NOVEL PROCESS FOR THE PREPARATION OF RIVAROXABAN

The present application claims the benefit of prior provisional application No.3375/CHE/2012, filed on 16.08.2012, which is incorporated herein by reference.

FIELD OF THE INVENTION

The present invention relates to a process for the preparation of Rivaroxaban and its intermediates thereof. Specifically, it relates to the preparation of (R)-4-[4-(5-Chloromethyl-2-oxo-oxazolidin-3-yl)-phenyl]-morpholin-3-one thereof, which is used as an intermediate in the preparation of Rivaroxaban.

BACKGROUND OF THE INVENTION

Rivaroxaban is chemically described as 5-chloro-N-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl) phenyl]-l,3-oxazolidin-5-yl} methyl)-2-thiophene carboxamide and is structurally represented by formula I.

Formula I Rivaroxaban is an anticoagulant, which is an inhibitor of blood coagulation factor Xa and is used in the prophylaxis and treatment of thromboembolic diseases such as heart attack, angina pectoris, reocclusion and restenosis following angioplasty or bypass, reduce the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation, pulmonary embolism and deep vein thrombosis. Rivaroxaban is marketed under the brand name "Xarelto". In the United States, it is marketed by "Janssen Pharmaceutica" having dosage of lOmg, 15mg and 20 mg.

Rivaroxaban was originally disclosed in WO 01/47919 Al. The process for the preparation of Rivaroxaban, its intermediates and their preparation is disclosed in WOO 1/47919 (Example 44). WO'919 discloses the synthesis of Rivaroxaban from an intermediate, 2-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-l,3-oxazolidn-5-yl}methyl)-lH-isoindol-l,3(2H)-dione.

The process of 919 is illustrated in the following scheme:

The process of WO '919 discloses various disadvantages in the reaction management which has particularly unfavorable effects for preparation of the Rivaroxaban on the industrial scale. Furthermore, Rivaroxaban is purified by "tedious chromatographic purification", i.e. by flash-chromatography from a mixture of dichloromethane and methanol.

Journal of Medicinal Chemistry, 2005,48,5900-5908 and DE10129725 discloses a process for the preparation of Rivaroxaban according to the process disclosed in WO 01/47919.

US20070149522 relates to a method for producing 5-chloro-N-({5S}-2-oxo-3-[4-(3-oxo-4-morpholinyl)-phenyl]-l,3-oxazolidin-5-yl} methyl)-2-thiophene carboxamide (i.e. Rivaroxaban) by reaction of 5-chloro thiophene-2-carbonyl chloride with (2S)-3-aminopropane-l,2-diol hydrochloride and subsequently with 4-(4-aminophenyl)-3-morpholinone and further reaction with phosgene or phosgene equivalent.

The major drawback of the '522 process is 5-chloro thiophene-2-carbonyl chloride used in presence of a biphasic system of aqueous sodium hydrogen carbonate solution and 2-methyltetrahydrofuran may easily get hydrolyzed to its acid form, which may lead to incompletion of reaction. Also, the introduction of the Oxazolidine ring in the penultimate step of obtaining Rivaroxaban in '522 process, may lead to impurities formed in the product and require a number of purification steps.

US20070066611 disclosed the process for the preparation of Rivaroxaban comprising reacting 4-(4-aminophenyl)-3-morpholinone with 2-[(2S)-2-oxiranylmethyl]-lH-isoindole-l ,3(2H)-dione and subsequently with 5-chlorothiophene-2-carbonyl chloride. It also covers process of preparation of 4-(4-aminophenyl)-3-morpholinone from 4-(4-nitrophenyl)-3-morpholinone. The focus of '611 is on the preparation of 4-(4-aminophenyl)-3-morpholinone and does not disclose the reaction conditions for preparing Rivaroxaban.

The inventors have provided herein, the simple, robust and industrially viable process, which is economical and provides highly pure Rivaroxaban without column purification.

OBJECT OF THE INVENTION

An object of the present invention is to provide a novel, simple and industrially viable process for the preparation of Rivaroxaban.

Another object of the present invention is to provide an industrially feasible, economical process to prepare compound of formula (IV).

Yet another object of the present invention is formation of oxazolidine ring formation in one step.

