PXRD pattern of crystalline betrixaban, as obtained in Example 1.
DETAILED DESCRIPTION OF THE INVENTION
[0017] In one embodiment, the present invention provides amorphous betrixaban maleate, a compound of formula I.
I
[0018] In one embodiment, the present invention provides amorphous betrixaban maleate having PXRD pattern, which is substantially in accordance with Fig. 4.
[0019] In one embodiment, the present invention provides amorphous betrixaban maleate characterized by differential scanning calorimetric (DSC) thermogram having an endothermic peak at about 113.94±2ºC.
[0020] In one embodiment, the present invention provides amorphous betrixaban maleate characterized by differential scanning calorimetric (DSC) thermogram, which is substantially in accordance with Fig. 5.
[0021] In one embodiment, the present invention provides amorphous betrixaban maleate characterized by thermogravimetric analysis (TGA) thermogram, showing a weight loss of about 1.66% at 100ºC and 2.81% at 150oC determined over the temperature range of 0ºC to 350ºC and heating rate of 10ºC/min.
[0022] In one embodiment, the present invention provides amorphous betrixaban maleate characterized by thermogravimetric analysis (TGA) thermogram, showing a weight loss of about 1.66% at 100ºC and 2.81% at 150oC determined over the temperature range of 0oC to 350ºC and heating rate of 10ºC/min which is substantially in accordance with Fig. 6.
[0023] In one embodiment, the present invention provides a process for the preparation of amorphous betrixaban maleate, a compound of formula I comprising:
a) dissolving betrixaban maleate in a solvent or mixture of solvents thereof to provide a solution; and
b) removing the solvent from the solution obtained in (a).
[0024] In one embodiment, in step a), the dissolution of betrixaban maleate may be achieved by heating a suspension or slurry of betrixaban maleate in solvent or mixture of solvents.
[0025] In one embodiment, the solvent in step a) may be selected from the group consisting of water, alcohols, ketones ethers, esters, amides, hydrocarbons and mixtures thereof.
[0026] In one embodiment, the solvent in step a) may be selected from the group consisting of water; alcohols such as methanol, ethanol, propanol, isopropanol, butanol, isobutanol, tert-butanol, n-pentyl alcohol, n-octyl alcohol and the like; ethers such as di isopropyl ether, diethyl ether, methyl tert-butyl ether, tetrahydrofuran, dioxane and the like; ketones such as acetone, ethyl methyl ketone, methyl isobutyl ketone and the like; esters such as ethyl acetate, methyl acetate, isopropyl acetate, isobutyl acetate, diisopropyl acetate; amides such as dimethylacetamide, dimethylformamide and the like; sulfoxide such as dimethyl sulfoxide; chlorinated solvents such as dichloromethane, chloroform, ethylene dichloride and the like; hydrocarbons such as benzene, hexane, toluene, xylene, cyclohexane, methylcyclohexane, heptane and the like; and mixtures thereof.
[0027] In one embodiment, the solvent is water.
[0028] In one embodiment, the solvent is a mixture of water and alcohol.
[0029] In one embodiment, the solvent is a mixture of water and methanol.
[0030] In one embodiment, the removal of solvent in step b) may be achieved by a process comprising complete evaporation of the solvent or concentrating the solution, cooling the solution if required and filtering to obtain the solid. The solution may also be completely evaporated in, for example, a rotavapor, rotacone vacuum dryer, a vacuum paddle dryer or in a conventional reactor under vacuum above about 700mm Hg, or evaporated by solvent distillation, vacuum distillation, lyophilization, freeze-drying technique, spray drying, fluid bed drying, flash drying, spin flash drying, thin-film drying etc.
[0031] In one embodiment, the removal of solvent in step b) may be achieved by a process comprising vacuum distillation, lyophillisation, spray drying, fluid bed drying, flash drying, spin flash drying, thin-film drying or filtration.
In one embodiment, the removal of solvent in step b) is achieved by lyophillisation.
In one embodiment, the amorphous betrixaban maleate is obtained by lyophillisation.
[0032] In one embodiment, the present invention provides amorphous betrixaban maleate which is isolated from an aq. alcoholic solution comprising betrixaban maleate.
