Improved process for the preparation of Rivaroxaban
Field of the Invention
The present invention provides an improved process for the preparation of Rivaroxaban with high yield, high degree of purity with fewer impurities, which is economically viable on commercial scale. Specifically, the invention provides a method for the preparation of pure Rivaroxaban involving the use of mixture of acetic acid and water for the purification of Rivaroxaban, wherein acetic acid and water is present in the ratio of 1:2 to 1:7.
Background of the Invention
Rivaroxaban is chemically known as 5-chloro-N-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-l,3-oxazolidin-5-yl}methyl)-2-thiophenecarboxamide. Rivaroxaban is an orally active factor Xa inhibitor for the prevention and treatment of deep vein thrombosis and pulmonarembolism in patients undergoing knee and hip replacement surgery developed by Bayer Healthcare. Rivaroxaban is marketed under trade name XARELTO® by Janssen Pharmaceuticals, Inc. Rivaroxaban has an oxazolidinone nucleus and represented by the following structural formula:
^b °
(I)
Rivaroxaban was first disclosed in US Patent Number 7,157,456. According to U.S.
Patent No. 7,585,860, Rivaroxaban is prepared by reacting 2-[(2S)-2-oxiranylmethyl]-lH-
isoindole-l,3(2H)-dione (III) with 4-(4-aminophenyl)-3-morpholinone (II) to obtain 2-
((2R)-2-hydroxy-3-{[4-(3-oxo-4-morpholinyl)phenyl]amino}propyl-lH-isoindole 1,3
(2H)-dione (IV). Thus the obtained compound of formula (IV) is cyclized by N,N -carbonyldiimidazole in the presence of dimethylaminopyridine in tetrahydrofuran and to

yield 2-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-l,3-oxazolidin-5-yl}methyl)-lH-isoindole-l,3(2H)-dione (V) followed by deprotection of the phthalimide protective group to obtain 4-[4-[(5S)-5-(aminomethyl)-2-oxo-l,3-oxazolidin-3-yl]phenyl]morpholin-3-one (VI). The compound 4-[4-[(5S)-5-(aminomethyl)-2-oxo-l,3-oxazolidin-3-yl]phenyl]morpholin-3-one (VI) thus obtained is reacted with 5-chlorothiophene-2-carbonyl chloride in the presence of pyridine to obtain crude Rivaroxaban (I). The crude Rivaroxaban was further purified by Flash chromatography (dichloromethane/methanol mixtures) to produce Rivaroxaban (Scheme 1).
Scheme 1


OH O

US Patent Number 7,816,355 disclosed another process for preparation of Rivaroxaban which involves the use of methyl N-(2R,3-epoxy-l-propyl)-N-[4-(3-oxo-4-morpholinyl)phenyl]carbamate (X) as an intermediate. The said intermediate is synthesized by reacting R-(-)-epichlorohydrin with 4-(4-amino-phenyl)-morpholin-3-one to obtain (R)-4-(4-((oxiran-2-ylmethyl)amino)phenyl)morpholin-3-one (VIII). The compound of formula (VIII) thus obtained is further reacted with methyl chloroformate to provide said intermediate compound of formula (X). Said patent also provides alternate

process wherein intermediate compound of formula (X) can be prepared by reacting 4-(4-amino-phenyl)-morpholin-3-one (II) with methyl chloroformate to give methyl N-[4-(3-oxo-4-morpholinyl)phenyl]carbamate (IX), which, on further reaction with R-(-)-epichlorohydrin to provide said intermediate compound of formula (X). Finally, the intermediate compound of formula (X) is reacted with 5-chlorothiophene-2-carboxamide (VII) to yield Rivaroxaban (I) (Scheme 2).

Scheme 2

o Cl
O N—^ V- NH2 0
fill \ ■ o
0 M—P y—HH

(VIII)
_J> o
O^NHf\NA
\ / \=/ H
\M/ *

(IX)

»o

(X)
H2N-\rSs
II />-CI

US Patent Number 8,106,192 describes another process for the preparation of Rivaroxaban, which involves preparing 5-chlorothiophene-2-carbonyl chloride (VII) in a first step by chlorinating 5-chlorothiophene-2-carboxylic acid: reacting said 5-chlorothiophene-2-carbonyl chloride (VII) in a second step with (2S)-3-aminopropane-1,2-diol hydrochloride (Vila) to give N-((S)-2,3-dihydroxypropyl)-5-chlorothiophene-2-carboxamide (XIX) followed by conversion of intermediate of formula (XIX) in a third step to N-((S)-3-bromo-2-hydroxypropyl)-5-chlorothiophene-2-carboxamide (XX). Converting said N-((S)-3-bromo-2-hydroxypropyl)-5-chlorothiophene-2-carboxamide (XX) in a fourth step by reacting with 4-(4-aminophenyl)-3-morpholinone (II) to N-{(R)-2-hydroxy-3-[4-(3-oxomorpholin-4-yl)phenylamino]propyl}-5-chlorothiophene-2-carboxamide (XXI) and reacting said compound of formula (XXI) in a fifth step with phosgene or a phosgene equivalent to obtain Rivaroxaban (I) (Scheme 3).

