FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003 COMPLETE SPECIFICATION (See section 10 and rule 13)
1.TITLE OF THE INVENTION:
"A Process for purification of Rivaroxaban"
2. APPLICANT (S)
(a) NAME: Wanbury Ltd.
(b) NATIONALITY: An Indian Company incorporated under the Indian Companies ACT 1956
(c) ADDRESS:
Wanbury Ltd.,
BSEL Tech Park, B-Wing, 10th Flr, Sec-30A, Opp. Vashi Railway Station, Vashi, Navi Mumbai-400703 Ph. No. 91-22-64570555
3. PREAMBLE TO THE DESCRIPTION
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 a process for purification of Rivaroxaban ; 5-chloro-N-({(5S)-2-oxo-3-[4-(3-oxomorpholin-4-yl)phenyl]-l,3-oxazolidin-5-yl}methyl)thiophene-2-carboxamide. formula (I).

BACKGROUND OF THE INVENTION:
5-chloro-N-({(5S)-2-oxo-3-[4-(3-oxomorpholin-4-yl)phenyl]-1,3-oxazoIidin-5-yl}methyl)thiophene-2-carboxamide (herein after referred as "Rivaroxaban") also known as Xarelto®, as a trade name and having structural formula (I):


rivaroxaban is an orally active direct factor Xa (FXa) inhibitor drug, used for the prevention and treatment of various thromboembolic diseases, and firstly described in WO2001/047919.
WO 01/47919 application describes a method for preparation of rivaroxaban of formula (1), wherein 4-(4-aminophenyl)morpholin-3-one is reacted with 2-[(2S)-oxiran-2-yImethyl]-lH-isoindole-l,3(2H)-dione, in presence of solvent to obtain 2-[(2R)-2-hydroxy-3-{[4-(3-oxornorpholin-4-yl)phenyl]amino}propyl]-lH-isoindole-1,3(2H)-dione which is further converted to 2-({(55)-2-oxo-3-[4-(3-oxomorphoiin-4-yl)phenyl]-l,3-oxazolidin-5-yl}methyt)-lH-isoindole-l,3(2H)-dione by phosgene equivalent.Departing of the pthalamide group affords 4-{4-[(5S)-5-(arninornethyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl}morpho!in-3-one, which is finally coupled with 5-ch!orothiophene-2-carbonyl chloride to give 5-chloro-N-({(5S)-2-oxo-3-[4-(3-oxomorpholin-4-yl)phenyl]-l,3-oxazolidin-5-yl}melhyl)thiophene-2-carboxamide i.e. rivaroxaban of formula (1) as shown in scheme-1;


However this process posses several draw backs such as, lengthy reaction periods, excess mole ratios of reactants and reagents, use of unsafe solvents etc. Moreover title compound is isolated by column chromatography which is not feasible on commercial scale.
According to the US7,351,823 B2, rivaroxaban prepared by treating 4-{4-[(5S)-5-(aminomethyI)-2-oxo-l,3-oxazolidin-3-yl]phenyl}morpholin-3-one hydrochloride with 5-chlorothiophene-2-carbonyl chloride in acetone and water mixture, exert the

crude rivaroxaban which further recrystallized in acetic acid to yield rivaroxaban. The said patent is silent over the purity of rivaroxaban.
WO2011/01232 Al. teaches the process for purification of rivaroxaban by recrystalization by adding anti-solvents, wherein the crude rivaroxaban is dissolved in the polar solvents and isolating the pure rivroxaban by adding anti-solvents. However, the solvents used for the dissolution of crude rivaroxaban are high boiling and are very intricate to remove from final products.
There are several drawbacks associated with the processes described in the arts. These drawbacks include the use of tedious chromatography for purification which may not be feasible on a commercial scale, use of toxic substances during the reaction, and low yields. Therefore there is still a need for improved process for purification of rivaroxaban which is based on inexpensive, environment friendly solvents by avoiding number of purifications which concomitantly exert a simple and economical process which is better suited for industrial application.
According to all above said prior arts, the disclosed processes for purifications of rivaroxaban having limitations, hence in order to remove said limitations and complies the product from regulatory point of view, the present invention comes with an improved process for purification of rivaroxaban.