[0033] In one embodiment, the present invention provides a process for the preparation of amorphous betrixaban maleate comprising subjecting an aqueous methanolic solution comprising betrixaban maleate to lyophillisation.
[0034] In one embodiment, the present invention provides a process for the preparation of amorphous betrixaban maleate comprising dissolving betrixaban maleate in methanol to obtain a reaction mixture. This reaction mixture is subjected to distillation under vacuum to obtain residue. The residue obtained is treated with methyl tert-butyl ether and the precipitated betrixaban maleate is filtered to isolate amorphous betrixaban maleate.
[0035] In one embodiment, the lyophillisation is carried out at a pressure of about less than 100 millitorr.
[0036] In one embodiment, the lyophillisation is carried out under following condition:
Lyophilizer Instrument: BenchTop Pro with Omnitronics TM SP Scientific Lyophillisation condition: Condenser temperature: -75°C to -85°C, Vacuum: less than 100 millitorr, Run time: 24h to 48h.
[0037] In one embodiment, the present invention provides a process for the preparation of amorphous betrixaban maleate by solvent-antisolvent method.
[0038] The isolation of amorphous betrixaban maleate which is precipitated on addition of an anti-solvent may be achieved by filtration or centrifugation.
[0039] The anti-solvent may be selected from the group consisting of water; hydrocarbons such as benzene, hexane, toluene, xylene, cyclohexane, methylcyclohexane, heptane and the like; ether such as di isopropyl ether, diethyl ether, methyl tert-butyl ether, tetrahydrofuran, dioxane and the like and mixtures thereof.
[0040] In one embodiment, the present invention provides a process for the preparation of amorphous betrixaban maleate, a compound of formula I, comprising:
I
a) contacting betrixaban maleate in water to obtain a reaction mixture; and
b) isolating amorphous betrixaban maleate from the above reaction mixture.
[0041] As used herein, the term “contacting” refers to suspending, slurrying or dissolving betrixaban maleate in a solvent.
[0042] In one embodiment, step ‘b’ involves isolation by lyophillisation.
[0043] In one embodiment, the present invention provides a purification of betrixaban by acid base method.
[0044] In one embodiment, the present invention provides stable amorphous form of betrixaban maleate which is at least stable during storage and drying.
[0045] As used herein, the term “stable” refers to betrixaban maleate, which retains its original polymorphic form without undergoing polymorphic conversion over time.
[0046] In one embodiment, the present invention provides amorphous betrixaban maleate which does not get converted to any other crystalline form of betrixaban maleate.
[0047] In one embodiment, the amorphous betrixaban maleate does not get converted to any other crystalline form of betrixaban maleate when exposed to a relative humidity of 75% at 40ºC or 60 % at 25ºC for a period of at least three months.
[0048] In one embodiment, the present invention provides a process for the preparation of a stable amorphous betrixaban maleate having no or little tendency to convert to any of the other polymorphic forms.
[0049] In one embodiment, the present invention provides a process for the preparation of a stable amorphous betrixaban maleate wherein the stable amorphous betrixaban maleate has no detectable quantity of any other crystal form of betrixaban maleate on storage.
[0050] In one embodiment, the present invention provides amorphous betrixaban maleate which is stored under nitrogen atmosphere at a temperature of about 2 ºC to about 8ºC.
[0051] The stable amorphous form of betrixaban maleate is stored under nitrogen atmosphere and packed in a LDPE (low density polyethylene) bag followed by black LDPE bag optionally containing oxygen busters and sealing it, which is kept in triple laminated aluminum pouch optionally containing oxygen busters and sealing it, which is placed in HDPE (high density polyethylene) drum and stored in controlled environment chamber, at a temperature of about below 8°C. Preferably, the stable amorphous form of betrixaban maleate is stored under nitrogen atmosphere and packed in a LDPE bag followed by black LDPE bag and is kept in triple laminated aluminum pouch placed in HDPE drum at about 2°C to about 8°C.
[0052] In one embodiment, the present invention provides a solvate of betrixaban maleate.