Scheme 3



1 ci
CI + HO.
(VII)

(Vila)

,NH2 HCI

HO

OH

O (XIX)

CI
f

Cl 0 N-<\ />-NH7
O (II)

Br

OH

HBr in AcOH

CI
To
(XX)

US Patent Number 8,648,189 describes another process for the preparation of Rivaroxaban which involves reaction of compound of formula (XV) with a compound of formula R1SO2-X to obtain a compound of formula (XVI). The compound of formula (XVI) is first reacted with phosgene or an equivalent thereof and the reaction product thereof is subsequently reacted with a compound of formula (II) to obtain a compound of formula (XVII), which undergoes a cyclization reaction to obtain compound of formula (I) (Scheme 4).

Scheme 4
OH
HO. /L

O (XV)

Hal

R102SO.

OH

CI
O (XVI)
1. Phosgene or eqvt

o
O N—(\ /)—N ? H
O
(I)

O

S Hal

2-°^n /rNH2
o o
^o
Q N^ /^NH ^ ^ j ^
S Hal
OS02R-i ° (XVII)

Several other United States Patent Publications and PCT Patent Publications also disclose process for the preparation of Rivaroxaban.
It is known that synthetic compounds can contain extraneous compounds or impurities resulting from their synthesis or degradation. The impurities can be unreacted starting materials, by-products of the reaction, products of side reactions, or degradation products. Generally, impurities in a compound may arise from degradation of the compound itself, or during the preparation of the API. Impurities in Rivaroxaban or any active pharmaceutical ingredient (API) are undesirable and might be harmful, as they would be carried over to pharmaceutical compositions, used for human consumption.
Regulatory authorities worldwide require drug manufactures to isolate, identify and characterize the impurities in their products. Furthermore, it is also required to control these impurities in the final drug substance, as obtained by the manufacturing process and to ensure that these impurities are present in the lowest possible level and within prescribed limits, even if structural determination is not possible.
The prior art processes disclosed above for the preparation of Rivaroxaban involve longer reaction time; involves the use of hazardous reagents such as phosgene, hydrobromic acid and flammable solvent like pyridine; purification by chromatography and lower yield. Accordingly, these processes are not suitable on an industrial scale.
Thus, there remains a need to develop an industrial friendly process, which is substantially free of impurities for the preparation of Rivaroxaban on commercially economical scale with high purity and higher yield.
Summary of the Invention
The present invention relates to an improved process for the preparation of 5-chloro-N-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-l,3-oxazolidin-5-yl}methyl)-2-thiophene carboxamide (Rivaroxaban).

It is another object of the present invention to provide a simple, convenient, commercially viable, industrial friendly process for synthesizing Rivaroxaban.
In yet another object of present invention, it provides a process for preparation of Rivaroxaban (I), which is substantially free of genotoxic impurities.
A yet another object of the present invention provides a process for producing Rivaroxaban (I) by employing the use of mixture of acetic acid and water preferably in the ratio of 1:2 to 1:7.
In an another object of present invention, it provides a process for the preparation of Rivaroxaban (I), which comprises the steps of: (a) reacting 4-(4-aminophenyl)-3-morpholinone (II) with 2-[(2S)-2-oxiranylmethyl]-lH-isoindole-l,3(2H)-dione (III) to obtain 2-((2R)-2-hydroxy-3-{[ 4-(3-oxo-4-morpholinyl)phenyl]amino}propyl-lH-isoindole-l,3(2H)-dione (IV); (b) compound of formula (IV) is cyclized in the presence of N,N'-carbonyldiimidazole to yield 2-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-l,3-oxazolidin-5-yl}methyl)-lH-isoindole-l,3(2H)-dione (V); (c) reacting compound of formula (V) with ethanolamine to obtain (S)-N1-(2-hydroxyethyl)-N2-((2-oxo-3-(4-(3-oxomorpholino)phenyl)oxazolidin-5-yl)methyl)phthalamide (XVIII); (d) conversion of compound of formula (XVIII) to 4-[4-[(5S)-5-(aminomethyl)-2-oxo-l,3-oxazolidin-3-yl]phenyl]morpholin-3-one (VI); (e) reacting 4-[4-[(5S)-5-(aminomethyl)-2-oxo-l,3-oxazolidin-3-yl]phenyl]morpholin-3-one (VI) with 5-chlorothiophene-2-carbonyl chloride in presence of a suitable base to obtain Rivaroxaban; (f) optionally, purifying Rivaroxaban in presence of a suitable solvent or mixture thereof; wherein, steps (c) to (e) are carried out with or without isolation of the respective intermediates.
In yet another embodiment compound of formula (IV) is cyclized in the presence of N,N'-carbonyldiimidazole and in presence of an ester solvent to yield 2-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-l,3-oxazolidin-5-yl}methyl)-lH-isoindole-l,3(2H)-dione (V).