OBJECTS OF THE PRESENT INVENTION:
The main object of the present invention is to provide easy and commercial process for purification of rivaroxaban.
Another object of the present invention is to provide a process for purification of rivaroxaban of formula (I), wherein the obtained rivaroxaban is substantially free from impurities and an efficient process for large scale preparation.
DETAILED DESCRIPTION OF THE INVENTION:
Before the present invention is described, it is to be understood that this invention is not limited to particular methodologies and materials described, as these may vary as per the person skilled in the art. It is also to be understood that the terminology used in the description is for the purpose of describing the particular embodiments only, and is not intended to limit the scope of the present invention.
Before the present invention is described, it is to be understood that unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Further, it is to be understood that the present invention is not limited to the methodologies and materials similar or equivalent to those described herein can be

used in the practice or testing of the present invention, the preferred methods and materials are described, as these may vary within the specification indicated. Unless stated to the contrary, any use of the words such as "including," "containing," "comprising," "having" and the like, means "including without limitation" and shall not be construed to limit any general statement that it follows to the specific or similar items or matters immediately following it. Embodiments of the invention are not mutually exclusive, but may be implemented in various combinations. The described embodiments of the invention and the disclosed examples are given for the purpose of illustration rather than limitation of the invention as set forth the appended claims. Further the terms disclosed embodiments are merely exemplary methods of the invention, which may be embodied in various forms.
A term herein "reflux temperature" means the temperature at which the solvent or the solvent system refluxes or boils at atmospheric pressure.
The term "substantially free" in reference to a composition, as used herein, means that an absent substance cannot be detected in the composition by methods known to those skilled in the art at the time of the filing of this application.
In one of the embodiments, the present invention encompasses the preparation of crude rivaroxaban (Route A) of formula (I) comprising the steps of:

a) reacting, 4-(4-aminophenyl)morpho!in-3-one of formula (II) with 2-[(2S)-
oxiran-2-yImethyl]-lH-isoindole-1,3(2H)-dione of formula (III) in a suitable
solvent to obtain 2-[(2R)-2-hydroxy-3-{[4-(3-oxomorpholin-4-
yl)phenyl]amino}propyl]-lH-isoindoie-1,3(2H)-dione of formula (IV);

b) preparing compound of formula (VI) by reacting compound of formula (IV) using di-lH-imidazol-1-ylmethanone of formula (V);


c) eliminating the pthalamide group from compound of formula (VI) in suitable
solvent using a de-protecting agent and acid in order to get the acid addition
salt of 4-{4-[(5S)-5-(aminomethyl)-2-oxo-l,3-oxazolidin-3-
yl]phenyl}morpholin-3-one formula (VII), optionally compound of formula (VII) can be isolated as free base;

Wherein: A is referred as acid addition salt
d) reacting compound formula (VII) or free base with compound formula (VIII) or 5-chIorothiophene-2-carboxylic acid or acid chloride in suitable solvent and base to obtain the crude rivaroxaban formula (I).


In yet another embodiment of the present invention, the preparation of crude rivaroxaban (Route-B) comprises:
a) reacting compound of formula (VII) or free base of formula (VII) with organic acid in suitable solvent, optionally in the presence of a base to obtain N-({(5S)-2-oxo-3-[4-(3-oxomorpholin-4-yI)phenyl]-l,3-oxazolidin-5-yl}methyl)formamide formula (A);

b) reacting compound formula (A) with compound formula (VIII) or 5-chlorothiophene-2-carbonitrile in suitable solvent and base in order to obtain the novel intermediate or precursor of Rivaroxaban formula (B), optionally in the presence of catalyst and/or activating agents


Wherein;
Y may be sulfonyloxy, imidazole, triazole, tetrazole, alkoxy, substituted alkoxy, tri-halomethoxy, N-hydroxysuccinamide, hydroxy, esters, primary amine, secondary amine p-nitrophenol, N-hydroxythalamide, N-hydroxybenzotriazole. chlorine, fluorine, bromine& iodine. Base used may be inorganic or organic.
c) treating compound formula (B) with acid or base in suitable solvent in order to depart the aldehyde group from compound formula (B) to obtain the title compound rivaroxaban formula (I);

