Field of the Invention
Disclosed herein is an improved process for the preparation of 5-chloro-N-({(5S)-2-oxo-3-[4-
(3 -oxo-4-morpholinyl)phenyl] -1,3 -oxazolidin-5 -yl} methyl)-2-thiophenecarboxamide
(Rivaroxaban) and intermediates thereof. Specifically, the present invention relates to an
improved process for the preparation of rivaroxaban via novel intermediate and use thereof for
the preparation of medicament useful for the prevention and treatment of deep vein thrombosis
and pulmonary embolism in patients undergoing knee and hip replacement surgery. Further,
present invention also provides rivaroxaban, substantially free of residual solvent(s).
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 pulmonary embolism 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:
( T )
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-isoindolel,
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-l,3(2H)-dione (IV). Thus the
r P O . D E L H I : 2 3 . - 1 2 - 2 Q I 5 1 7 : 54
obtained compound of formula (IV) is cyclised 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
N W //
(M)
NH 2 +
EtOH, H20,
reflux
r\ yo
N
(VI)
MeNH2, EtOH
NH,
pyridine
0°C
r(IV)
OH Q
N
y
DMAP, THF N* «N
VilYNf>
O
US Patent Number7,816,355 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-aminophenyl)-
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),
LP-& DELHI Z3 - 1 2 - 2 - B I S 1 7 :• S4
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
(VII)
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-l,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-carboxarnide (XXI) and reacting said
compound of formula (XXI) in a fifth step with phosgene or a phosgene equivalent to obtain
Rivaroxaban (I) (Scheme 3).
XF-Q D;EfLHhl: 2 5 - 1 2 . - - 2 B i 5 17 : 5 4
4
Scheme 3
CI TX
CI + HO
O
(VII) (Vila)
NH2
HCI
r^ r^H H°. K
O N-(\ />-NH?
O (||)
(XX)
US Patent Number 8648189 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
HCL J^^
O
(XV)
f\ Hal
O
(I)
o
S Hal
R-i02S(X
OH
,N. J\. CI
r ^
0 N-
0
O
(XVI)
1. Phosgen or eqvt
2 0 N—I />—NH2
' 0
0
/ = \ ...iV-O u
( if S Hal
OS02R! °
(XVII)
I F
Several other United States Patent Publications and PCT Patent Publications also disclose
iELH,X 2 3 - I 2 - 2 0 1 5 1 7 : 5.4
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 required to control the levels of
these impurities in the final drug substance obtained by the manufacturing process and to
ensure that the impurity is present in the lowest possible level and within the limits, even if
structural determination is not possible.
The prior art processes disclosed above for the preparation of rivaroxaban involve long reaction
times, involves the use of hazardous reagents, such asphosgene hydrobromic acid andsolvents
like pyridine and chromatography and provide products in lower yield. Accordingly, these
processes are not suitable on an industrial scale.
Thus, there remains a need to develop an industrial friendly, substantially free of
impuritiesprocess for the preparation of rivaroxaban on commercially economical scaleand
yielding high purity with higher yields.
Description of the Drawings
FIG. 1 depicts a powder X-ray diffractogram of Rivaroxaban.
FIG. 2 represents differential scanning calorimetry (DSC) of Rivaroxaban.
FIG. 3 represents fhermogravimetric analysis (TGA) of Rivaroxaban.
Summary of the Invention
The present invention relates to the 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-thiophenecarboxamide
(Rivaroxaban) and intermediates thereof.
It is an another object of the present invention to provide a simple, convenient, commercially
viable, industrial friendly process for synthesizing Rivaroxaban.
IP Q, DELM I 2 3 - 12 - 2.0.15- 17 : 5 4
A yet another object of the present invention provides a process for producing Rivaroxaban (I)
employing the use of the novel intermediate (S)-N'-(2-hydroxyethyl)-N2-((2-oxo-3-(4-(3-
oxomorpholino)phenyl)oxazolidin-5-yl)methyl)phthalamide (XVIII).
It is another object of the present invention to provide novel intermediate compound of formula
(XVIII)
HONH
O
(XVIII)
In yet another embodiment the invention provides a process for producing a novel intermediate
compound of formula (XVIII).
In an another object of present invention, it provides a process for 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] -1,3 -oxazolidin-5 -yl} methyl)-1 H-isoindole-1,3 (2H)-
dione (V); (c) reacting compound of formula (V) with ethanolamine to obtain (S)-N'-(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) - (e) can be carried out with or without isolation of the respective intermediates.