In yet another embodiment the invention provides substantially solvent-free Rivaroxaban and process for preparation thereof.
The above and other objects are further attained and supported by the following embodiments described herein. However, the scope of the invention is not restricted to described embodiments herein after.
Detailed Description of the Invention
While this specification concludes with claims particularly pointing out and distinctly claiming that, which is regarded as the invention, it is anticipated that the invention can be more readily understood through reading the following detailed description of the invention and study of the included examples.
In an object, the present invention provides a process for the preparation/purification of Rivaroxaban, which comprises the steps of:
a) providing mixture of Rivaroxaban in an organic acid;
b) optionally, heating the reaction mixture of step (a);
c) adding water to the reaction mixture;
d) optionally, cooling the reaction mixture; and
e) isolating Rivaroxaban
wherein ratio of organic acid and water is from 1:2 to 1:7.
In accordance with yet another object of the present invention, there is provided a process for the preparation of modification I of Rivaroxaban, which comprises the steps of:
a) providing mixture of Rivaroxaban in an organic acid;
b) optionally, heating the reaction mixture of step (a);
c) adding water to the reaction mixture;
d) optionally, cooling the reaction mixture; and
e) isolating Rivaroxaban

wherein ratio of organic acid and water is from 1:2 to 1:7.
The organic acid as referred above is selected from the group comprising of formic acid, acetic acid, propanoic acid, butanoic acid and the like, preferably formic acid or acetic acid, more preferably acetic acid.
In accordance with yet another object of the present invention, there is provided a process for the preparation/purification of Rivaroxaban, which comprises the steps of:
a) providing mixture of Rivaroxaban in acetic acid;
b) optionally, heating the reaction mixture of step (a);
c) adding water to the reaction mixture;
d) optionally, cooling the reaction mixture; and
e) isolating Rivaroxaban
wherein ratio of organic acid and water is 1:2 to 1:7.
In accordance with yet another object of the present invention there is provided a process for the preparation/purification of Rivaroxaban, which comprises the steps of:
a) providing mixture of Rivaroxaban in acetic acid;
b) optionally, heating the reaction mixture of step (a) from 80°C to 100°C;
c) adding water to the reaction mixture;
d) optionally, cooling the reaction mixture; and
e) isolating Rivaroxaban
wherein ratio of organic acid and water is 1:2 to 1:7.
In accordance with yet another object of the present invention, there is provided a process for preparation/purification of Rivaroxaban, which comprises the steps of:
a) providing mixture of Rivaroxaban in acetic acid;

b) optionally, heating the reaction mixture of step (a);
c) adding water to the reaction mixture;
d) optionally, cooling the reaction mixture; and
e) isolating Rivaroxaban
wherein ratio of organic acid and water is from 1:3.
The present invention has been developed to obtain the pure Rivaroxaban and to improve the yield by employing the use of organic acid and water as purifying solvents wherein organic acid and water is present in the ratio of 1:2 to 1:7. We have observed that ratio of organic acid and water is very critical to obtain Rivaroxaban in better yield and high purity. By employing the above-referred ratio of organic acid and water, the improvement in yield and purity is observed in comparison to other ratio of said solvent system. Further, as per the process of the current invention, less amount of organic acid is required, which also impart economic benefits to the process.
In accordance with yet another object of the present invention there is provided a process for the preparation of Rivaroxaban (I) (Scheme 5) comprising the steps of:
(i) reacting 4-(4-aminophenyl)-3-morpholinone (II) with 2-[(2S)-2-oxiranylmethyl]-lH-isoindole-l,3(2H)-dione (III) in presence of a suitable solvent to obtain 2-((2R)-2-hydroxy-3-{[4-(3-oxo-4-morpholinyl)phenyl]amino}propyl-lH-isoindole-l,3(2H)-dione(IV);
(ii) optionally, purifying 2-((2R)-2-hydroxy-3-{[4-(3-oxo-4-morpholinyl)phenyl] amino}propyl-lH-isoindole-l,3(2H)-dione (IV) in presence of a suitable solvent or mixture thereof;
(iii) compound of formula (IV) is cyclized in presence of cyclization agent to yield 2-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-l,3-oxazolidin-5-yl}methyl)-lH-isoindole-l,3(2H)-dione (V);

(iv) reacting compound of formula (V) with ethanolamine to obtain (S)-N1-(2-hydroxyethyl)-N2-((2-oxo-3-(4-(3-oxomorpholino)phenyl)oxazolidin-5-yl)methyl)phthalamide (XVIII);
(v) conversion of compound of formula (XVIII) to 4-[4-[(5S)-5-(aminomethyl)-2-oxo-l,3-oxazolidin-3-yl]phenyl]morpholin-3-one (VI);
(vi) reacting 4-[4-[(5S)-5-(aminomethyl)-2-oxo-l,3-oxazolidin-3-yl]phenyl]morpholin-3-one (VI) with 5-chlorothiophene-2-carbonyl chloride in presence of a suitable base to obtain Rivaroxaban; and
(vii) optionally, purifying Rivaroxaban in presence of a suitable solvent or mixture thereof wherein, steps (iii) to (vi) are carried out with or without isolation of the respective intermediates.

Scheme 5
°\ /N V^/ NH2 + N (ii)

(in)

O N
i

// \ H
(IV)

OH O
o

HO


¥ O
Ti-CI

H o
O N
i
(XVIII)
O.
^O
0 N-f "v—N
(VI)

O

NH
NHo

V9 °
o,
0 N—f V—N
o
(V)
CI
o sA
VO H
o
o
O N^ ^>—N
(I)