SUMMARY OF THE INVENTION

In one aspect, the present invention provides a process for preparing 5-Chloro-N-(((5S)-2-oxo-3-(4-(3-oxomorpholin-4-yl)phenyl)-l,3-oxazolidin-5-yl)methyl)thiophene-2-carboxamide (Rivaroxaban) (Formula-I) comprising

a) reacting [4-(3-Oxo-morpholin-4-yl)-phenyl]-carbamic acid alkyl/ aryl ester (Formula-V) in polar solvent

wherein R= methyl, ethyl, isopropyl, butyl, isobutyl, benzyl, preferably ethyl, methyl with (R)-epichlorohydrin to give (R)-4-[4-(5-Chloromethyl-2-oxo-oxazolidin-3-yl)-phenyl]-morpholin-3-one (Formula-IV) in presence of strong base in organic solvent;

b) reacting compound of formula (IV) in polar solvent with potassium phthalimide to give (S)-2-{2-Oxo-3-[4-(3-oxo-morpholin-4-yl)-phenyl]-oxazolidin-5-ylmethyl}-isoindole-l,3-dione, compound of formula (III);

c) treating compound of formula (III) with hydrazine hydrate or methylamine in presence of organic solvent to give (S)-4-[4-(5-Aminomethyl-2-oxo-oxazolidin-3-yl)-phenyl]-morpholin-3-one, compound of formula (II) and

d) reacting compound of formula (II) with 5- Chloro-thiophene-2-carboxylic acid chloride or its acid derivatives to give Rivaroxaban of formula (I).

Another aspect of the present invention provides process for preparing (R)-4-[4-(5-Chloromethyl-2-oxo-oxazolidin-3-yl)-phenyl]-morpholin-3-one (Formula-IV) comprising a) reacting [4-(3-Oxo-morpholin-4-yl)-phenyl]-carbamic acid alkyl/ aryl ester (Formula-V) in polar solvent

R = Methyl, Ethyl, Isopropyl, Butyl, Isobutyl, benzyl (Formula-V)

wherein R= methyl, ethyl, isopropyl, butyl, isobutyl, benzyl, preferably ethyl, methyl with (R)-epichlorohydrin to give (R)-4-[4-(5-Chloromethyl-2-oxo-oxazolidin-3-yl)-phenyl]-morpholin-3-one (Formula-IV)

(Formula-IV) in presence of strong base in organic solvent.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides simple, robust and industrially viable, economical process for preparing highly pure Rivaroxaban without column purification.

The present invention involves the preparation of Rivaroxaban and the various reaction stages as depicted in the scheme below:

One aspect of the invention is to provide a novel process for the preparation of Rivaroxaban as depicted in the above scheme.

Another aspect of the invention is the reaction between compound of formula V, [4-(3-Oxo-morpholin-4-yl)-phenyl]-carbamic acid alkyl/ aryl ester with (R)-epichlorohydrin to generate a cyclized product (R)-4-[4-(5-Chloromethyl-2-oxo-oxazolidin-3-yl)-phenyl]-morpholin-3-one of formula IV. None of the prior art processes describe direct cyclisation of compound of formula V to IV, more so by the usage of epichlorohydrin. The reaction has been carried out using strong bases like butyl lithium, sodium hydride, sodium methoxide and lithium tertiary butoxide in suitable solvent.

The solvent is selected from polar solvent such as THF, dioxane, cyclopentyl methyl ether, preferably THF and non polar solvents such as hexane, heptane, cyclohexane, preferably hexane.

The cyclized compound of (R)-4-[4-(5-Chloromethyl-2-oxo-oxazolidin-3-yl)-phenyl]-morpholin-3-one of formula IV is subsequently converted to Rivaroxaban by processes known in the art, that is by converting (R)-4-[4-(5-Chloromethyl-2-oxo-oxazolidin-3-yl)-phenyl]-morpholin-3-one of formula IV to (S)-2-{2-Oxo-3-[4-(3-oxo-morpholin-4-yl)-phenyl]-oxazolidin-5-yl methyl}-isoindole-l,3-dione of formula III using potassium Phthalimide in solvent like DMF.

(S)-2-{2-Oxo-3-[4-(3-oxo-morpholin-4-yl)-phenyl]-oxazolidin-5-yl methyl}-isoindole-l,3-dione of formula III is converted to 4-[4-(5-Aminomethyl-2-oxo-oxazolidin-3-yl)-phenyI]-morpholin-3-one of formula II by using hydrazine hydrate or methylamine in organic solvent. The organic solvent is selected from methanol, ethanol, Isopropanol, n-Butanol, isobutanol, dimethyl formamide, dimethyl acetamide, tetrahydrofuran, acetone, preferably methanol.

