FORM 2
THE PATENT ACT, 1970
(39 OF 1970)
AND
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13)
1. TITLE OF THE INVENTION:
PROCESS FOR PURIFICATION OF RIVAROXABAN
2. APPLICANT:
a. NAME: INDOCO REMEDIES LIMITED
b. NATIONALITY: INDIAN
c. ADDRESS: Indoco House, 166 C.S.T. Road, Santacruz East,
Mumbai - 400 098, Maharashtra , India
3. PREAMBLE TO THE DESCRIPTION:
The following specification particularly describes the invention and the manner in
which it is to be performed.


TITLE: process for purification of rivaroxaban
FIELD OF INVENTION:
The present invention relates to a process for purification crude Rivaroxaban.
The present invention further relates to a process for the preparation of pure rivaroxaban crystal modification I.
BACKGROUND OF THE INVENTION:
The compound 5-chloro-N-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-l,3-oxazolidin-5-yl}methyl)-2-thiophene-carboxamide commonly known as rivaroxaban represented below as the compound of formula - I, is a novel anticoagulant approved in US and Europe for the prevention of venous thromboembolism in adult patients undergoing elective hip or knee replacement surgery and for non-valvular atrial fibrillation to reduce stroke risk in cardiac patients. Rivaroxaban is available in the market under the brand name Xarelto® as 10 mg tablets in Europe and US.

Formula -1
U.S. Patent No. US 7,585,860 describes morpholinyl oxazolidinone thiophene carboxamides including rivaroxaban or pharmaceutically acceptable acid addition salts thereof, a pharmaceutical composition and a method of treatment.
Rivaroxaban may be prepared according to the procedures described in WO 01/47949, wherein rivaroxaban is obtained in WO 01/47949 as crystalline

modification I by purifying the crude product using column chromatography with a dichloromethane/methanol eluent. It is further discussed in WO 2007/039132. Modification I has a melting point of approximately 230°C and a characteristic DSC, X-ray powder diffractogram, IR spectrum, Raman spectrum, FIR spectrum and NIR spectrum as set out in Figures 1 to 6 of WO 2007/039132.
A drawback of the procedures set out in WO 01/47949 is the use of flash chromatography for purification, which is not suitable on industrial scale. Also use of dichloromethane solvent in the purification step is difficult to remove leads to exceeding the limit of organic volatile impurities (OVI).
The PCT patent application WO 2005/068456 discloses a method for preparation of rivaroxaban, where the crude rivaroxaban is purified by recrystallization in acetic acid. The drawback of the process is the use of acetic acid which is toxic and difficult to handle because of corrosiveness and causing environmental pollution.
Another PCT application WO 2011/012321 discloses a method for purification of rivaroxaban comprising the following steps: a) dissolving rivaroxaban in a solvent or a mixture of solvents b) crystallization of rivaroxaban c) optionally washing and drying the crystals and d) obtaining pure rivaroxaban; where the crystallization is achieved either by (i) decreasing the temperature of a rivaroxaban crystallization mixture comprising rivaroxaban and a solvent from a temperature between room temperature and the reflux temperature of the solvent to a temperature within the range -20°C to 40°C, (ii) the addition of an anti-solvent to a solution of rivaroxaban in a solvent or (iii) the addition of a solution of rivaroxaban in a solvent to an anti-solvent.
Another PCT application WO 2011/080341 discloses the purification of rivaroxaban by crystallization in dioxane or a mixture of ethanol-w7ater.
Indian patent application 2219/MUM/2012 discloses a method for purification of rivaroxaban comprising dissolving rivaroxaban in solvent sulfolane and optionally

adding anti-solvents to the solution, cooling the solution for crystallization of rivaroxaban.
Another Indian patent application 2723/MUM/2013 discloses a method for purification of rivaroxaban comprising treating the crude rivaroxaban with an acid in a solvent to obtain a clear solution and isolating pure rivaroxaban from the clear solution by addition of suitable anti-solvent and optionally washing the pure rivaroxaban with a solvent.
PCT Patent application WO 2013/053739 disclosed a process for preparing pure rivaroxaban, wherein the process comprises: a) heating a mixture comprising crude rivaroxaban with at least two organic solvents, wherein first solvent is selected from acetic acid, formic acid, DMF, and aqueous mixture thereof, preferably formic acid and aqueous mixture thereof; and second solvent is selected from acetone, acetonitrile, MEK, MIBK and mixtures thereof, preferably acetone, MEK, MIBK and mixtures thereof, to a temperature higher than 50CC; b) obtaining pure rivaroxaban by decreasing the temperature of the mixture obtained in step (a) to a temperature between 0-30°C, preferably between 20-30°C.
Indian Patent application 290/CHE/2014 discloses a method for preparation of highly pure rivaroxaban crystal modification I. The method comprises providing a solution of rivaroxaban in a solvent medium comprising water and acetone at an ambient temperature, optionally subjecting the solution to carbon treatment to get a filtrate, cooling the solution obtained at a temperature below 35°C to cause crystallization, and recovering the highly pure rivaroxaban crystal modification I.
Another PCT application WO 2016/062828 discloses a method for preparation of rivaroxaban crystal modification I comprising: dissolving rivaroxaban in a mixture of a solvent and an anti-solvent, where the anti-solvent lias a higher boiling point than the solvent; removing the solvent by distillation; and collecting the resultant rivaroxaban crystal modification I.

