FIELD OF THE INVENTION
The present invention relates to a process for the preparation of- Betrixaban maleate of Formula-I
BACKGROUND OF THE INVENTION
Betrixaban is chemically known as N-(5-chloropyridin-2-yl)-2[4-(N,N-dimethyl carbamimidoyl)-benzoylamino]-5-methoxybenzamide and structure depicted by Formula-II
Betrixaban has been approved in USFDA and marketed by Portola Pharmaceuticals under the Trade name of BEVYXXA®, vvhich contains Betrixaban in the form of its maleate salt, i.e Betrixaban maleate. Betrixaban maleate has the structure as shown below.
BEVYXXA is in the form of capsules with approved dosages of 40 mg and 80 mg for oral
administration, BEVYXXa is indicated for the prophyiaxis of venonus 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.
U.S. Patent No.6,376,515 (US.'515) discloses Betrixaban and pharmaceutically acceptable salts thereof.
U.S. Patent No. 7,598,276 discloses Betrixaban maleate crystalline Form-I and its process for the preparation thereof; U.S. Patent No. 8,946,269 discloses Betrixaban maleate crystalline Form-II, Form-III and its process for the preparation thereof.
US'515 and Bioorganic & Medicinal Chemistry Letters 2009, Volume 19(8), Pages: 2179-2185 discloses the following scheme for the preparation of Betrixaban.
This process involves a two-step method, in the first step nitrile is first converted to the methoxy imidate intermediate and in the second step dimethylamine is reacted. In first step methanol and highly corrosive HC1 gas has been used to yield methoxy imidate intermediate. This process involves HC1 (gas) in huge quantities and due to its corrosive nature industrially not acceptable.

US 8,394,964 B2 (US'964) discloses a process for the preparation of Betrixaban. The process disclosed in US'964 is as shown below:
US 8,524,907 (US'907) discloses a process for the preparation Betrixaban. The process disclosed in US'907 is as shown below:
In the above process reagent LiN(CH3)2 has been prepared by contacting dimethylamine with n-hexyllithium. However, this reagent is expensive and requires more stringent storage conditions and there by results in higher production cost.

The present inventors has repeated the above process and observed that the product obtained by these processes requires tedious workup, difficult to remove inorganic metals and impurities i.e dechlorinated impurities, which lead to low yields and low purity of Betrixaban.
CN 107382897 A discloses a process for the preparation Betrixaban, which is as shown below:
Tn the above process NaHMDS has been used, which is highly expiosive reagent and hence it is very difficult to handle in the industrial production.
CN 104693114 (CNM 14) discloses a process for the preparation of Betrixaban. The process disclosed in CN'l 14 is as shown below.
The present inventors have repeated the above process and observed that the reaction is incomplete; time consuming; formation of more impurities; low yield and purity.
Further the prior art processes discloses the column purification methods to increase the purity of Betrixaban, however it is not economie, commercial and industrially feasible.

In view of the above, to overcome the prior-art problems the present inventors had now developed an improved process for the preparation of Betrixaban, which is industrially viable process» having industrially friendly solvents, and does not include tedious work up and time lagging steps.
OBJECTIVES OF THE INVENTION
The objective of the present invention is to provide a process for the preparation of Betrixaban maleate, which is commercially and industrially feasible / viable.
Another objective of the present invention is to provide a process for the preparation of Betrixaban maleate, which results in high yield and high purity.
Another objective of the present invention is to avoid column chromatography and obtain Betrixaban in high purity.
SUMMARY OF THE INVENTION
The present invention relates to a process for the preparation of Betrixaban maleate compound of formula I, which comprises:
a. reacting the compound of Formula III or its acid addition salts;
with dimethyl amine or its salt thereof and a compound of formula IV ,

optionally in the presence of an organic solvent;
b. adjusting the pH to 1.0 - 3.0 with suitable acid to obtain compound of Formuia-V as its
acid addition salts;
c. desalifying the compound of Formula V to obtain Betrixaban of Formula-II;
d. optionally purifying the Betrixaban; and
e. converting Betrixaban to Betrixaban maleate of compound Formula I.
The present invention relates to a process for the preparation of Betrixaban maleate compound of formula I, which comprises:
a. reacting the compound of Formula 111 or its acid addition salts;