4-[4-(5-Aminomethyl-2-oxo-oxazolidin-3-yl)-phenyl]-morpholin-3-one of formula II is converted to Rivaroxaban of Formula I by using 5-Chloro-thiophene-2-carboxylic acid chloride or its acid derivatives in presence of reagents such as Carbonyldiimidazole and triethylamine in polar solvent. The polar solvent is selected from THF, ethyl acetate, DMF, preferably DMF.

The process of the present invention thus described is less cumbersome by way of reduced reaction stages, thereby increasing the purity and quantity of the yield of Rivaroxaban.

The process of the present invention is detailed former in the following examples:

Example-1: Preparation of (R)-4-[4-(5-Chloromethyl-2-oxo-oxazoIidin-3-yl)-phenyl]-morpholin-3-one [Formula-IV]

To a solution of 51.6g (0.15 moles) [4-(3-Oxo-morpholin-4-yl)-phenyl]-carbamic acid alkyl/ aryl ester [formula-V] in tetrahydrofuran (500 ml), 95 ml (0.15moles) of ~15%w/w n-butyl lithium in hexanes was added over a period of 30-40 min at -30 to -40°C. The solution was stirred for 30 min at -30 to -40°C. 18 g (0.19 moles) of R-epichlorohydrin was added over 30-40 min at -30 to -20°C to the reaction mixture, stirred continuously and the temperature was slowly raised to 50-55°C. The reaction was maintained (~4 hrs) at 50-55°C. The solvent was removed by distillation under reduced pressure to obtain a thick residue. The residue was dissolved in methylene chloride (500 ml) and washed with water (300 ml x 2). The methylene chloride layer was concentrated to give an oily residue. A mixture of isopropanol (30ml and hexanes (120ml) was added to the residue under stirring. The solid was filtered and the wet cake was washed with a mixture of hexanes (40 ml) and isopropanol (10ml) at 25-30°C. The wet cake was dried at 40-45°C to yield 30.2g (purity 95%) of (R)-4-[4-(5-Chloromethyl-2-oxo-oxazolidin-3-yl)-phenyl]-morpholin-3-one. Pure sample was obtained by re-crystallization from isopropanol.

'H-NMR in CDC13 (300 MHz): 3.74 - 3.78 (m, 4H), 3.95 - 3.97 (dd, 2H) 3.99 (t, 2H), 4.06 (t,lH), 4.34(5,2H), 4.89 (m, 1H, oxazolidinone) 7.36 (m , 2H, Ar- H), 7.6 (m, 2H, Ar-H)

Mass spectrum shows a peak at m/z: 311 with chloro pattern in +ve mode

Example-2: Preparation of (S)-2-{2-Oxo-3-[4-(3-oxo-morphoIin-4-yl)-phenyl]-oxazolidin-5-yl methyI}-isoindole-l,3-dione [Formula-Ill]

To a solution of 50 g (0.15 moles) of (R)-4-[4-(5-Chloromethyl-2-oxo-oxazolidin-3-yl)-phenyl]-morpholin-3-one (formula-IV) in dimethyl formamide (100 ml), 36.8 g (0.20 moles) of potassium phthalimide was added at 25-30°C. The suspension was heated at 130-140°C for 2 hrs. The suspension was cooled to 30°C and poured in to water (200 ml). The resulting solid was collected by filtration. The wet cake was suspended in ethyl acetate (100 ml) at 25-30°C and stirred for 30-40 min. The slurry was cooled to 0-5°C, filtered and the wet cake was washed with pre-cooled ethyl acetate (50 ml) to yield 56 g (chromatographic purity: 96%) of (S)-2-{2-Oxo-3-[4-(3-oxo-morpholin-4-yl)-phenyl]-oxazolidin-5-ylmethyl}-isoindole-l,3-dione.