There is always a need to develop a safe and cost effective process for the preparation of pure rivaroxaban crystal modification I, by using safe reagents and industrially feasible process, which makes the process industrially viable and overcomes the problems associated with the processes known in the art. The present invention therefore seeks to address these issues.
OBJECTIVES OF THE INVENTION:
The objective of the present invention is to prepare pure rivaroxaban, the compound of formula -1 with an industrially viable and cost effective process.
Another objective of the present invention is to provide a process for the preparation of rivaroxaban crystal modification I.
SUMMARY OF THE INVENTION:
Accordingly, the present invention provides a process for preparing pure rivaroxaban the compound of formula -1 using readily available, cost effective, and industrially safe reagents.
Formula -1
which comprises the steps of:
According to primary object of the present invention, there is provided a novel, simple, cost effective and industrially safe process for the preparation of pure rivaroxaban the compound of formula -1,


a) suspending crude rivaroxaban the compound of formula -1 in the solvent formamide sufficient to achieve complete dissolution to get clear solution in hot condition;
b) optionally quenching the clear solution in second solvent;
c) stilling and cooling the clear solution gradually to crystallize out solid mass; and
d) filtering the solid obtained to isolate pure rivaroxaban, the compound of formula -I.
Yet, in another aspect, the present invention provides a process for purification of crude rivaroxaban to get pure rivaroxaban crystal modification I.
DETAILED DESCRITION OF THE INVENTION:
The present invention relates to a process for preparing'pure rivaroxaban, the compound of formula -I.

Formula -I
The present invention discloses process for the preparation of pure rivaroxaban. Within the context of the present disclosure, the process provides an improved and efficient method by using industrial friendly solvent and reduced solvent volume, making the process economically feasible.
In an aspect, the present invention provides a process for the preparation of pure rivaroxaban, the compound of formula -I, which comprises the steps of;

a) suspending crude rivaroxaban the compound of formula -I in the solvent formamide sufficient to achieve complete dissolution to get clear solution in hot condition;
b) optionally quenching the clear solution in second solvent;
c) stirring and cooling gradually the reaction solution to crystallize out solid mass; and
d) filtering the solid obtained to isolate pure rivaroxaban, the compound of formula -I.
In an embodiment of the present invention, in step (a) of the process, the clear solution is obtained at temperature in the range of 90°C to 120°C, more preferably at temperature of 100°C to 110°C.
In an embodiment of the present invention, in step (b) of the process, the solvents used for quenching are the solvents which is miscible with solvent formamide and selected from the group consisting of water, methanol, n-propanol and isopropanol. More preferable solvent used for quenching are water and n-propanol, wherein the most preferred solvent for quenching is water.
In an embodiment of the present invention, in step (c) of the process, the reaction solution is cooled to 0°C to 30°C, wherein most preferred temperature is 20°C to 30°C for complete precipitation of pure rivaroxaban.
In an embodiment of the present invention provides a process for the preparation of pure rivaroxaban crystal modification I, which comprises the steps of;
e) suspending crude rivaroxaban the compound of formula -I in the solvent formamide sufficient to achieve complete dissolution to get clear solution -in hot condition;
f) quenching the clear solution in second solvent;
g) stirring and cooling gradually the reaction solution to crystallize out solid mass; and

h) filtering the solid obtained to isolate pure rivaroxaban crystal modification I.
In an embodiment of the present invention, in step (e) of the process, the clear solution is obtained at temperature in the range of 90°C to 120°C, more preferably at temperature of 100°C to 110°C.
In an embodiment of the present invention,, in step (f) of the process, the solvents used for quenching are. the solvents which is miscible with solvent formamide and selected from the group consisting of water, methanol, n-propanol and isopropanol. More preferable solvent used for quenching are water and n-propanol, wherein the most preferred solvent for quenching is water.
In an embodiment of the present invention, in step (g) of the process, the reaction solution is cooled to 0°C to 30°C. wherein most preferred temperature is 20°C to 30°C for complete precipitation of pure rivaroxaban crystal modification I.
The advantage of the present invention over the existing prior art is that, it helps to get rid of the process impurities to less than 0.1%. The present invention also used less volume of solvent formamide provides the final compound, rivaroxaban in increased yield, and avoids cumbersome purification process to get rid of the impurities, which makes the process industrially viable and overcome the problems associated with the processes known in the art. Thus, the present invention results in an industrially beneficial process and meets the ICH guidelines on the impurities to prepare pure rivaroxaban, the compound of formula -1.
The following examples, which fully illustrate the practice of the preferred embodiments of the present invention, are intended to be for illustrative purpose only, and should not be considered to be limiting to the scope of the present invention.