optionally in presence of an organic solvent;
b. adjusting the pH to 1.0 - 3.0 with suitable acid to obtain compound of Formula-V as its
acid addition salts;
c. desalifying the compound of Formula V to obtain Betrixaban of Formula-II;
d. optionally purifying the Betrixaban; and
e. converting Betrixaban to Betrixaban maleate of Formula I.
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to a process for the preparation of Betrixaban maleate, which comprises: reacting the compound of Formula III or its acid addition salts with dimethylamine or its salt and a compound of Formula IV,optionally in the presence of an organic solvent, foliowed by adjusting the pH 1-3 with suitable acid to get compound of Formula V as its acid addition salts; desalifying compound of Formula V with base in

presence suitable solvent to obtain Betrixaban compound of Formula-II; optionally purifying the Betrixaban compound of Formula-II; and converting Betrixaban to Betrixaban maleate of Formula I.
In another aspect of the present invention, atternate process for the preparation of compound of Formula V, which comprises: reacting the compound of Formula III or its acid addition salts with compound of Formula VI, optionally in the presence of an organic solvent, foliowed by adjusting the pH 1-3 with suitable acid to get compound of Formula V as its acid addition salts.
In another aspect of the present invention, acid addition salt of Formula III is selected from group comprising of hydrochloric acid, methane sulfonic acid, maleic acid, hydrobromic acid, tartaric acid, succinic acid, oxalic acid and sulphuric acid.
In another aspect of the present invention, compound of Formula III or its acid addition salts with dimethylamine or its salt thereof and a compound of Formula IV is performed optionally in the presence of solvent; wherein solvent is selected from the group comprising of ethers and hydrocarbons; ethers include but not limited to such as diethylether, di isopropyl ether, dibutyl ether, diisobutyl butyl ether, methyl tert-butyl ether, l,4dioxane, tetrahydrofuran, methyltetrahydrofuran, cyclopentylmethyl ether, ethylene glycol ether, anisole, dimethoxymethane; Hydrocarbons includes but not limited to toluene, xylene, hexane, heptane and cyclohexane or a mixed solvents thereof.
In another aspect of the present invention, reacting compound of Formula III or its acid addition salts with dimethylamine or its salts and a compound of Formula IV is performed at suitable temperature, wherein suitable temperature is in the range of -10°C to 40°C, preferably 0°C to 10°C;
In another aspect of the present invention, compound of Formula III or its acid addition salts with compound of Formula VI performed at suitable temperature and optionally in the presence of solvent; suitable temperature is in the range of -10°C to 40°C, preferably 0°C to 10°C; wherein the soivent is selected from the group comprising of ethers and hydrocarbons; ethers include but not limited to such as diethylether, diisopropyl ether, di

butylether, di isobutyl butyl ether, methyl tert-butyl ether, l,4dioxane, tetrahydrofuran, methyltetrahydrofuran, cyclopentylmethyl ether, ethylene glycol ether, dimethoxymethane; Hydrocarbons includes but not limited to toluene, xylene, hexane, heptane and cyclohexane or a mixed solvents thereof.
In another aspect of the present invention, the process preparation of compound of Formula VI, which comprises reacting the compound of Formula IV (is also known as turbo grignard reagent) with dimethyl amine or its salts, optionally in presence of an organic solvent, wherein organic solvent selected from the group comprising of ethers; ethers include but not limited to such as diethylether, diisopropyl ether, dibutyl ether, di isobutyl ether, methyl tert-butyl ether, l,4dioxane, tetrahydrofuran, methyltetrahydrofuran, cyclopentylmethyl ether, ethylene glycol ether, dimethoxymethane.
The compound of Formula VI is isolated and it is more stable reagent and accordingly can be stored under normal conditions. This is very beneficia! industriaily as some times if batch process delays and product is stable and is not decomposed.
In another aspect of the present invention, turbogrignard reagent is reacted with dimethylamine or its salt at suitable temperature to get compound of Formula VI.
In another aspect of the present invention, turbogrignard reagent is reacted with dimethylamine or its salt at a temperature of-10°C to 40°C, preferably 0°C to 25°C.
In another aspect of the present invention, the pH of the reaction mass is adjusted to 1.0 - 3.0 using suitable acid, then added suitable solvent to the reaction mass and stirred for 30-60 min at 25-30°C and filtered the solid to obtain compound of Formula V as its acid addition salt; wherein solvent is selected from the group comprising of ethers, such ds diethyl ether, dipropyl ether, dibutyl ether, diisobutyl ether tetrahydrofuran, dioxane; ketones, such as acetone, ethyl methyl ketone; esters, such as methyl acetate, ethyl acetate, nitrogen-containing solvents, such as dimethylacetamide, N,N-dimethyl formamide, formamide, acetonitrile, pyridine, N-methylpyrrolidone, sulfur-containing solvents, such as carbon disulfide, dimethyl sulfoxide, sulfolane.