[0053] The solvate may be selected from the group consisting of methanol, ethanol, propanol, isopropanol, butanol, isobutanol, tert butanol, methyl tert butyl ether, tetrahydrofuran, acetone, methyl ethyl ketone.
[0054] In one embodiment, the present invention provides crystalline betrixaban maleate characterized by X-ray Diffraction (XRD) spectrum having peak reflections at about 3.4, 11.4, 19.8, 21.2 and 24.9 ±0.2 degrees 2 theta.
[0055] In one embodiment, the present invention provides crystalline betrixaban maleate characterized by X-ray diffraction (XRD) spectrum having peak reflections at about 3.4, 11.4, 19.8, 21.2 and 24.9±0.2 degrees 2 theta which is substantially in accordance with Fig. 1.
[0056] In one embodiment, the present invention provides crystalline betrixaban maleate characterized by differential scanning calorimetric (DSC) thermogram having endothermic peak at about 86.85±2oC.
[0057] In one embodiment, the present invention provides crystalline betrixaban maleate characterized by differential scanning calorimetric (DSC) thermogram having endothermic peak at about 86.85±2oC which is substantially in accordance with Fig 2.
[0058] In one embodiment, the present invention provides crystalline betrixaban maleate characterized by thermogravimetric analysis (TGA) thermogram, showing a weight loss of about 3.14% at 100oC and about 2.07% at 150oC determined over the temperature range of 0oC to 350oC and heating rate 10oC/min.
[0059] In one embodiment, the present invention provides crystalline betrixaban maleate characterized by thermogravimetric analysis (TGA) thermogram, showing a weight loss of about 3.14% at 100oC and about 2.07% at 150oC and heating rate 10oC/min., which is substantially in accordance with Fig. 3.
[0060] In one embodiment, the present invention provides a hydrate of betrixaban maleate having a water content of about 2% to about 8% as measured by Karl Fischer method.
[0061] In one embodiment, the present invention provides a process for the preparation of crystalline betrixaban maleate comprising:
a) contacting betrixaban with a solvent or a mixture of solvents to obtain reaction mixture;
b) adding maleic acid to the reaction mixture of step ‘a’;
c) optionally, heating the above mixture of step ‘b’;
d) optionally filtering the reaction mass;
e) cooling the filtrate; and
f) isolating crystalline betrixaban maleate.
[0062] In one embodiment, step ‘a’ of the above process involves contacting betrixaban with a suitable solvent to obtain a reaction mixture.
[0063] In one embodiment, the solvent may be selected from the group consisting of water, alcohol, ether, ketone, hydrocarbon, esters and mixtures thereof.
[0064] The suitable solvent may be selected from the group consisting of water; alcohols such as methanol, ethanol, propanol, isopropanol, butanol, isobutanol, tert-butanol, n-pentyl alcohol, n-octyl alcohol and the like; ethers such as diisopropyl ether, diethyl ether, methyl tert-butyl ether, tetrahydrofuran, dioxane and the like; ketones such as acetone, ethyl methyl ketone, methyl isobutyl ketone and the like; esters such as ethyl acetate, propyl acetate, isopropyl acetate and the like; amides such as dimethyl formamide, dimethyl acetamide and the like; sulfoxides such as dimethyl sulfoxide; chlorinated solvents such as dichloromethane, chloroform, ethylene dichloride, and the like; hydrocarbons such as benzene, hexane, toluene, xylene, cyclohexane, methylcyclohexane, heptane and the like and mixtures thereof.
[0065] In one embodiment, the solvent is a mixture of water and alcohol.
[0066] In one embodiment, the solvent is a mixture of water and ethanol.
[0067] In one embodiment, step ‘b’ of the process involves adding maleic acid to the above reaction mixture of step ‘a’.
[0068] In one embodiment, step ‘c’ of the process involves heating of the above reaction mixture of step ‘b’ from a temperature of about 30ºC to about reflux temperature of the solvent.
[0069] In one embodiment, in step ‘c’ of the process, the reaction mixture is heated to a temperature of about 50ºC to about 55ºC.
[0070] In one embodiment, step‘d’ of the process involves filtering the reaction mixture to remove any undissolved impurities.