In accordance with yet another object of the present invention there is provided a process for the preparation of Rivaroxaban (I) comprising the steps of:
(i) reacting 4-(4-aminophenyl)-3-morpholinone (II) with 2-[(2S)-2-oxiranylmethyl]-lH-isoindole-l,3(2H)-dione (III) in presence of an aqueous alcoholic solvent to obtain 2-((2R)-2-hydroxy-3-{[4-(3-oxo-4-morpholinyl)phenyl]amino} propyl-1H-isoindole-l,3(2H)-dione (IV);
(ii) compound of formula (IV) is cyclized in presence of N, N'-carbonyldiimidazole in presence of an ester solvent to yield 2-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-l,3-oxazolidin-5-yl} methyl)-lH-isoindole-l,3(2H)-dione (V);
(iii) reacting compound of formula (V) with ethanolamine to obtain (S)-N1-(2-hydroxyethyl)-N2-((2-oxo-3-(4-(3-oxomorpholino)phenyl)oxazolidin-5-yl)methyl)phthalamide (XVIII);
(iv) conversion of compound of formula (XVIII) to 4-[4-[(5S)-5-(aminomethyl)-2-oxo-l,3-oxazolidin-3-yl]phenyl]morpholin-3-one (VI);
(v) reacting 4-[4-[(5S)-5-(aminomethyl)-2-oxo-l,3-oxazolidin-3-yl]phenyl]morpholin-3-one (VI) with 5-chlorothiophene-2-carbonyl chloride in presence of a suitable base to obtain Rivaroxaban, preferably bases is added after addition of 5-chlorothiophene-2-carbonyl chloride; and
(vi) optionally, purifying Rivaroxaban in presence of a suitable solvent or mixture thereof wherein, steps (iii) to (vi) are carried out with or without isolation of the respective intermediates.

In accordance with yet another object of the present invention there is provides a process
for preparation of Rivaroxaban (I) comprising the steps of:
(i) reacting 4-(4-aminophenyl)-3-morpholinone (II) with 2-[(2S)-2-oxiranylmethyl]-lH-isoindole-l,3(2H)-dione (III) in presence of mixture of isopropanol and water to obtain 2-((2R)-2-hydroxy-3-{[4-(3-oxo-4-morpholinyl)phenyl]amino} propyl-lH-isoindole-l,3(2H)-dione (IV);
(ii) optionally, purifying 2-((2R)-2-hydroxy-3-{[4-(3-oxo-4-morpholinyl)phenyl] amino}propyl-lH-isoindole-l,3(2H)-dione (IV) in presence of an aqueous alcoholic solvent;
(iii) compound of formula (IV) is cyclized in presence of N, N'-carbonyldiimidazole in presence of ethyl acetate solvent to yield 2-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-l,3-oxazolidin-5-yl} methyl)-lH-isoindole-l,3(2H)-dione (V);
(iv) reacting compound of formula (V) with ethanolamine to obtain (S)-N1-(2-hydroxyethyl)-N2-((2-oxo-3-(4-(3-oxomorpholino)phenyl)oxazolidin-5-yl)methyl)phthalamide (XVIII);
(v) conversion of compound of formula (XVIII) to 4-[4-[(5S)-5-(aminomethyl)-2-oxo-l,3-oxazolidin-3-yl]phenyl]morpholin-3-one (VI);
(vi) reacting 4-[4-[(5S)-5-(aminomethyl)-2-oxo-l,3-oxazolidin-3-yl]phenyl]morpholin-3-one (VI) with 5-chlorothiophene-2-carbonyl chloride in presence of a suitable base to obtain Rivaroxaban, preferably base is added after the addition of 5-chlorothiophene-2-carbonyl chloride; and
(vii) purifying Rivaroxaban by dissolving in mixture of acetic acid and water or by dissolving Rivaroxaban in acetic acid followed by addition of water

wherein, steps (iii) to (vi) are carried out with or without isolation of the respective intermediates and ratio of acetic acid and water is from 1:2 to 1:7.
In accordance with yet another object of the present invention there is provides a process for preparation of Rivaroxaban (I) comprising the steps of:
(i) reacting 4-[4-[(5S)-5-(aminomethyl)-2-oxo-l,3-oxazolidin-3-yl]phenyl]morpholin-3-one (VI) with 5-chlorothiophene-2-carbonyl chloride in presence of a suitable base to obtain Rivaroxaban, preferably base is added after addition of 5-chlorothiophene-2-carbonyl chloride; and
(ii) purifying Rivaroxaban by dissolving in mixture of acetic acid and water or by
dissolving Rivaroxaban in acetic acid followed by the addition of water wherein, ratio of acetic acid and water is from 1:2 to 1:7.
In another object of present invention, it provides a process for preparation of Rivaroxaban (I) which is substantially free of genotoxic impurities. In accordance with yet another object of the present invention there is provided a process for the preparation/purification of Rivaroxaban substantially free of one or more of the following genotoxic impurities, comprising the steps of:
a) providing mixture of Rivaroxaban in acetic acid;
b) heating the reaction mixture of step (a);
c) adding water to the reaction mixture;
d) optionally, cooling the reaction mixture; and
e) isolating Rivaroxaban
wherein ratio of organic acid and water is from 1:2 to 1:7.
OH n
H2N. ^ ^O „ „,^^t
^^ o o o


HN

-\J °wN-\>NO>


%s) ci-^sXci
Thorough evaluation to assess the safety with respect to genotoxicity based on presence of structural alerting compounds of reagents, chemicals used and or generated during the synthesis of Key starting material (KSM) and Active pharmaceutical ingredient (API) has been done in line with the European Medicines Agency (EMEA) guidance on genotoxicity, as per ICH guidelines M7 and based on sound scientific evaluation of impurities generated during synthesis of KSM/ APL The above referred impurities/ compounds have been identified as potentially genotoxic on the basis of structural alert.
As per the process of the current invention said genotoxic compounds, which are either introduced or formed during the process are well controlled in Rivaroxaban. Further, as per the process of the instant invention Rivaroxaban is substantially free of the said genotoxic impurities, which is in line with Committee for human medicinal products (CHMP)/Centre for drug evaluation and research (CDER) guidelines/ European Medicines Agency (EMEA) guidance on genotoxicity and ICH guidelines M7 on genotoxic compounds.