In another aspect of the present invention, "acid addition salts" as used herein can be prepared from the free base forms of the compounds by reaction of the latter with pharmaceutically acceptable acid, foliowed by isolation of salt by conventional techniques, if required. A salt can be prepared Insitu during the final isolation and purification of a compound or by separately reacting the purifled compound in its free base form with a suitable organic or inorganic acid and isoiating the salt thus formed.
Suitable acids for forming acid addition salts of the compounds used in the present invention include, but are not limited to acetic acid , benzoicacid, p-toluene sulphonic acid, benzenesulfonic acid, hydrobromic acid, hydrochloric acid, citricacid, succinic acid, tartaricacid, lacticacid, malie acid, maleicacid, oxalicacid, camphorsulphonicacid, methanesulfonic acid, palmoic acid, salicylic acid, stearic acid, succinicacid, sulfuric acid.
In another aspect of the present invention, desaliflcation of the compound of Formula-V is carried out by treating with base. Base is added to adjust the pH 7-9 in presence of suitable solvcnt, stirred for 1-2 hrs and filtered the solid to obtaiu Belrixaban of Formula-II; wherein suitable base includes organic base or inorganic base; organic bases such as organic primary, secondary or tertiary amines, preferably triethylamine; inorganic bases such as carbonates, bicarbonates of a metal cation or ammonia. Suitable solvents selected from the group comprising of ketones, preferably acetone.
In another aspect of the present invention, the yield of Betrixaban compound of Formula-II has been obtained more than 90% and its purity is > 99% by HPLC chromatography.
In another aspect of the present invention, optionally purifying the compound of Formula-II. Betrixaban can be purified by conventional purification methods. The term "conventional techniques" as used herein includes but not limited to distillation, distillation under reduced pressure or vacuüm, evaporation, solvent-anti solvent, recrystallization, spray drying, lyophilization or freeze drying.
In another aspect of the present invention, Betrixaban purified by solvent-anti solvent method by using solvents selected from N,N-dimethylacetamide and toluene.

In another aspect of the present invention, Betrixaban obtained by using this process can be used in the synthesis of Betrixaban maleate.
In another aspect of the present invention, the use of compound of Formula-IV or Formula VT in the synthesis of Betrixaban maleate.
Betrixaban maleate prepared by the processes disclosed herein controls the desmethyl impurity, amide impurity, deschloro impurity formation. The formation of impurities within the limits/.e lessthanO.1%
In the following section embodiments are described by way of examples to illustrate the process of invention. However, these do not limit the scope of the present invention. Variants of these examples would be evident to persons ordinarily skilied in the art.
Examples:
Example-l:
Preparation of N-(5-chloropyridin-2-yl)-2[4-(N,N-dimethyl carbamimidoyl)-
benzoylamino|-5-methoxybenzamide hydrochloride (compound of Formula V)
To a solution of dimethylamine in THF (675 ml) added to N-(5-chloropyridin-2-yl)-2(4 cyano benzamido]-5-methoxybenzamide hydrochloride (lOOgm) at 25-30°C and stirred for 15-30 min and cooled to 0-5°C. To this reaction mass isopropyl magnesium chloride.LiCl (955 ml) added drop wise over a period of 1 hr at 0-5°C. Stirred the reaction mass for 1-2 hours and quenched the reaction mass by adjusted the pH 1-2 with HC1. Added ethyl acetate (lOOOml) and stirred the above reaction mass for 30-60 min at 25-30°C. Filtered the solid to get desired compound. Yield: 120 gms Chromatographic purity - 99.3% (by HPLC)
Example-2:
Preparation of N-(5-chloropyridin-2-yl)-2[4-(N,N-dimethyl carbamimidoyl)-
benzoylamino|-5-methoxybenzamide hydrochloride (compound of Formula V)

