CLIAMS:
1. A process for the preparation of intermediate rivaroxaban of formula I:

Formula I
or a pharmaceutically acceptable salt thereof, which comprises reaction of thioester of formula II:

Formula II
wherein R is alkyl, aryl, 2-pyridyl, pyrimidinyl, triazolyl or thiazolyl, 2-benzothiazolyl, benzimidazole, benzisoxazole.

or a pharmaceutically acceptable salt thereof with 4-{4-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl}morpholine-3-one of formula III:

Formula III
or a pharmaceutically acceptable salt thereof.

2. The process of claim 1, wherein the compound of Formula II is thioester of formula II:

Formula IIA

3. The process of claim 1, wherein the reaction is performed in presence of solvent and base.

4. A thioester of compound of Formula II

Formula II
wherein R is alkyl, aryl, 2-pyridyl, pyrimidinyl, triazolyl or thiazolyl, 2-benzothiazolyl, benzimidazole, benzisoxazole.
or a pharmaceutically acceptable salt thereof.

5. A thioester of compound of Formula IIA:

Formula IIA
or a pharmaceutically acceptable salt thereof.

6. A process for the preparation of compound of Formula IIA:

Formula IIA
or pharmaceutically acceptable salt thereof, which comprises esterification of 5-chlorothiophene-2-carboxylic acid of formula IV


Formula IV
with 1,2-Bis(2-benzothiazolyl) disulfide of Formula V

Formula V
in the presence of triphenylphosphine.

7. The process of claim 6, wherein the reaction is performed in presence of chlorinated solvent such as dichloromethane.

8. A process for the preparation of rivaroxaban of Formula I:

Formula I

or a pharmaceutically acceptable salt thereof, which comprises reaction of thioester of formula IIA:

Formula IIA
with 4-{4-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl}morpholine-3-one of formula III:

Formula III

or a pharmaceutically acceptable salt thereof.

9. The process of claim 8, wherein the reaction is preformed in the presence of solvent such as tetrahydrofuran.

10. The process of claim 8, wherein the reaction is performed in the presence of base such as triethyl amine.
,TagSPECI:Field of Invention

Aspects of the present invention relates to a process for the preparation of Rivaroxaban, intermediates thereof, or a pharmaceutically acceptable salt thereof.

Background of the invention

The drug compound having the adopted name “Rivaroxaban” has chemical name: 5-chloro-N-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-1,3-oxazolidin-5­ yl}methyl)-2-thiophenecarboxamide; and has the structural formula I:

Formula I

The commercial pharmaceutical product XARELTO® tablets contains rivaroxaban as active ingredient. Rivaroxaban is a factor Xa inhibitor useful as oral anticoagulant. Rivaroxaban can be used for the prevention and treatment of various thromboembolic diseases, in particular of deep vein thrombosis (DVT), pulmonary embolism (PE), myocardial infract, angina pectoris and restenoses after angioplasty or aortocoronary bypass, cerebral stroke, transitory ischemic attacks, and peripheral arterial occlusive diseases.

U.S. Pat. No. 7,157,456 describes Rivaroxaban and process for the preparation thereof. The process of US ‘456 for rivaroxaban involves reaction of 2-[(2S)-2-oxiranylmethyl]-1H-isoindole-1,3(2H)-dione with 4-(4-aminophenyl)-3-morpholinone to provide 2-((2R)-2-hydroxy-3-{[4-(3-oxo-4-morpholiny)phenyl]amino}propyl)-1H-isoindole-1,3(2H)-dione, which on cyclization using N,N-carbonyl diimidazole to afford 2-({5S)-2-Oxo-3-[4-(3-oxo-4-morpholiny)phenyl]-1,3-oxazolidin-5-yl}methyl)-1H-isoindole-1,3(2H)-dione, which on reacted with methylamine followed by reaction with 5-chlorothiophene-2-carbonyl chloride to provide Rivaroxaban.

Various processes for the preparation of rivaroxaban, its intermediates, and related compounds are disclosed in U.S. Patent Nos. 7,585,860; 7,351,823, 7,816,355, and 8,101,609; patent application Nos. WO 2011/012321, WO 2012/156983, WO 2012/153155, WO 2013/053739, WO 2013/098833, WO 2013/156936, WO 2013/152168, WO 2013/120464, WO 2013/164833, US 2012/0283434 and US 2013/184457; and J. Med. Chem. 2005, 48, 5900-5908.

The reported processes suffers one or the other problems like lower yield, use of carcinogenic reagents like hydrobromic acid at elevated temperature, longer reaction time, and the like.

Therefore, there is a need to develop a simple and industrially feasible process for rivaroxaban, intermediates thereof, or a pharmaceutically acceptable salt thereof.