[0071] In one embodiment, in step ‘e’, the filtrate containing betrixaban maleate is gradually cooled to a temperature below 50ºC.
[0072] In one embodiment, in step ‘e’, the filtrate containing betrixaban maleate is gradually cooled to a temperature below 25ºC.
[0073] In one embodiment, step ‘e’ the filtrate containing betrixaban maleate is gradually cooled to a temperature below 19ºC.
[0074] In one embodiment, in step ‘e’, the filtrate containing betrixaban maleate is gradually cooled to a temperature between about 0 to about 5ºC.
[0075] This filtrate is subjected to stirring for a period of about 10 min to about 3 hours to obtain complete precipitation.
[0076] In one embodiment, the filtrate is cooled to a temperature below 19ºC.
[0077] In one embodiment, step ‘f’ of the process involves isolation of the precipitated betrixaban maleate by filtration or centrifugation.
[0078] In one embodiment, the present invention provides a process for the preparation of crystalline betrixaban maleate comprising cooling an alcoholic solution comprising betrixaban maleate to obtain crystals of betrixaban maleate.
[0079] In one embodiment, the present invention provides a process for the preparation of crystalline betrixaban maleate wherein the molar ratio of the content of betrixaban maleate and content of ethanol in the solution is about 1: 10 to about 1:70.
[0080] In one embodiment, the present invention provides a process for the preparation of crystalline betrixaban maleate wherein the molar ratio of content of betrixaban maleate and content of ethanol in solution is about above 1: 25 to about 1:70.
[0081] In one embodiment, the present invention provides a process for the preparation of crystalline betrixaban maleate wherein the molar ratio of content of betrixaban maleate and content of ethanol in the solution is about above 1: 35 to about 1:70.
[0082] In one embodiment, the present invention provides a process for the preparation of crystalline betrixaban maleate wherein the molar ratio of content of betrixaban maleate and content of ethanol in the solution is about above 1: 45 to about 1:70.
[0083] In one embodiment, the present invention provides a process for the preparation of crystalline betrixaban maleate wherein the molar ratio of content of betrixaban maleate and content of ethanol in the solution is about above 1: 55 to about 1:70.
[0084] In one embodiment, the present invention provides a process for the preparation of crystalline betrixaban maleate wherein the molar ratio of content of betrixaban maleate and content of ethanol in the solution is 1: 54.5.
[0085] In one embodiment, the present invention provides a process for the preparation of crystalline betrixaban maleate wherein betrixaban is reacted with maleic acid in a mole ratio of 1:1.
[0086] In one embodiment, the present invention provides a process for the preparation of crystalline betrixaban maleate comprising:
a) reacting betrixaban and maleic acid in a molar ratio of 2:1 to 1:1.9 in aqueous C1-C5 alcoholic solvent;
b) heating the reaction mixture to about 40ºC to about 80ºC for about 0.5h to about 2h;
c) optionally, filtering the reaction mixture;
d) cooling the reaction mixture to about below 15ºC and maintaining for about 30 min; and
e) isolating crystalline betrixaban maleate.
[0087] In one embodiment, the present invention provides a process for the preparation of crystalline betrixaban maleate wherein betrixaban maleate is crystallized during cooling an aqueous alcoholic solution comprising betrixaban maleate.
[0088] In one embodiment, the present invention provides a process for the preparation of crystalline betrixaban maleate wherein betrixaban maleate is crystallized during cooling an aqueous ethanolic solution comprising betrixaban maleate.
[0089] In one embodiment, it is envisaged that crystalline betrixaban maleate may be obtained from a solution of acetone and water.
[0090] In one embodiment, it is envisaged that crystalline betrixaban maleate may be obtained from a solution of tetrahydrofuran and water.
[0091] In one embodiment, the present invention provides crystalline betrixaban maleate characterized by X-ray diffraction (XRD) spectrum having peak reflections at about 3.4, 11.4, 19.8, 21.2 and 24.9 ±0.2 degrees 2 theta isolated without seeding.
[0092] In one embodiment, the present invention provides crystalline betrixaban maleate by solvent-anti-solvent method.