For purposes of the present invention, "substantially free of impurities" means Rivaroxaban having purity more than 99.5% and amount of any of the above referred impurity less than 0.10% Preferably less than, 0.05% and more preferably less than 0.02%.
The solvent as defined above is selected from the group comprising of nitriles, alcohols, esters, halogenated hydrocarbons, ethers, amides, dialkylsulfoxides, aromatic or aliphatic hydrocarbons, water or the mixtures thereof. Nitriles are selected from the group comprising of acetonitrile, propionitrile, butyronitrile, valeronitrile and the like, preferably acetonitrile. Alcohols are selected from the group comprising of methanol, ethanol, «-propanol, isopropanol, «-butanol and the like. Esters are selected from the group comprising of ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate and the like. Halogenated hydrocarbons are selected from the group comprising of dichloromethane (DCM), chloroform, dichloroethane, chlorobenzene and the like. Ethers are selected from the group comprising of diethyl ether, methyl tert-buty\ ether (MTBE), diisopropyl ether, tetrahydrofuran (THF), dioxane and the like. Amides are selected from the group comprising of N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMA), N-methylformamide, N-methylpyrrolidone and the like. Dialkyl sulfoxides are selected from the group comprising of dimethylsulfoxide, diethylsulfoxide, dibutylsulfoxide and the like. Aliphatic hydrocarbons are selected from the group comprising of alkanes or cycloalkanes such as pentane, hexane, heptane, octane, cyclohexane, cyclopentane and the like. Aromatic hydrocarbons are selected from the group comprising of toluene, xylene and the like.
A suitable base as defined above is selected from a group comprising of an organic or
inorganic bases. The inorganic base is selected from group comprising of carbonates,
bicarbonates, hydroxides of alkali and alkaline earth metals and the like. Organic base is
selected from the group comprising of triethylamine (TEA), N,N-diisopropylethylamine,
tributylamine, triisopropylamine, pyridine, l,8-diazabicyclo[5.4.0]undec-7-ene (DBU),
l,5-diazabicyclo[4.3.0]non-5-ene (DBN), l,4-diazabicyclo[2.2.2]octane (DABCO), 4-
dimethylaminopyridine (4-DMAP), l,8-bis-(dimethylamino)naphthalene, 1-

ethylpiperidine, 1-methylmorpholine, lutidine and mixtures thereof. Carbonates are selected from the group comprising of K2CO3, CS2CO3 and Na2C03 and the like. Bicarbonates are selected from the group comprising of NaHCCb, KHCO3 and the like. Hydroxides are selected from the group comprising of NaOH, KOH, LiOH, CsOH and the like.
Cyclization agents as defined above is selected from a group comprising of carbonyl diimidazole (CDI), diethyl carbonate, dimethyl carbonate, N,N'-disuccinimidyl carbonate, l,l'-carbonyl-di-(l,2,4-triazole (CDT), 2,2'-carbonylbis(4-methyl-l,2,4-oxadiazolidine-3,5-dione), Bis(trichloromethyl)carbonate and the like.
In another aspect there is provided a pharmaceutical composition that includes a therapeutically effective amount of Rivaroxaban (I) according to the process of the present invention and one or more pharmaceutically acceptable carriers, excipients or diluents.
In another aspect there is provided a pharmaceutical composition that includes a therapeutically effective amount Rivaroxaban (I), according to the process of the present invention, useful for the prevention and treatment of deep vein thrombosis and pulmonary embolism in patients undergoing knee and hip replacement surgery.
The details of the process of the invention are provided in the Examples given below, which are provided by way of illustration only and therefore are not intended to limit the scope of the invention.
Examples
Example 1
Preparation of 2-((2R)-2-hydroxy-3-{[ 4-(3-oxo-4-morpholinyl)phenyl]amino}propyl
-lH-isoindole-l,3(2H)-dione
R)-2-(2-hydroxy-3-((4-(3-oxomorpholino) phenyl) amino) propyl) isoindoline-l,3-dione