Example-3: Preparation of (R)-4-[4-(5-Chloromethyl-2-oxo-oxazolidin-3-yl)-phenyl]-morpholin-3-one [FormuIa-IV]

To a solution of 40.2 g (0.15 moles) [4-(3-Oxo-morpholin-4-yl)-phenyl]-carbamic acid alkyl/ aryl ester in tetrahydrofuran (380 ml), 95 ml (0.15 moles) of ~15%w/w n-butyl lithium in hexanes was added over a period of 30-40 min at 0 to -10°C and stirred for 30 min at 0 to -10°C. 18 g (0.19 moles) of R-epichlorohydrin was added to the reaction mixture over 30-40 min at 0 to -10°C, stirred continuously and the temperature was slowly raised to 50-55°C. The reaction was maintained (~4 hrs) at 50-55°C. The solvent was removed by distillation under reduced pressure to obtain a thick residue. The residue was dissolved in methylene chloride (500 ml) and washed with water (300 ml x 2). The methylene chloride layer was concentrated to get an oily residue. Isopropanol (100 ml) was added to the residue and stirred for 15 min at 50-55°C. The resultant product slurry was stirred for 30 min. The product was filtered, washed the wet cake with pre cooled isopropanol (25 ml) and dried at 40-45°C to yield 30g (purity 96%) of (R)-4-[4-(5-Chloromethyl-2-oxo-oxazolidin-3-yl)-phenyl]-morpholin-3-one. Pure sample was obtained by re-crystallization from isopropanol.

Example-4: Preparation of (R)-4-[4-(5-Chloromethyl-2-oxo-oxazolidin-3-yl)-phenyl]-morpholin-3-one [Formula-IV]

To a solution of 40.2 g (0.15 moles) [4-(3-Oxo-morpholin-4-yl)-phenyl]-carbamic acid ethyl ester in tetrahydrofuran (400 ml), 95 ml (0.15 moles) of ~15%w/w n-butyl lithium in hexanes was added over a period of 30-40 min at 0 to -10°C and stirred for 30 min at 0 to -10°C. 18 g (0.19 moles) of R-epichlorohydrin was added over 30-40 min at 0 to -10°C, stirred continuously and the temperature was slowly raised to 50-55°C The reaction was maintained (~4 hrs) at 50-55°C. The solvent was removed by distillation under reduced pressure to obtain a thick residue. The residue was dissolved in methylene chloride (500 ml) and washed with water (300 ml x 2). The methylene chloride layer was concentrated to get an oily residue. Isopropanol (100ml) was added to the residue and stirred for 15 min at 50-55°C. The resulting product slurry was stirred for 30 min. The product was filtered, washed the wet cake with pre cooled isopropanol (25ml) and dried at 40-45°C to yield 29.8 g (purity 96%) of (R)-4-[4-(5-Chloromethyl-2-oxo-oxazolidin-3-yl)-phenyl]-morpholin-3-one. Pure sample was obtained by re-crystallization from isopropanol.

Example-5: Preparation of (R)-4-[4-(5-Chloromethyl-2-oxo-oxazolidin-3-yI)-phenyl]-morpholin-3-one [Formula-IV]

To a solution of 40.2 g (0.15 moles) [4-(3-Oxo-morpholin-4-yl)-phenyl]-carbamic acid ethyl ester in Tetrahydrofuran (400 ml), 17.7 g(0.22 moles) of lithium tertiary butoxide was added at 0 to -10°C and stirred for 30 min at 0 to -10°C. 18 g (0.19 moles) of R-epichlorohydrin was added over 30-40 min at 0 to -10°C, stirred the reaction mass for 4 h at 0-10°C and the temperature was slowly raised to 50-55°C The reaction was maintained (~4 hrs) at 50-55°C. The solvent was removed by distillation under reduced pressure to obtain a thick residue. The residue was dissolved in Methylene chloride (400 ml) and washed with water (300 ml x 2). The Methylene chloride layer was concentrated to get an oily residue. Isopropanol (75 ml) was added to the residue and stirred for 15 min at 50-55°C. The resulting product slurry was stirred for 30 min. The product was filtered, washed the wet cake with pre cooled isopropanol (25ml) and dried at 40-45°C to yield 30.2 g (purity 95%) of (R)-4-[4-(5-Chloromethyl-2-oxo-oxazolidin-3-yl)-phenyl]-morpholin-3-one. Pure sample was obtained by re-crystallization from isopropanol.