[0093] In one embodiment, the present invention provides crystalline betrixaban maleate characterized by XRPD spectrum which is substantially in accordance with Fig 1.
[0094] In one embodiment, the present invention provides crystalline betrixaban maleate characterized by differential scanning calorimetric (DSC) thermogram having endothermic peak at about 86.85±2oC which is substantially in accordance with Fig 2.
[0095] In one embodiment, the present invention provides crystalline betrixaban maleate having melting point of about 85.5°C.
[0096] In one embodiment, the present invention provides stable crystalline betrixaban maleate which does not get converted to any other crystalline form of betrixaban maleate.
[0097] As used herein, the term “stable” refers to crystalline betrixaban maleate, characterized by XRD spectrum which is substantially in accordance with Fig 1 and retains its original polymorphic form without undergoing polymorphic conversion over time.
[0098] In one embodiment, crystalline betrixaban maleate of the present invention does not get converted to any other crystalline form of betrixaban maleate when exposed to a relative humidity of 75% at 40ºC or 60 % at 25ºC for a period of at least three months.
[0099] In one embodiment, the present invention provides a process for the preparation of a stable crystalline betrixaban maleate having no or little tendency to convert to any of the other polymorphic forms.
[0100] In one embodiment, the present invention provides a process for the preparation of a stable crystalline betrixaban maleate wherein the stable crystalline betrixaban maleate has no detectable quantity of any other form of betrixaban maleate on storage.
[0101] In one embodiment, the present invention provides a process for the preparation of betrixaban comprising:
a) contacting a compound of formula III
III II
with a reagent selected from the group consisting of methyl chloroaluminum N,N-dimethyl amide, tetrakis(dimethylamino)titanium and dimethyl amine/CuCl and mixtures to form compound of formula II; and
b) isolating betrixaban, a compound of formula II.
[0102] In one embodiment, step a) of above process is carried out in presence of a suitable solvent.
[0103] The solvent may be 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, pyran, 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, carbon tetrachloride and the like; dimethylsulfoxide; sulfolane; amides such as dimethyl acetamide, dimethylformamide; water and mixtures thereof.
[0104] In one embodiment, step ‘b’ involves isolation of betrixaban by filtration, extraction, distillation and the like.
[0105] In one embodiment, the present invention provides crystalline betrixaban.
[0106] In one embodiment, the present invention provides betrixaban characterized by X-ray diffraction (XRD) spectrum having peak reflections at about 8.2, 15.2, 15.9, 23.4 and 27.2 ±0.2 degrees 2 theta.
[0107] In one embodiment, betrixaban obtained by the above process may be converted further to an acid addition salt.
[0108] In one embodiment, the present invention provides crystalline betrixaban characterized by X-ray Diffraction (XRD) spectrum which is substantially in accordance with Fig 7.
[0109] The acid addition salt may be selected from maleic acid, succinic acid, hydrochloric acid, oxalic acid, benzoic acid and fumaric acid.
[0110] In one embodiment, the present invention provides a process for the preparation of betrixaban comprising converting the compound of formula III to betrixaban or a salt thereof in absence of lithium dimethylamine.
[0111] In one embodiment, the present invention provides betrixaban with a chemical purity of at least 99% w/w and chiral purity of at least 99% as measured by HPLC.
[0112] In one embodiment, the present invention provides betrixaban with a chemical purity of at least 99.9% w/w and chiral purity of at least 99.9% as measured by HPLC.
[0113] 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.
[0114] 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.
[0115] 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.
[0116] 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 as defined in the features and advantages.