(5.0 g) was added to the 25% aqueous solution of IP A (100 mL) at 25-30°C. Suspended solution was heated to 60-65°C and stirred at same temperature for about 3h. Cooled to 25-30°C and stirred for 2h. The solid was collected by filtration and dried, yielding 4.1g (82%) of the title compound as white solid.
Example 1A
Purification of 2-((2R)-2-hydroxy-3-{[ 4-(3-oxo-4-morpholinyl)phenyl]amino}propyl
-lH-isoindole-l,3(2H)-dione
In 3.0L glass reactor Charged DM water (500 mL) and isopropyl alcohol (1500 mL) and 4-(Aminophenyl)morpholin-3-one (100.0 g) and ((^-2-(Oxiran-2-yl-methyl)isoindoline-1,3-dione (116.29 g) at RT (25-30°C). Heated the reaction mass to 60-65°C. Stirred the reaction mass at 60-65°C for 23-26h. Monitored by HPLC. Cooled the reaction mass to 32-38°C. Stirred at 32-38°C for 30-60 min. Filtered the solid under vacuum at 32-38°C and washed the solid with 25% aq. Isopropyl alcohol (75 mL DM water in 225 mL Isopropyl alcohol) at 32-38°C under vacuum. Dried the solid under suction for 45-60 min at 25-30°C. Dried the solid in vacuum oven at 60-70°C. (Yield: 86%; HPLC Purity: 98.0%).
Example 2
Preparation of 2-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-l,3-oxazolidin-5-
yl}methyl)-lH-isoindole-l,3(2H)-dione
2-((2R)-2-Hhydroxy-3 -{[ 4-(3-oxo-4-morpholinyl)phenyl]amino}propyl-1 H-isoindole-1,3 (2H)-dione (140.Og) was charged to Round Bottom Flask containing DCM (1400mL) at 25-30°C, followed by the addition of CDI (57.41 g). Resulted suspension was stirred for 6h at 30-35°C, followed by addition of CDI (5.741 g). Reaction mass was concentrated in vacuum, residual solid was taken in ethyl acetate (700mL) and refluxed for 30 min. Reaction was cooled to 25-30°C, stirred for 2h and filtered. Filtered solid was washed with ethyl acetate (280mL) and dried to obtain titled compound 140.Og (98.50 %)
Example 2A

Preparation of 2-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-l,3-oxazolidin-5-yl}methyl)-lH-isoindole-l,3(2H)-dione
In 2.0L glass reactor Charged ethyl acetate (1000 mL) and Charged (2i?)-2-(2-Hydroxy-3-((4-(3-oxomorpholino) phenyl)amino)propyl)isoindoline-l,3-dione (100.0 g) RT (25-30°C).Charged CDI (57.20 g) to it at RT (25-30 °C). Heated the reaction mass at to 78-82°C. Refluxed the reaction mass for 12-15h. Monitored by HPLC. Cooled the reaction mass at 25-30°C (~l-2h). Stirred the reaction mass for 2-3h at 25-30°C. Filtered the solid under vacuum at 25-30°C. Washed the solid under vacuum with ethyl acetate (100 mLx2). Dried the solid under vacuum at 60-65°C. (Yield: 99.0%; HPLC purity: 99.0%)
Example 3
Preparation of (5»V)-5-Chloro-JV-((2-oxo-3-(4-(3-oxomorpholino) phenyl)oxazolidin-5-
yl)methyl)thiophene-2-carboxamide from (5»S)-2-((2-Oxo-3-(4-(3-
oxomorpholino)phenyl) oxazolidin-5-yl)methyl)isoindoline-l,3-dione
In 2.0L glass reactor Charged Ethanolamine (400 mL) and f5$-2-((2-Oxo-3-(4-(3-oxomorpholino)phenyl) oxazolidin-5-yl)methyl)isoindoline-l,3-dione (100.Og) to at RT (25-30°C). The temperature of the reaction mass was raised to 30-35°C followed by stirring the reaction mass for 4-6 h at 30-35°C. Charged DCM and 25% (w/v) aq. brine solution at 30-35°C. The reaction mass was stirred at 30-35°C for 30 min followed by separation of the organic layer. The aqueous layer was extracted with DCM. The combined DCM layer was washed with 25% (w/v) aq. Brine solution and separated the layers. Distilled out solvent 10-12V (-60%) atmospherically at NMT 45°C. Cooled the reaction mass at 0-10°C. To this solution 5-chlorothiophene-2-carbonyl chloride in DCM and triethylamine (43.10g) was added at 0-10°C in 30-60 min Stirred the reaction mass at 0-10°C for l-2h. Charged DM water (600 mL) at 0-10°C. Raised the temp, at 20-25°C and stirred for l-2h at 20-25°C. Filtered the solid under vacuum at 20-25°C. Washed the solid with DM Water and DCM. Dried the solid (wet wt: ~125gm; HPLC purity: 99%)
Example 4

Preparation of Rivaroxaban
In 1.0L glass reactor (5,S)-5-Chloro-jV-((2-oxo-3-(4-(3-oxomorpholino)
phenyl)oxazolidin-5-yl)methyl)thiophene-2-carboxamide Crude (-125.Og) and 20% Methanol was dissolved in 3600 mL of 20% methanol in dichloromethane at reflux temperature and solution was allowed to cool at 25-30°C. Clear solution was micronized and concentrated to obtain solid. 480 mL of Methanol was added to the solid, heated to 55-60°C for 30 min and cooled to 25-30°C. The solid obtained was filtered after stirring at 25-30°C for lh, washed with methanol and Suck dried the solid under suction for lh at 25-30°C.(Wetwt:~90g)
In 3.0L glass reactor Charged (5,S)-5-Chloro-jV-((2-oxo-3-(4-(3-oxomorpholino) phenyl)oxazolidin-5-yl)methyl)thiophene-2-carboxamide Crude (~90g) and acetic acid (1200 mL to at RT (25-30°C). Heated the reaction mass to 88-95°C followed by stirring the reaction mass at 88-95°C. Passed filtrate through 0.45-micron filter at 78-85°C and added slowly DM water (1200 mL) at temperature NLT 40°C. The reaction mass was cooled to 10-15°C followed by stirring at 10-15°C for 4-5h. The solid was filtered, washed with DM water and dried. Charged the wet solid into glass reactor at 25-30°C followed by addition of 1% aq. NaHCCh solution. The reaction mass was stirred for 30 min at 25-30°C. The solid was filtered washed with DM water and dried under vacuum at 55-60°C for 10-14h to get the tile compound Rivaroxaban. (Yield: 63%; HPLC purity: 99.0%).
Example 5
Preparation of Rivaroxaban
In 1.0L glass reactor (55)-5-Chloro-iV-((2-oxo-3-(4-(3-oxomorpholino)
phenyl)oxazolidin-5-yl)methyl)thiophene-2-carboxamide Crude (-125.Og) and methanol (400 mL) was charged. The reaction mass was heated to 50-55°C followed by stirring the reaction mass at 50-55°C for lh. The reaction mass was cooled to 25-30°C and stirred at 25-30°C for about 2h. The solid was filtered, washed with methanol and dried. (Wet wt: ~90g).