According to CHMP ASSESSMENT REPORT FOR Xarelto (EMEA 2008), i.e. product containing rivaroxaban as an active substance, 18 process impurities

originating from the starting materials and the synthetic process have been identified, and further impurities may come from product of side reactions, byproducts and itself degradation of product (API) which may harmful to the patient treated with dosage form of active substance.
According to best mode of invention the present invention provides the process for purification of the crude rivaroxaban comprising the steps of:
a) adding the crude rivaroxaban in suitable solvent;
b) obtaining the clear solution of step (a), by adding suitable acid wherein, the acid is independently selected from inorganic or organic acid or mixture thereof;
c) isolating the pure rivaroxaban by addition of suitable anti-solvent to the solution of step (b);
d) optionally washing the obtained pure rivaroxaban with solvent:
e) drying, at temperature 60 ±5°C under vacuum to obtain rivaroxaban having purity more than 99.8%.
Herein above and after the word "pure rivaroxaban'' designating as rivaroxaban having purity more than 99.8% by high resolution HPLC method and the "crude rivaroxaban" designating as rivaroxaban having purity from 95 - 98%.

According to process for purification of rivaroxaban, adding the crude rivaroxaban in suitable solvent independently selected from the polar or non polar solvents, such as methanol, ethanol, tetrahydrofuron, methylene dichloride or mixture thereof but preferably methylene dichloride .
Further adding acid in step (a) in order to get the clear solution of rivaroxaban wherein the acid is independently selected from inorganic or organic acid or mixture thereof. An inorganic acid is independently selected from the hydrochloric acid, nitric acid, sulphuric acid, perchloric acid, hydrofluoric acid, hydrobromic acid and organic acid is independently selected from oxalic acid, acetic acid, trifluroacetic acid, formic acid, but preferably organic acid such as trifluroacetic acid. It is surprisingly found that trifluroacetic acid encompasses unexpected added advantages in terms of the removal of all impurities in a single purification from crude rivaroxaban.
According to an embodiment of present invention, step a) and b) are carried out together, in absence of solvent, wherein clear solution is obtained by adding suitable acid directly to crude rivaroxaban.
According to step (c), rivaroxaban solution obtained by combining the steps (a) & (b), a suitable anti-solvent is added to precipitate Out the pure rivoraxaban from the rivaroxaban solution wherein the suitable anti-solvent is selected from the class of

polar solvent such as water, methanol, ethanol. acetone, acetorritrile, n-propanol, iso-propanol, ethyl acetate or mixture thereof but preferably is methanol. After the complete precipitate out the rivaroxaban the obtained cake optionally wash with solvent selected from ethanol, methanol, acetone, acetonitrile, n-propanol, iso propanol, ethyl acetate or mixture thereof but preferably is methanol.
Alternatively the effective volume ratio of trifluoroacetic acid and methylene dichloride in solution obtained by combining the step (a) and (b) is ranging between 0.1 and 0.5 v/v at ambient temperature. Anti solvent is added to the solution of rivaroxaban in volume ratio of rivaroxaban solution is 1:0.5 to 1:10 v/v, but preferably 1:1 v/v at ambient temperature in order to get complete precipitate out the pure rivaroxaban.
According to present invention during the synthesis is of rivaroxaban by route- A and route -B, following major impurities were observed.
Route- A:
Impurity A (Compound of formula-VII) Impurity at 0.95 RRT = Unknown Impurity at 0.58 RRT= Unknown

Route-B:
Impurity at 0.34 RRT = unknown
Surprisingly it was found that these impurities were significantly reduced to pharmaceutically acceptable limits when purification is carried out in as per the present invention. Whereas these impurities were not reduced to acceptable limits when purification was conducted in prior art process per se acetic acid, re-crystallization. Furthermore, none of the methods known in prior art discloses an impurity at 1.5 RRT,
The detection of impurities is carried out by high resolution HPLC method which depicted as below:
Column: Zorbax SB-CN (250x4.6x5u)
Buffer: 1.36 gm KH2PO4+1 gm 1-Heptane sulphonic acid +1 ml
Triethylamine in 1000 ml, pH adjusted to 6.7 with diluted ortho-pohosphoric acid solution.
Eluent A: Buffer
Eluent B: Acetonitrile:Water (80:20 v/v)