I P O DEL.ttX 2 , 3 . - 1 2 - 2 0 : 1 . 5 1 7 : 54
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.
In yet another embodiment the invention provides substantially solvent-free rivaroxaban and
process for preparation thereof.
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, it provides a process for preparation of Rivaroxaban (I)
(Scheme 4) 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-1 H-isoindolel,
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-
({(5 S)-2-oxo-3 -[4-(3 -oxo-4-morpholinyl)phenyl] -1,3 -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);
I P O D E L H I 2 5 - 12 - 2 0 1 S- 1.7 : 54
8
(v) conversion of (S)-N'-(2-hydroxyethyl)-N2-((2-oxo-3-(4-(3-
oxomorpholino)phenyl)oxazolidin-5-yl)methyl)phthalamide (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)- (vi) can be carried out with or without isolation of the respective
intermediates.
In yet another object the present invention provides a process for preparing Rivaroxaban from
compound of formula (V) comprising the steps of:
(i) reacting compound of formula (V) with ethanolamine to obtain (S)-N'-(2-
hydroxyethyl)-N2-((2-oxo-3-(4-(3-oxomorpholino)phenyl)oxazolidin-5-yl)methyl)
phthalamide (XVIII);
(ii) conversion of (S)-N'-(2-hydroxyethyl)-N2-((2-oxo-3-(4-(3-oxomorpholino)
phenyl)oxazolidin-5-yl)methyl)phthalamide (XVIII) to 4-[4-[(5S)-5-
(aminomethyl)-2-oxo-l,3-oxazolidin-3-yl]phenyl]morpholin-3-one (VI);
(iii) 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
(iv) optionally, purifying Rivaroxaban in presence of a suitable solvent or mixture
thereof
In yet another object the present invention provides one-pot process for preparing
Rivaroxaban from compound of formula (V) comprising the steps of:
IPQ DELHiI 2.3-1 2 - 2.B1 5 17 : 5-4 9
(i) reacting compound of formula (V) with ethanolamine to obtain (S)-N'-(2-
hydroxyethyl)-N2-((2-oxo-3-(4-(3-oxomorpholino)phenyl)oxazolidin-5-yl)methyl)
phthalamide (XVIII);
(ii) conversion of (S)-N'-(2-hydroxyethyl)-N2-((2-oxo-3-(4-(3-oxomorpholino)
phenyl)oxazolidin-5-yl)methyI)phthalamide (XVIII) to 4-[4-[(5S)-5-
(aminomethyl)-2-oxo-l,3-oxazolidin-3-yl]phenyl]morpholin-3-one (VI);
(iii) reacting 4-[4-[(5S)-5-(aminomethyl)-2-oxo-l,3-oxazolidin-3-ylJphenyl]morpholin-
3-one (VI) with 5-chlorothiophene-2-carbonyl chloride in presence of a suitable
base to obtain Rivaroxaban and
(iv) optionally, purifying Rivaroxaban in presence of a suitable solvent or mixture
thereof
wherein, steps ' (i) - (iii) are carried out in-situ without isolation of any intermediate.
In yet another object the present invention provides a process for preparing intermediate
compound of formula (V) from 4-(4-aminophenyl)-3-morpholinone (II) comprising the steps
of:
(i) 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-1 H-isoindole-1,3(2H)-dione (IV);
(ii) optionally, purifying 2-((2R)-2-hydroxy-3-{[4-(3-oxo-4-
morpholinyl)phenyl]amino}propyl-1 H-isoindole-1,3(2H)-dione (IV) in presence of
a suitable solvent or mixture thereof;
(iii) compound of formula (IV) is cyclized in the presence of presence of cyclization
agentto yield 2-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-l,3-oxazolidin-
5 -yl} methyl)-1 H-isoindole-1,3 (2H)-dione (V), which can further be used for the
next reaction step without isolation.
Scheme 5
IPO DELHI 23-12.-2815- 1 7 : 54 10
O N
(II) (III)
oo-
(XVIII)
O
C I " V S .