Examples
Example 1: Preparation of N-(5-chloropyridin-2-yl)-2-[4-(N,N-dimethyl-carbamimidoyl)-benzoylamino]-5-methoxybenzamide
In a flask with nitrogen atmosphere dimethyl amine solution (56mL 2N in tetrahydrofuran (THF)) was added and cooled to about 0°C to about 5°C. To this solution, hexyl lithium solution (54mL, 33% in hexane) was added slowly at about
-5°C to about 5°C. The suspension was stirred at about 0°C to about 5°C for about 30 mins. In another flask N-(5-chloropyridin-2-yl)-2-[(4-cyanobenzoyl) amino]-5-methoxybenzamide (10g) was added to THF (100mL). The slurry was cooled to about -10°C and added above dimethyl amide solution slowly. The reaction mixture was stirred for about 2h at a temperature of about -15°C to about -10°C. The temperature of reaction mixture was raised to about -5°C and quenched with saturated solution of sodium bicarbonate and sodium carbonate. The temperature of reaction mixture was raised to about room temperature and stirred overnight. The solid was filtered, washed with water and suck dried under vacuum. The aqueous layer was extracted with ethyl acetate and distilled under vacuum to get residue. To the obtained residue, diisopropyl ether was added and stirred for about 30 mins and filtered to get betrixaban which was dried in vacuum tray dryer at 40-45°C to get betrixaban free base as yellow solid (6.1g).
1H-NMR (400MHz, DMSO, d6) peaks at 2.97, 3.82 , 6.81, 7.04-7.09 , 7.58 , 7.83, 7.93-8.13 , 8.26-8., 10.66
13C-NMR (100 MHz, DMSO, d6) peaks at 167.8, 166.4, 164.4, 162.4, 154.8, 152.1, 150.9, 146.7, 146.3, 141.6, 137.7, 136.7, 128.5, 127.9, 126.6, 123.8, 123.5, 117.8, 115.6, 114.2, 110.6, 55.8.
IR (KBr, umax/cm-1): 3315, 3159, 2932, 1667, 1645, 1593, 1515, 1455, 1419, 1371, 1292, 1211, 1115, 1069, 823, 771

XRD peaks of betrixaban
Pos. [°2Th.] d-spacing [Å] Rel. Int. [%] Pos. [°2Th.] d-spacing [Å] Rel. Int. [%]
6.35 13.90 12.27 21.20 4.18 25.23
8.20 10.77 51.48 22.50 3.95 5.32
9.21 9.59 6.39 23.25 3.82 14.85
10.16 8.70 31.29 23.50 3.78 75.89
11.018 8.02 24.63 23.98 3.71 20.53
12.75 6.94 5.09 24.79 3.59 8.08
13.77 6.42 61.41 25.64 3.47 17.51
15.2 5.77 37.00 25.89 3.44 29.21
15.90 5.57 22.12 26.47 3.36 21.05
16.42 5.39 45.98 26.84 3.32 20.87
17.63 5.03 33.38 27.32 3.26 100.00
18.06 4.90 5.96 27.75 3.21 9.11
18.55 4.78 9.14 28.31 3.15 7.61
18.82 4.71 10.16 28.75 3.10 11.20
19.84 4.47 30.38 29.74 3.00 2.79
20.37 4.35 26.66 30.86 2.89 8.92
20.70 4.29 12.40
DSC: Endothermic peaks at 144.47, 153.33, 198.93 and 249.28°C; TGA: 0.46% upto 100°C.
Example 2:
In a suspension of N-(5-chloropyridin-2-yl)-2-[(4-cyanobenzoyl)amino]-5-methoxybenzamide (3g) in methanol (150mL) and ethyl acetate (150 mL); HCl gas was purged till saturation. The reaction mixture was stirred overnight and evaporated to get a solid. The obtained solid was suspended in methanol (200mL) and dimethylamine gas was purged in the solution till alkaline pH was reached. The reaction mixture was refluxed for about 5h. The reaction mixture was cooled to about room temperature and evaporated to get solid betrixaban free base (2g).
Example 3:
To a suspension of N-(5-chloropyridin-2-yl)-2-[(4-cyanobenzoyl) amino]-5-methoxybenzamide (5g) in dry toluene; a solution of methylchloroaluminum N, N-dimethylamide (2.0 eq) was added. The reaction mixture was heated to about 80°C for about 24h under nitrogen atmosphere. The reaction mixture was distilled to get residue, which was purified by column chromatography using methylene dichloride/methanol as an eluent to get solid betrixaban free base (2.5g).