Gradient of Eluent:

Time (min) Eluent A(%) Eluenl B (%)
0 80 20
5 75 25
25 50 50
38 50 50
42 80 20
50 80 20
Stop time: 50 min.
Equilibration time: 30 minutes
Flow: 1.5ml/min
Detector (UV): 240 nm
Injection volume: 20μl
Diluent: (Mobile phase A: Mobile phase B) 50:50 v/v
Column temperature: 35°C

Rivaroxaban Standard solution (For peak identification):
Weigh accurately 25 mg of RVR standard in 50ml volumetric flask ,add 1 ml dimethyl sulphoxide ,sonicate to dissolve .further add diluent and make up to the mark with diluent.
Rivaroxaban Test sample preparation:
Weigh accurately 25 mg of RVR test sample in 50ml volumetric flask .add 1 ml dimethyl sulphoxide ,sonicate to dissolve ,further add diluent and make up to the mark with diluent.
Calculation:

Route-A
Impurity of compound of formula VII = 0.10% Impurity at 0.95 RRT = 0.02% - unknown impurity Impurity at 0.58 RRT= 1.46 % -Unknown Impurity
Route-B
Impurity at 0.34 RRT = 0.05% - unknown impurity

The above impurities are identified in percentage by using the above formula.
The present invention is described in the examples given below; further these are provided only to illustrate the invention and therefore should not be construed to limit the scope of the invention.
EXAMPLE 1
To a solution of crude rivaroxaban (Purity = 97,9%, Impurity of compound of formula VII = 0.29%, impurity at 0.95 RRT - 0.1%, Impurity at 0.58 RRT= 1.47 % -Unknown impurity) obtained from Route A (10 gm) with Dichloromethane (40 ml), slowly added trifluoroacetic acid (5.0 ml) at 25-30°C to obtain a clear solution. Obtained clear solution then stirred at 25 to 30°C for 20 minutes. To this clear solution slowly added methanol (50 ml) at 25-30 C, Obtained reaction mixture then stirred for 30 minutes at 25-30°C followed by filtration and wet cake is washed by methanol (20 ml). Dried the solid under vacuum at 60°C. Yield = 8.5 gm HPLC purity 99.85%
Impurity of compound of formula VII = 0.10% Impurity at 0.95 RRT = 0.02% Impurity at 0.58 RRT = 0.02-0.05%

EXAMPLE 2
Acetic acid (70 ml) is added to Crude rivaroxaban (Purity = 97.9%, Impurity of
compound of formula VI] = 0.29%, impurity at 0.95 RRT - 0.1%, Impurity at 0.58
RRT= 1.47 % -Unknown impurity) obtained from route A (10 gm). The resulted
mixture then heated to 90-95°C to obtain the clear solution. The resulted clear
solution gradually cooled to 25-30°C, followed by filtration. Wet cake is washed by
water (20 ml). Dried the solid under vacuum at 60-65°C.
Yield = 8.5 gm
HPLC purity 99.52%
Impurity of compound of formula VII = 0.28%
Impurity at 0.95 RRT - 0.09%
Impurity at 0.58 RRT = 1.46% (remains unchanged)
EXAMPLE 3
To a solution of crude rivaroxaban (Purity = 98.09%, impurity at 0.34 RRT = 0.84%) obtained from Route B (10 gm) and Dichloromethane (40 ml), slowly added Trifluoroacetic acid (5.0 ml) at 25-30°C to obtain a clear solution. Obtained clear solution then stirred at 25 to 30°C for 20 minutes. To this clear solution slowly added methanol (50 ml) at 25-30°C. Obtained reaction mixture then stirred for 30 minutes at 25-30°C followed by filtration and wet cake is washed by with methanol (20 ml). Dried the solid under vacuum at 60 C. Yield-8.5 gm