Example-6: Preparation of 4-[4-(5-Aminomethyl-2-oxo-oxazolidin-3-yl)-phenyl]-morpholin-3-one [Formula-II]

100 g (0.237 moles) of (S)-2-{2-Oxo-3-[4-(3-oxo-morpholin-4-yl)-phenyl]-oxazolidin-5-yl methyl}-isoindole-l,3-dione was reacted with 50 g (1.0 moles) of hydrazine hydrate in water and Methanol at 70-75°C for 30-60 min. After completion of reaction, the product was extracted in Methylene dichloride, distilled out completely and the compound was isolated in ethyl acetate to obtained 63 g of title compound with more than 98% HPLC purity.

Example-7: Preparation of 5-chloro-N-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl) phenyl]-l,3-oxazolidin-5-yl} methyl)-2-thiophene carboxamide [Formula-I]

250 g (0.858 moles) of 4-[4-(5-Aminomethyl-2-oxo-oxazolidin-3-yl)-phenyl]-morpholin-3-one was reacted with 120 g (0.738 moles) of 5- Chloro-thiophene-2-carboxylic acid in presence of 150 g (0.925 moles) of Carbonyldiimidazole and Triethylamine in N,N-Dimethyl formamide at 0-5°C. After completion of the reaction, the reaction mass was quenched in purified water at 0-5°C to give a crude compound. The crude material was further purified in acetic acid and water to obtain 300 g (80%) of 5-chloro-N-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-l,3-oxazolidin-5-yl} methyl)-2-thiophene carboxamide with 99.8% purity.

CLAIMS

We claim:

1. A process for preparing 5-Chloro-N-(((5S)-2-oxo-3-(4-(3-oxomorpholin-4-yl)phenyl)-l,3-oxazolidin-5-yl)methyl)thiophene-2-carboxamide (Rivaroxaban) (Formula-I) comprising

a) reacting [4-(3-Oxo-morpholin-4-yl)-phenyl]-carbamic acid alkyl/ aryl ester (Formula-V) in polar solvent

wherein R= methyl, ethyl, isopropyl, butyl, isobutyl, benzyl, preferably ethyl, methyl with (R)-epichlorohydrin to give (R)-4-[4-(5-Chloromethyl-2-oxo-oxazolidin-3-yl)-phenyl]-morpholin-3-one (Formula-IV) in presence of strong base in organic solvent;

c) treating compound of formula (III) with hydrazine hydrate or methylamine in presence of organic solvent to give (S)-4-[4-(5-Aminomethyl-2-oxo-oxazolidin-3-yl)-phenyl]-morpholin-3-one, compound of formula (II) and

d) reacting compound of formula (II) with 5- Chloro-thiophene-2-carboxylic acid chloride or its acid derivatives to give Rivaroxaban of formula (I).

2. A process according to claim la), wherein the strong base is selected from n-butyl lithium, sodium hydride and sodium methoxide, preferably n-butyl lithium, Lithium tert -butoxide .

3. A process according to claim la), wherein the polar solvent is selected from THF, dioxane, cyclopentyl methyl ether, preferably THF and organic solvent is selected from non polar solvents such as hexane, heptane, cyclohexane, preferably hexane.

4. A process according to claim lb), wherein the polar solvent is selected from dimethylformamide, dichloromethane, preferably dimethylformamide.

5. A process according to claim lc), wherein the organic solvent is selected from methanol, ethanol, Isopropanol, n-Butanol, isobutanol, dimethyl formamide, dimethyl acetamide, tetrahydrofuran, acetone, preferably methanol.

6. A process according to claim Id), wherein reagents such as Carbonyldiimidazole and triethylamine are used in presence of polar solvent such as THF, ethyl acetate, DMF, preferably DMF.

7. A process for preparing (R)-4-[4-(5-Chloromethyl-2-oxo-oxazolidin-3-yl)-phenyl]-morpholin- 3-one (Formula-IV) comprising a) reacting [4-(3-Oxo-morpholin-4-yl)-phenyl]-carbamic acid alkyl/ aryl ester (Formula-V) in polar solvent

wherein R= methyl, ethyl, isopropyl, butyl, isobutyl, benzyl, preferably ethyl, methyl with (R)-epichlorohydrin to give (R)-4-[4-(5-Chloromethyl-2-oxo-oxazolidin-3-yl)-phenyl]-morpholin-3-one (Formula-IV) in presence of strong base in organic solvent.

8. An improved process according to any of the preceding claims substantially as herein described with reference to examples.