EXAMPLES:
Example 1: Purification of crude rivaroxaban;
Crude rivaroxaban (125 gm) suspended in formamide (1725 ml) at 25°C to 30°C. Stirred and raised the temperature slowly to 100°C. Maintained for 30 minutes at 100°C to 105°C to get clear solution. Gradually cooled to 15°C to 20°C and maintained under stirring for 30 minutes. Filtered the solid obtained and washed with purified water. Dried the product pure rivaroxaban till constant weight.
Yield = 112.0 gm; HPLC Purity - 99.90%.
Example 2: Purification of crude rivaroxaban:
Crude rivaroxaban (125 gm) suspended in formamide (1725 ml) at 25°C to 30°C. Stirred and raised the temperature slowly to 100°C. Maintained for 30 minutes at 100°C to 105°C to get clear solution. Quenched the clear solution into purified water (1725 ml) at 50°C. Gradually cooled to 25°C to 30°C and maintained under stirring for 30 minutes. Filtered the solid obtained and washed with purified water. Dried the product pure rivaroxaban till constant weight.
Yietd = 112.50 gm: HPLC Purity - 99.86%.
Example 3: Purification of crude rivaroxaban:
Crude rivaroxaban (125 gm) suspended in formamide (1725 ml) at 25°C to 30°C. StiiTcd and raised the temperature slowly to 100°C. Maintained for 30 minutes at 100°C to 105°C to get clear solution. Quenched the clear solution into purified
water (1725 ml) at 25-35°C. Gradually cooled to 25°C to 30°C and maintained
*
under stirring for 30 minutes. Filtered the solid obtained and washed with purified water. Dried the product pure rivaroxaban till constant weight.
Yield = 113.00 gm; HPLC Purity = 99.85%.

Example 4: Purification of crude rivaroxaban:
Crude rivaroxaban (125 gm) suspended in formamide (1725 ml) at 25°C to 30°C. Stirred and raised the temperature slowly to 100°C. Maintained for 30 minutes at 100°C to 105°C to get clear solution. Quenched the clear solution into n-propanol (1725 ml) at 25-35°C. Gradually cooled to 25°C to 30°C and maintained under stirring for 30 minutes. Filtered the solid obtained and washed with purified water. Dried the product pure rivaroxaban till constant weight.
Yield - 108.75 gm; HPLC Purity = 99.86%.
Example 5: Purification of crude rivaroxaban:
Crude rivaroxaban (125 gm) suspended in formamide (1725 ml) at 25°C to 30°C. Stirred and raised the temperature slowly to 100°C. Maintained for 30 minutes at 100°C to 105°C to get clear solution. Quenched the clear solution into methanol (1725 ml) at 25-35°C. Gradually cooled to 25°C to 30°C and maintained under stirring for 30 minutes. Filtered the solid obtained and washed with purified water. Dried the product pure rivaroxaban till constant weight.
Yield = 98.40 gm; HPLC Purity = 99.81%.
Example 6: Purification of crude rivaroxaban:
Crude rivaroxaban (125 gm) suspended in formamide (1725 ml) at 25°C to 30°C. Stirred and raised the temperature slowly to 100°C. Maintained for 30 minutes at 100°C to 105°C to get clear solution. Quenched the clear solution into isopropanol (1725 ml) at 25-35°C. Gradually cooled to 25°C to 30°C and maintained under stirring for 30 minutes. Filtered the solid obtained and washed with purified water. Dried the product pure rivaroxaban till constant weight.
Yield = 118.75 gm; HPLC Purity = 99.84%.

Claims:
1. A process for preparation of pure rivaroxaban the compound of formula -I,

Formula -I
which comprises the steps of:
a) suspending crude rivaroxaban the compound of formula - I in the
solvent formamide sufficient to achieve complete dissolution to get
clear solution in hot condition;
b) optionally quenching the clear solution in second solvent;
c) stirring and cooling the clear solution gradually to crystallize out solid mass; and
d) filtering the solid obtained to isolate pure rivaroxaban, the compound of formula -I.

2. The process according to claim 1, wherein in step (a) the temperature to get clear solution is in the range of 90°C to 120°C.
3. The process according to claim 1, wherein the solvents used for quenching in step (b) are selected from the_group-consisting of water, methanol, n-propanol and isopropanol.
4. A process for the preparation of pure rivaroxaban crystal modification I; which comprises the steps of;

e) suspending crude rivaroxaban the compound of formula - I in the solvent formamide sufficient to achieve complete dissolution to get clear solution in hot condition;
f) quenching the clear solution in second solvent;

g) stirring and cooling gradually the reaction solution to crystallize out
solid mass; and h) filtering the solid obtained to isolate pure rivaroxaban crystal
modification I.
5. The process according to claim 1, wherein in step (e) the temperature to get clear solution is in the range of 90°C to 120°C.
6. The process according to claim 1, wherein the solvents used for quenching in step (f) are selected from the group consisting of water, methanol, n-propanol and isopropanol.