HPLC purity 99.80% Impurity at 0.34 RRT = 0.05%
EXAMPLE 4
Acetic acid (70 mi) is added to Crude rivaroxaban (Purity = 98.09%, impurity at 0.34 RRT = 0.84%) obtained from Route B (10 gm). The resulted mixture then heated to 90-95°C to obtain the clear solution. The resulted clear solution gradually cooled to 25-30°C. followed by filtration. Wet cake is washed by water (20 ml). Dried the solid under vacuum at 60-65°C. Yield = 7.5 gm HPLC purity 99.41% Impurity at 0.34 RRT = 0.44%
Example 5
To crude Rivaroxaban (Purity = 97.59%, Impurity of compound of formula VII = 0.12%, impurity at 0.95 RRT = 0.09%, impurity at 0.58 RRT = 1.46%) obtained from Route A (65g), was added trifluoroacetic acid (195ml) and the mixture was heated to 40-45°C to obtain the clear solution. To this clear solution, water (390ml) was slowly added at 40-450C and the mixture was stirred for 30 minutes at same temperature. The solid obtained was filtered out and the wet cake was washed with methanol (325 ml) and dried under vacuum at 600C Yield=55gm

HPLC Purity 99.83%
Impurity of compound of formula VII=0.10%
Impurity at 0.95 RRT = Nil
Impurity at 0.58 RRT - 0.02-0.05%
Example 6
To a solution of crude Rivaroxaban (Purity- 99.29%, impurity at 0.34 RRT = 0.04%) obtained from Route B (80g) with Dichloromethane (320ml), slowly added trifluoro acetic acid (40ml) at 25-300Cto obtained clear solution. Obtained clear solution is then stirred at 25-300C for 15-20 minutes. To this clear solution slowly added methanol (400ml) at 25-300C. Obtained reaction mixture then stirred for 30 minutes at 25-300C followed by filtration and wet cake is washed by methanol (160ml) suck dry it, and charged in trifluoroacetic acid (80 ml), stirred reaction mass for 15-20, to this clear solution added water (480ml), stirred for30 minutes followed by filtration and wet cake is washed by water (160ml). Dry the solid under vacuum at 600C. Yield= 62gm HPLC Purity 99.92% Impurity at 0.34 RRT = Nil

We Claim
1) A process for purification of rivaroxaban comprising:
a) treating the crude rivaroxaban with an acid in suitable solvent to obtain a clear solution;
b) isolating pure rivaroxaban from the clear solution by addition of a suitable anti-solvent;
c) optionally, washing the isolated pure rivaroxaban with solvent.

2) The process as claimed in claim 1. wherein the acid used in step a) is independently selected from an inorganic acid like hydrochloric acid, nitric acid, sulphuric acid, perchloric acid, hydrofluoric acid, hydrobromic acid or an organic acid like oxalic acid, acetic acid, trifluroacetic acid, formic acid or a mixture thereof.
3) The process as claimed in claim 1, wherein the solvent used in step a) is independently selected from polar or non polar organic solvent such as methanol, ethanol, tetrahydrofuran, methylene dichloride or a mixture thereof.
4) The process as claimed in claim 1, wherein the solvent used in step a) is methylene dichloride.
5) The process as claimed in claim 1, wherein the anti-solvent used in step b) is independently selected from polar solvents such as water, methanol, ethanol,

acetone, ethyl acetate, acetonitrile, 77-propanol, iso-propanol or mixture thereof but preferably methanol is used.
6) The process as claimed in claim 1, wherein the organic solvent used in step c) is selected from ethanol, methanol, acetone, acetonitrile, n-propanol, iso propanol, ethyl acetate or mixture thereof, but preferably methanol is used.
7) A process for purification of rivaroxaban or its pharmaceutically acceptable salt comprising:

a) treating the crude rivaroxaban with trifluoroacetic acid at temperature ranging from 40-45°C to obtain a clear solution;
b) isolating pure rivaroxaban from the clear solution of step a) by addition of water as anti-solvent;
c) optionally, washing the isolated pure rivaroxaban with methanol.
8) The process as claimed in claim 1 and 7 wherein rivaroxaban obtained has purity
of not less than 99.5%.