Charged N-(5-chloropyridin-2-yl)-2[4cyano benzamido]-5-methoxybenzamide hydrochloride (25gm) and dimethylamine in THF(170 ml) and cooled to 0-5°C. To this reaction mass isopropyl magnesium chloride.LiCl (24.8 ml) added drop wise at 0-5°C. Stirred the reaction mass for 1-2 hours and quenched the reaction mass by adjusted the pH 1-2 with HC1(50 ml). Added ethyl acetate (250ml) and stirred the above reaction mass for 30-60 min at 25-30°C. Filtered the solid to get desired compound. Yield: 30 gms Chromatographic purity - 99.4% (by HPLC)
ExampIe-3:
Preparation of N-(5-chloropyridin-2-yl)-2|4-(N,N-dimethyl carbamimidoyl)-
benzoylamino|-5-methoxybenzamide (compound of FormuIa-II)
Charged acetone (lOOOml) to N-(5-chloropyridin-2-yl)-2[4-(N>N-dimethylcarbamimidoyl)-
benzoylamino]-5-methoxybenzamide hydrochloride(120gm) at 25-30°C and adjusted pH 7-
8 with TEA, stirred for 45-60 min and filtered the solid to get desired compound.
Yield: 96 gms
Chromatographic purity - 99.47% (by HPLC)
Example-4:
Preparation of N-(5-chloropyridin-2-yl)-2[4-(N,N-dimethyl carbamimidoyl)-
benzoylamino]-5-methoxybenzamide (Compound of Formula-11)
Charged dimethylamine (677ml, 2M in THF) into RB flask and cooled to 15-20°C. To the above mass Isopropyl magnesium chloride lithium complex (955 ml, 1.3M in THF) was added over a period of 30-45 minutes. Stirred for 1-2 hours to get desired complex of Formula-VI. Charged N-(5-chloropyridin-2-yl)-2-(4-cyanobenzoylamino)-5-methoxy benzamide HC1 (100 gm) and THF in another RB flask and cooled to 10°C. To the above solution complex of Formula VI was added over a period of 30 minutes and maintained stirring for 2 hours. Adjusted the reaction mass pH to 1.0-2.0 with HC1 solution and added ethyl acetate (1000 ml) to the reaction mass for 15- 30 minutes at below 30°C Filtered the solid to get compound of FormulaV. Charged acetone (lOOOml) to N-(5-chloropyridin-2-yl)-2[4-(N,N-dimethylcarbamimidoyl)-benzoylamino]-5-methoxy