Example 4:
To a solution of N-(5-chloropyridin-2-yl)-2-[(4-cyanobenzoyl) amino]-5-methoxybenzamide (3g) in dimethyl sulfoxide (20mL); copper (I) chloride (1g) was added. The reaction mixture was stirred for about 15 mins followed by addition of 30mL dimethyl amine solution (2N in THF). The resulting slurry mass was heated to about 80°C and maintained for about 24h. The reaction mixture was cooled to about room temperature and quenched with sodium hydroxide solution. The product was extracted with ethyl acetate. The organic layer concentrated under vacuum at about 45°C to give betrixaban free base (1.5g).
Example 5: Preparation of crystalline betrixaban maleate
Betrixaban (5.0g, 0.011moles) and maleic acid (1.3g, 0.011moles) was suspended in a mixture of ethanol/water (60mL, 35:65). The slurry was heated to about 55°C and stirred for about 30 mins. To this slurry; a mixture of ethanol/water (20mL, 35:65) was added and the reaction mixture was maintained at about 55°C for about 30 mins. The reaction mixture was filtered and washed with mix of ethanol-water (20mL, 35:65). The filtrate was cooled to a temperature from about 5°C to about 0°C and maintained for 30 mins. The solid was filtered, washed with water and dried in tray dryer at about 40°C to about 45°C to obtain 2.85g of betrixaban maleate.
1H-NMR (400MHz, DMSO, d6) peaks at 3.0, 3.25 , 3.86 , 6.05 , 7.44 , 7.77 , 7.91-8.14 , 8.49, 9.05 , 9.4, 11.06, 11.15 , 13C-NMR (100MHz, DMSO, d6) peaks at 167.7, 166.4, 164.4, 162.4, 154.8, 152.1, 150.9, 146.7, 146.3, 141.6, 137.7, 136.7, 128.5,,127.9, 126.6, 123.8, 123.5, 120.15, 117.8, 115.6, 114.2, 110.6, 55.7; IR (KBr, umax/cm-1): 3418, 3108, 2947, 1660, 1633, 1598, 1537, 1461, 1374, 1297, 1236, 1115, 1034, 849, 833, 742, 711.
XRD table of crystalline betrixaban maleate
Pos. [°2Th] d-spacing [Å] Rel. Int. [%] Pos. [°2Th] d-spacing [Å] Rel. Int. [%]
3.4 26.1 100.00 17.17 5.16 10.07
6.86 12.8 2.53 19.82 4.47 28.84
8.40 10.52 14.46 21.20 4.19 15.63
10.29 8.59 3.74 24.09 3.69 20.10
11.41 7.75 38.20 24.94 3.56 28.17
11.97 7.38 14.13 26.41 3.37 35.09
13.65 6.48 23.43 31.21 2.86 12.03
14.24 6.21 13.58 34.82 2.57 5.60

DSC: Endothermic peak at about 86.85±2oC. TGA: 3.14% at 100oC, water content by K.F: 7.2% w/w.
Example 6: Preparation of amorphous betrixaban maleate
Crystalline betrixaban maleate (0.5g) was dissolved in 50 mL methanol. Methanol was distilled under vacuum from this solution at about below 45°C to get a residue. Methyl tert-butyl ether was added to the residue and distilled under vacuum to get solid amorphous betrixaban maleate (0.45g). 1H-NMR (400MHz, DMSO, d6) peaks at 2.99 , 3.24 , 3.86 , 6.04, 7.2, 7.44 , 7.77, 7.91-8.14 , 8.44, 9.03 , 9.40 , 11.05 , 11.16
13C-NMR (100 MHz, DMSO, d6) peaks at 167.8, 166.4, 164.4, 162.4, 154.8, 152.1, 150.9, 146.7, 146.3, 141.6, 137.7, 136.7, 128.5, 127.9, 126.6, 123.8, 123.5, 117.8, 115.6, 114.2, 110.6, 55.8. IR (KBr, umax/cm-1): 3315, 3159, 2932, 1667, 1645, 1593, 1515, 1455, 1419, 1371, 1292, 1211, 1115, 1069, 823, 771 DSC: Endothermic peak at about 113.94±2oC. TGA: 1.66% at 100oC.