In 3.0L glass reactor (5,S)-5-Chloro-jV-((2-oxo-3-(4-(3-oxomorpholino)
phenyl)oxazolidin-5-yl)methyl)thiophene-2-carboxamide Crude (-90.Og) and acetic acid (800 mL was charged at 25-30°C. The reaction mass was heated to 88-95°C followed by stirring the reaction mass at 88-95°C for about 30 min. Passed filtrate through 0.45-micron filter at 78-85°C and added slowly DM water (2500 mL) at temperature NLT 40°C. Cooled the reaction mass to 10-15°C followed by stirring the reaction mass at 10-15°C for 4-5h. The solid was filtered, washed the solid with DM water and dried. Charged the wet solid into glass reactor at 25-30°C. Charged 1% aq. NaHCCb solution (400 mL) and stirred the mass for 30 min at 25-30°C. The solid was filtered, washed with DM water and dried at 55-60°C for 10-14h to get the tile compound Rivaroxaban. (Yield: 85%; HPLC purity: 99.0%)
Example 6
Preparation/purification of Rivaroxaban
In 3.0L glass reactor (5,S)-5-Chloro-jV-((2-oxo-3-(4-(3-oxomorpholino)
phenyl)oxazolidin-5-yl)methyl)thiophene-2-carboxamide (90.Og) and acetic acid (800 mL) was charged at 25-30°C. The reaction mass was heated to 88-95°C followed by stirring the reaction mass at 88-95°C till clear solution. Passed filtrate through 0.45-micron filter at 78-85°C and added slowly DM water (3000 mL) at temperature of about 40°C. The reaction mass was cooled to 10-15°C followed by stirring the reaction mass at 10-15°C for 4-5h. The solid was filtered under vacuum, washed with DM water and dried. The wet solid was charged into glass reactor at 25-30°C followed by addition of 1% aq. NaHCCb solution (400 mL). The reaction mass was stirred for 30 min at 25-30°C followed by filtering and washing the solid with DM water. The solid was dried under vacuum at 55-60°C for 10-14h to get the tile compound Rivaroxaban. (Yield: 85%; HPLC purity: 99.0%)
Example-7
Preparation/purification of Rivaroxaban

In 3.0L glass reactor (5,S)-5-Chloro-jV-((2-oxo-3-(4-(3-oxomorpholino)
phenyl)oxazolidin-5-yl)methyl)thiophene-2-carboxamide Crude (-45.Og) and acetic acid (400 mL) was charged at RT (25-30°C). The reaction mass was heated to 88-95°C followed by stirring. Passed filtrate through 0.45-micron filter at 78-85°C and added slowly DM water (750 mL) at temperature NLT 40°C. Cooled the reaction mass to 10-15°C. Stirred the reaction mass at 10-15°C for 4-5h. Filtered the solid under vacuum and washed the solid with DM water. Dried the solid under suction for 60 min at 25-30°C.Charged the wet solid into glass reactor at 25-30°C.Charged 1% aq. NaHC03 solution and stirred the mass for 30 min at 25-30°C. Filtered the solid under vacuum and washed the solid with DM water. Dried the solid under vacuum at 55-60°C for 10-14h to get the tile compound Rivaroxaban. (Yield: 40%; HPLC purity: 99.0%)

We claim:

1. A process for the preparation and/or purification of Rivaroxaban, which comprises
the steps of:
a) providing mixture of Rivaroxaban in acetic acid;
b) heating the reaction mixture of step (a);
c) adding water to the reaction mixture;
d) optionally, cooling the reaction mixture; and
e) isolating Rivaroxaban
wherein ratio of organic acid and water is from 1:2 to 1:7.
2. The process as claimed in claim 1, wherein Rivaroxaban is prepared by the
process comprising the steps of:
a) providing mixture of Rivaroxaban in acetic acid;
b) heating the reaction mixture of step (a);
c) adding water to the reaction mixture;
d) optionally, cooling the reaction mixture; and
e) isolating Rivaroxaban
wherein ratio of acetic acid and water is from 1:3.
3. The process as claimed in claim 1, wherein Rivaroxaban is prepared by the
process comprising the steps of:
a) providing mixture of Rivaroxaban in acetic acid;
b) heating the reaction mixture of step (a) to a temperature of 80°C-100°C;
c) adding water to the reaction mixture;
d) optionally, cooling the reaction mixture; and
e) isolating Rivaroxaban.
4. The process as claimed in claim 1, wherein Rivaroxaban is prepared by the
process comprising the steps of:
a) providing mixture of Rivaroxaban in acetic acid;