benzamide hydrochloride at 25-30°C and adjusted pH 7-8 with TEA, stirred for 45-60
min and filtered the solid to get compound of Formula TI.
Yield: 94gms
Chromatographic purity - 99.3% (by HPLC)
Example-5:
Preparation of Betrixaban maleate:
Charged 80% ethanol water (195 ml) to Betrixaban base (15gm) at 25-30°C, stirred for 20
min. Added maleic acid solution (7.7gm maleic acid in 80% ethanol water 30 ml) for 30-60
min, stirred for 2-3 hours. Distilled the ethanol and added DM water (30ml), cooled to 0-5°C,
Filtered the solid and dried to obtain Betrixaban maleate.
Yield: 14.5gm
Chromatographic purity- 99.89% (by HPLC)
Example-6:
Preparation of Betrixaban maleate:
Charged 80% ethanol water (1300 ml) to Betrixaban base (lOOgm) at 25-30°C, stirred for 20
min. Added maleic acid solution (5.1.3 gm maleic acid in 80% ethanol water 200 ml) for 30-
60 min? stirred for 2-3 hours. Distilled the ethanol and arlded DM water (200ml), cooled to 0-
5°C, Filtered the solid and dried to obtain Betrixaban maleate.
Yield: 98 gm
Chromatographic purity - 99.9% ( by HPLC)
Reference example:
Purification of N-(5-chloropyridin-2-yl)-2[4-(N,N-dimethyl carbamimidoyl)-
benzoyIamino]-5-methoxybenzamide
Charged N,N dimethylacetamide (200 ml) to N-(5-chloropyridin-2-yl)-2[4-(N,N-dimethyl carbamimidoyl)- benzoylamino]- 5-methoxybenzamide(50gm) , heated the reaction mass to 65-70°C and stirred for 30 min. Added toluene (400ml) for 30 min. Reaction mass cooled to 25°C, stirred and cooled to 0-5°C. Filtered the solid and dried. Chromatographic purity- 99.8% (by HPLC)

We claim:
1. A process for the preparation of Betrixaban maleate compound of Formula I, which comprises:
a. reacting the compound of Formula III or its acid addition salts;
with dimethyl amine or its satt thereof and a compound of Formula IV ,
optionally in the presence of an organic solvent;
b. adjusting the pH to 1.0 - 3.0 with suitable acid to obtain compound of Formula-V as its
acid addition salts;
c. desalifying the compound of Formula V to obtain Betrixaban of Formula-II;

d. optionally purifying the Betrixaban; and
e. converting Betrixaban to Betrixaban maleate of compound of Formula I.
2. A process for the preparation of Betrixaban maleate compound of Formuia I, which comprises:
a. reacting the compound of Formula III or its acid addition salts;
with a compound of Formula VI
optionally in presence of an organic solvent; b. adjusting the pH to 1.0 - 3.0 with suitable acid to obtain compound of Formula-V as its acid addition salts;

d. optionally purifying the Betrixaban; and
e. converting Betrixaban to Betrixaban maleate of Formula I.
3. The process according to claim I and 2, acid addition salt óf Formula III is selected from group comprising of hydrochloric acid, methane sulfonic acid, maleic acid, hydrobromic acid, tartanc acid, succinic acid, oxalic acid and sulphüric acid.
4. The process according to claim 1 and 2, wherein the organic solvent is selected from the group comprising of ethers, hydrocarbon solvent, and mixtures thereof, wherein the ether is selected from the group consisting diethylether, diisopropyl ether, dibutyl ether, di isobutyl butyl ether, methyl tert-butyl ether, 1,4 dioxane, tetrahydrofuran, ethylene glycol ether, methyltetrahydrofuran, cyclopentylmethyl ether, dimethoxymethane; anisole, and mixtures thereof, hydrocarbon solvent is selected from the group comprising of toluene, xylene, hexane, heptane and cyclohexane or mixture thereof.
5. The process according to claim 1, wherein the reacting compound of Formula III or its acid addition salts with dimethylamine or its salts and a compound of Formula IV is carried out at a temperature of between 0°C and 25°C, preferably 0-10°C.
6. The process according to claim 2, where in compound of Formula IV is reacted with
dimethylamine or its salts to obtain compound of Formula VI
7. The process according to claim 2, wherein the adding of dimethylamine and the adding of compound of Formula IV is carried out a temperature in the range of 10°C to 20°C
8. The process according to claim 1 and 2, adjusting the pH to 1.0 - 3.0 with suitable acid, wherein suitable acid is selected from the group comprising of hydrobromic acid, hydrochloric acid or sulfuric acid, preferably hydrochloric acid.
9. The process according to claim 1 and 2, desaliflcation of the compound of Formula-V is carried out by treating with base, wherein suitable base is selected form the group comprising of organic base or an inorganic base, wherein organic base is selected from the group comprising of amines, preferably trimethylamine; Inorganic base is selected from the group comprising of sodium carbonate, sodium bicarbonate, sodium hydroxide
and mixtures thereof.