Example 7: Preparation of amorphous betrixaban maleate
Betrixaban maleate (0.5g) was dissolved in 50mL acetone. The solution was distilled under vacuum at about below 45°C to obtain a residue. Methyl tert butyl ether was added to the residue and the resulting solution was distilled under vacuum to get amorphous betrixaban maleate (0.40g).
Example 8: Preparation of betrixaban maleate amorphous form
Betrixaban maleate (0.5g) was dissolved in 50mL THF. The solution was distilled under vacuum at about below 45°C to obtain a residue. Methyl tert butyl ether was added to the residue and the resulting solution was distilled under vacuum to get amorphous betrixaban maleate (0.42g).
Example 9: Amorphous form using lyophilization
Crystalline betrixaban maleate (0.5g) was dissolved in water (20mL) and 30 mL methanol was added to this solution. The resulting solution was cooled and water was further added (20mL) to the solution and reaction mass was lyophilized overnight using lyophilizer to get amorphous betrixaban maleate (0.4 g).
,CLAIMS:We Claim:
1] Amorphous betrixaban maleate, a compound of formula I.
I
2] Amorphous betrixaban maleate characterized by differential scanning calorimetric (DSC) thermogram having an endothermic peak at about 113.94±2oC.
3] A process for the preparation of amorphous betrixaban maleate, a compound of formula I comprising:
a) dissolving betrixaban maleate in a solvent or mixture of solvents to provide a solution; and
b) removing the solvent from the solution obtained in (a) to obtain amorphous betrixaban maleate.
4] The process as claimed in claim 3, wherein the solvent is selected from the group consisting of water, alcohol, ketone, ether, esters, amides, hydrocarbons and mixtures thereof.
5] The process as claimed in claim 4, wherein the solvent is water.
6] The process as claimed in claim 4, wherein the solvent is a mixture of water and alcohol.
7] The process as claimed in claim 3, wherein removal of solvent is achieved by a process comprising vacuum distillation, lyophillisation, spray drying, fluid bed drying, flash drying, spin flash drying, thin-film drying or filtration.
8] The process as claimed in claim 3, wherein removal of solvent is achieved by lyophillisation.
9] Crystalline betrixaban maleate characterized by X-ray Diffraction (XRD) spectrum having peak reflections at about 3.4, 11.4, 19.8, 21.2 and 24.9 ±0.2 degrees 2 theta.
10] A process for the preparation of crystalline betrixaban maleate, a compound of formula I comprising:
a) contacting betrixaban with a solvent or mixture of solvents to obtain reaction mixture;
b) adding maleic acid to the reaction mixture of step ‘a’;
c) optionally, heating the above mixture of step ‘b’;
d) filtering the reaction mass;
e) cooling the filtrate; and
f) isolating crystalline betrixaban maleate.
11] The process as claimed in claim 10, wherein the solvent is selected from the group consisting of water, alcohol, ether, ketone, hydrocarbon, esters and mixtures thereof.
12] The process as claimed in claim 10, wherein the solvent is a mixture of water and alcohol.
13] The process as claimed in claim 10, wherein the solvent is a mixture of water and ethanol.
14] The process as claimed in claim 10, wherein the filtrate is cooled to a temperature below 19ºC.
15] The process as claimed in claim 10, wherein the isolated crystalline betrixaban maleate is characterized by X-ray Diffraction (XRD) spectrum having peak reflections at about 3.4, 11.4, 19.8, 21.2 and 24.9 ±0.2 degrees 2 theta.
16] A process for the preparation of betrixaban comprising:
a) contacting a compound of formula III
with a reagent selected from the group consisting of methyl chloroaluminum N, N-dimethyl amide, tetrakis(dimethylamino)titanium and dimethyl amine/CuCl and mixtures to form compound of formula II;
III II
b) isolating betrixaban, a compound of formula II; and
c) optionally, converting betrixaban to salt, solvate or hydrate thereof.

Dated this 18th day of July, 2018

(Signed)____________________
Dr. Madhavi Karnik
Senior General Manager-IPM
Glenmark Pharmaceuticals Limited