b) heating the reaction mixture of step (a) to a temperature of 80°C-100°C;
c) adding water to the reaction mixture;
d) optionally, cooling the reaction mixture; and
e) isolating Rivaroxaban
wherein ratio of acetic acid and water is from 1:3 to 1:5.
5. The process as claimed in claim 1, wherein Rivaroxaban is prepared by the process comprising the steps of:
(i) reacting 4-(4-aminophenyl)-3-morpholinone (II) with 2-[(2S)-2-
oxiranylmethyl]-lH-isoindole-l,3(2H)-dione (III) in presence of a suitable
solvent to obtain 2-((2R)-2-hydroxy-3-{[4-(3-oxo-4-
morpholinyl)phenyl]amino}propyl-lH-isoindole-l,3(2H)-dione (IV);
(ii) optionally, purifying 2-((2R)-2-hydroxy-3-{[4-(3-oxo-4-
morpholinyl)phenyl] amino}propyl-lH-isoindole-l,3(2H)-dione (IV) in presence of a suitable solvent or mixture thereof;
(iii) compound of formula (IV) is cyclized in presence of cyclization agent to yield 2-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-l,3-oxazolidin-5-yl}methyl)-lH-isoindole-l,3(2H)-dione(V);
(iv) reacting compound of formula (V) with ethanolamine to obtain (S)-N1-(2-hydroxyethyl)-N2-((2-oxo-3-(4-(3-oxomorpholino)phenyl)oxazolidin-5-yl)methyl)phthalamide (XVIII);
(v) conversion of compound of formula (XVIII) to 4-[4-[(5S)-5-(aminomethyl)-2-oxo-l,3-oxazolidin-3-yl]phenyl]morpholin-3-one (VI);

(vi) reacting 4-[4-[(5S)-5-(aminomethyl)-2-oxo-l,3-oxazolidin-3-
yl]phenyl]morpholin-3-one (VI) with 5-chlorothiophene-2-carbonyl chloride in presence of a suitable base to obtain Rivaroxaban; and
(vii) optionally, purifying Rivaroxaban in presence of a suitable solvent or mixture thereof wherein, steps (iii) to (vi) are carried out with or without isolation of the respective intermediates.
6. The process as claimed in claim 1, wherein Rivaroxaban is prepared by the
process comprising the steps of:
(i) reacting 4-(4-aminophenyl)-3-morpholinone (II) with 2-[(2S)-2-
oxiranylmethyl]-lH-isoindole-l,3(2H)-dione (III) in presence of an aqueous
alcoholic solvent to obtain 2-((2R)-2-hydroxy-3-{[4-(3-oxo-4-
morpholinyl)phenyl]amino} propyl-lH-isoindole-l,3(2H)-dione (IV);
(ii) compound of formula (IV) is cyclized in presence of N, N'-
carbonyldiimidazole in presence of an ester solvent to yield 2-({(5S)-2-oxo-
3 - [4-(3 -oxo-4-morpholinyl)phenyl] -1,3 -oxazolidin-5 -yl} methyl)-1H-
isoindole-l,3(2H)-dione (V);
(iii) reacting compound of formula (V) with ethanolamine to obtain (S)-N1-(2-hydroxyethyl)-N2-((2-oxo-3-(4-(3-oxomorpholino)phenyl)oxazolidin-5-yl)methyl)phthalamide (XVIII);
(iv) conversion of compound of formula (XVIII) to 4-[4-[(5S)-5-(aminomethyl)-2-oxo-l,3-oxazolidin-3-yl]phenyl]morpholin-3-one (VI);
(v) reacting 4-[4-[(5S)-5-(aminomethyl)-2-oxo-l,3-oxazolidin-3-yl]phenyl]
morpholin-3-one (VI) with 5-chlorothiophene-2-carbonyl chloride in presence of a suitable base to obtain Rivaroxaban; and

(vi) optionally, purifying Rivaroxaban in presence of a suitable solvent or mixture thereof wherein, steps (iii) to (vi) are carried out with or without isolation of the respective intermediates.
7. The process as claimed in claim 1, wherein Rivaroxaban is prepared by the
process comprising the steps of:
(i) reacting 4-[4-[(5S)-5-(aminomethyl)-2-oxo-l,3-oxazolidin-3-yl]phenyl]
morpholin-3-one (VI) with 5-chlorothiophene-2-carbonyl chloride in presence of a suitable base to obtain Rivaroxaban; and
(ii) optionally, purifying Rivaroxaban in presence of a suitable solvent or mixture thereof wherein, steps (iii) to (vi) are carried out with or without isolation of the respective intermediates.
8. A process for the preparation and/or purification of Rivaroxaban substantially free
of one or more of the following genotoxic impurities, comprising the steps of:
a) providing mixture of Rivaroxaban in acetic acid;
b) heating the reaction mixture of step (a);
c) adding water to the reaction mixture;
d) optionally, cooling the reaction mixture; and
e) isolating Rivaroxaban
wherein ratio of organic acid and water is from 1:2 to 1:7.


H2N,
rNX) %


O
M /=
OM

HO

HN-