Summary of the Invention

The present invention provides a process for the preparation of rivaroxaban, intermediates thereof, or pharmaceutically acceptable salt thereof.

In an aspect, the present invention is to provide an intermediate of rivaroxaban, thioester of Formula II:

wherein R is alkyl, aryl, 2-pyridyl, pyrimidinyl, triazolyl or thiazolyl, 2-benzothiazolyl, benzimidazole, benzisoxazole.
or a pharmaceutically acceptable salt thereof.

In another aspect, the present invention is to provide an intermediate of rivaroxaban, thioester of Formula IIA:

Formula IIA
or a pharmaceutically acceptable salt thereof.

In another aspect, the present invention is to provide a process for the preparation of rivaroxaban of Formula I:

Formula I
or a pharmaceutically acceptable salt thereof, which comprises reaction of thioester of formula II:

Formula II
wherein R is alkyl, aryl, 2-pyridyl, pyrimidinyl, triazolyl or thiazolyl, 2-benzothiazolyl, , benzimidazole, benzisoxazole.
or a pharmaceutically acceptable salt thereof with 4-{4-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl}morpholine-3-one of formula III:

Formula III
or a pharmaceutically acceptable salt thereof.

In another aspect, the present invention is to provide a process for the preparation of rivaroxaban of Formula I:

Formula I

or a pharmaceutically acceptable salt thereof, which comprises reaction of thioester of formula IIA:

Formula IIA
with 4-{4-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl}morpholine-3-one of formula III:

Formula III
or a pharmaceutically acceptable salt thereof.

Description of the Invention

The term “alkyl” as used herein, unless otherwise defined, refers to methyl, ethyl, n-propyl, isopropyl and butyl.

The term “aryl” as used herein, unless otherwise defined, refers to substituted or unsubstituted phenyl. The substitution can be with alkyl, halo, nitro, amine and the like.

The intermediates and starting materials of the present invention may be used as free bases or its salts.

The salt or pharmaceutically acceptable salt as used herein, unless otherwise defined, refers to inorganic or organic salt. Inorganic salt may include hydrochloride, hydrobromide and the like; organic slat may include acetate, mesylate, tosylate and the like.

In an aspect, the present invention is to provide an intermediate of rivaroxaban, thioester of Formula II:

wherein R is alkyl, aryl, 2-pyridyl, pyrimidinyl, triazolyl or thiazolyl, 2-benzothiazolyl, benzimidazole, benzisoxazole.
or a pharmaceutically acceptable salt thereof.

In an embodiment, the compound of formula II of the present invention is selected from the compounds of:
, ,

and

In another embodiment, the compound of formula II of the present invention is selected from:

and

The process to provide the compound of Formula II may involve reaction of 5-chlorothiophene-2-carboxylic acid with sulfide compound (R’-S-R or R’-S-S-R), wherein R’ is benzothiazolyl, acetyl, substituted or unsubstituted benzoyl, benzopyridyl. The reaction may be performed in presence of a tri-(Iower alkyl)- or tri(aryl) phosphine or phosphite, in particular triphenylphosphine. The reaction may be performed at a temperature of below 100 °C, for example, from -30 °C to 60 °C, or -5 °C to 5 °C. The reaction may be performed in an inert, non-hydroxy-containing, organic solvent, for example a chlorinated hydrocarbon, such as methylene chloride; an ester solvent, such as ethyl acetate and optionally in the presence of water.

In another aspect, the present invention is to provide an intermediate of rivaroxaban, thioester of Formula IIA:

Formula IIA

In another aspect, the present invention is to provide a process for the preparation of compound of Formula IIA:

Formula IIA
or pharmaceutically acceptable salt thereof, which comprises esterification of 5-chlorothiophene-2-carboxylic acid of formula IV


Formula IV
with 1,2-Bis(2-benzothiazolyl) disulfide of Formula V

Formula V
in the presence of triphenylphosphine to provide the compound of Formula IIA.

The esterification reaction is performed in presence of solvent. The solvent includes but are not limited to a chlorinated solvent such as dichloromethane, dichloroethane, chloroform, chlorobenzene and the like; an ester such as ethyl acetate, and the like; a nitrile such as acetonitrile, propionitrile, and the like.

The temperature for performing the esterification is about -30 °C to 40 °C or -5 °C to 5 °C. The reaction may be maintained for a period of 30 minutes to 2 hours to complete at -5 °C to 5 °C.

In another aspect, the present invention is to provide a process for the preparation of rivaroxaban of Formula I:

Formula I
or a pharmaceutically acceptable salt thereof, which comprises reaction of thioester of formula II:

Formula II
wherein R is alkyl, aryl, 2-pyridyl, pyrimidinyl, triazolyl or thiazolyl, 2-benzothiazolyl, benzimidazole, benzisoxazole.

or a pharmaceutically acceptable salt thereof with 4-{4-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl}morpholine-3-one of formula III:

Formula III
or a pharmaceutically acceptable salt thereof.

The reaction may be carried out in the presence of an organic solvent and a base and optionally in the presence of water.

The reaction may be carried out at a temperature ranging from -5°C to about ambient temperature. The organic solvent used is selected from tetrahydrofuran, N,N-dimethylacetamide, N,N-dimethylformamide, chlorinated hydrocarbons, ketones, esters or a mixture thereof.

The reaction is carried out in the presence of bases such as inorganic base or organic base.

The compound of formula III may be prepared from the known processes, for example, US 7,157,456 or as disclosed in the scheme 1.

In another aspect, the present invention is to provide a process for the preparation of rivaroxaban of Formula I:

Formula I

or a pharmaceutically acceptable salt thereof, which comprises reaction of thioester of formula IIA:

Formula IIA
with 4-{4-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl}morpholine-3-one of formula III:

Formula III
or a pharmaceutically acceptable salt thereof.

The reaction may be carried out in the presence of an organic solvent and a base as herein described and optionally in the presence of water.

The reaction may be carried out at a temperature ranging from -5°C to about ambient temperature for about 2 to 12 hours. The organic solvent used is selected from tetrahydrofuran, N,N-dimethylacetamide, N,N-dimethylformamide, chlorinated hydrocarbons, ketones, esters or a mixture thereof.

The reaction is carried out in the presence of bases such as inorganic base or organic base. The organic base is selected from triethylamine, methyl amine, diisopropyl amine, N-methylpiperidine, pyridine, 1,8-diazabicycloundecene, 4-dimeth- ylaminopyridine, or a mixture thereof; inorganic base is selected from sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate or mixtures thereof.

In an embodiment, the process of the present invention is illustrated in the following scheme 1:

Scheme 1

The resultant rivaroxaban or a pharmaceutically acceptable salt thereof obtained from the present invention is useful for pharmaceutical composition.

In another aspect, the present invention relates to pharmaceutical composition comprising rivaroxaban or a pharmaceutically acceptable salt obtained from the present invention and pharmaceutically acceptable carriers and/or diluents thereof, and if desired, other active ingredients, which may be administered orally, intravascularly, subcutaneously, intramuscularly or topically for the use as anticoagulant in a mammal in need thereof.

The present invention may further be illustrated by the following examples which may be provided merely to be exemplary of the invention and do not limit the scope of the invention. Certain modifications and equivalents may be apparent to those skilled in the art and may be intended within the scope of the present invention.

EXAMPLES

EXAMPLE 1:

A process for the preparation of rivaroxaban

To a stirred mixture of thioester of compound IIA (10.7g) and 4-{4-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl}morpholine-3-one (10g) in tetrahydrofuran (30 ml) and water (30 ml),triethylamine was added (3.8g).The reaction mixture was stirred at 5-10°C for 4-6 hours. After completion of the reaction, it was quenched with water & extracted in methylene chloride. The aqueous layer was back extracted using methylne chloride and combined organic layer was acidified to pH 6-7with aqueous hydrochloric acid. Finally the organic layer was concentrated to get desired product. The product was purified and dried under reduced pressure to yield 11.5 gm of rivaroxaban.

EXAMPLE 2

EXAMPLE 2:

A process for intermediate of Formula IIA:

A slurry containing triphenylphosphine (161.32 gm) and mercaptobenzothiazole disulphide (214.72 gm) in methylene chloride was stirred at 25-30°C for 1 hr. 5-chlorothiophene-2-carboxylic acid (100g) were added at 10°C and stirred at 10-20°Cfor 2 hrs. After completion of the reaction, reaction mixture was filtered washed with methylene chloride (200 ml), isolated compound was dried under vacuum at 50-60°C for 4 hrs. (Yield 150 gm).

EXAMPLE 4:

A process for rivaroxaban in-situ:

A slurry containing triphenylphosphine (11.5g) and mercaptobenzothiazole disulphide (15.31g) in methylene chloride was stirred at 28-30°C for 1 hr. 5-chlorothiophene-2-carboxylic acid (7.2g) and triethylamine (3.8 g) were added at 09C and stirred at 0-25C for 1 hr. 4-{4-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl}morpholine-3-one (10g) and triethylamine (3.8g) were added and the resulting reaction mixture and further stirred for 2 hrs. After completion of the reaction, water was added and stirred for 10 min. Aqueous layer was separated and washed with methylene chloride. The aqueous layer was acidified to 6-7 with aqueous hydrochloric acid and finally the organic layer was concentrated to get desired product. The product was purified and dried under reduced pressure to yield 10.0 gm of rivaroxaban.