H-4 VN
^ 0 // -CI
NH,
(VI)
O N
i
O
o
// WH OH o
(IV)
o
(1 o
N—(( \—K
y-o
(V)
H-4 V-N
^ O
CI
o
(I)
In an object the present invention 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 (HI) in presence of an aqueous alcoholic solvent to
obtain 2-((2R)-2-hydroxy-3 - {[4-(3 -oxo-4-morpholinyl)phenyl] amino} propyl-1Hisoindole-
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 to
yield 2-( {(5 S)-2-oxo-3 - [4-(3 -oxo-4-morpholinyl)phenyl] -1,3 -oxazolidin-5 -
yl}methyl)-lH-isoindole-l,3(2H)-dione (V);
(iv) reacting compound of formula (V) with ethanolamine to obtain (S)-N'-(2-
hydroxyethyl)-N2-((2-oxo-3-(4-(3-oxomorpholino)phenyl)oxazolidin-5-yl)methyl)
phthalamide (XVIII);
XP-O1 D E L H I . 2 1 - 1 2 - 2 8 1 5 17 'S* n
(v) conversion of compound of formula (XVIII) to 4-[4-[(5S)-5-(aminomethyl)-2-oxol,
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 bases is added after addition of 5-
chlorothiophene-2-carbonyl chlorideand
(vii) optionally, purifying Rivaroxaban in presence of a suitable solvent or mixture
thereof.
wherein, steps (iii) - (vi) can be carried out with or without isolation of the respective
intermediates.
The solvent as defined above can be selected from the group comprising of nitriles, alcohols,
esters, halogenated hydrocarbons, ethers, amides, dialkylsulfoxides, aromatic or aliphatic
hydrocarbons or mixtures thereof, 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,
M-propanol, isopropanol, rc-butanol and the like. Esters as defined above 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-butyl ether (MTBE), diisopropyl ether, tetrahydrofuran
(THF), dioxane and the like. Amides are selected from the group comprising of N,Ndimethylformamide
(DMF), N,N-dimethylacetamide (DMA), N-methylformamide, Nmethylpyrrolidone
and the like. Dialkyl sulfoxides can be 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 can be selected from a group comprising of an organic or
inorganic bases. The inorganic base is selected from group comprising of carbonates,
XP Q DEL H I. 2 3 - 1 2 - 2 8 1 5 1.7 : S 4
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), 1,5-
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 etc. Bicarbonates are selected from the group
comprising of NaHCCh, KHCO3 etc. Hydroxides are selected from the group comprising of
NaOH, KOH, LiOII, CsOII etc.
Cyclization agents as defined above can be selected from a group comprising of carbonyl
diimidazole (CDI), diethyl carbonate, dimethyl carbonate, N,N'-disuccinimidyl carbonate,
l,r-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 accordance with another object of the present invention there is provided novel intermediate
compound of formula (XVIII).
(XVIII)
In accordance with yet another object of the present invention there is provided use of novel
intermediate compound of formula (XVIII) for the preparation of Rivaroxaban.
In accordance with another object of the present invention there is provided Rivaroxaban which
is substantially free of impurities, specifically impurities of structural formula mentioned
below:
D & L H I, 2 3 - I 2 - 2 Ori 5' 1 7' : S 4 13
o o
o ,-, -^/ o
In an embodiment the invention provides substantially solvent-free crystal of Rivaroxaban,
wherein the solvent content of the substantially solvent free Rivaroxaban is less than about
1200 ppm preferably less than about 1000 ppm, more preferable less than about 500 ppm.
In accordance with yet another object of the present invention there is provides a process for
purification of Rivaroxaban which comprises the steps of:
a) providing mixture of Rivaroxaban in an organic acid;
b) optionally, heating the mixture of step (a);
c) adding water to the reaction mixture;
d) optionally, cooling the reaction mixture and
e) isolating rivaroxaban.
In accordance with yet another object of the present invention there is provided a process for
preparation of modification I of Rivaroxaban, which comprises the steps of:
a) providing mixture of Rivaroxaban in an organic acid;
b) optionally, heating the mixture of step (a);
c) adding water to the reaction mixture;
d) optionally, cooling the reaction mixture and
e) isolating rivaroxaban.
~ X 2' 3. - 1.2: - 2 0 : 1 5 1 7 :. 5:4 • 14
— 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 another aspect there is provided a pharmaceutical composition that includes a therapeutically
effective amount of Rivaroxaban (1) 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-lHisoindole-
l,3(2H)-dione
4-(4-aminophenyl)-3-morpholinone (100.0 g) was added to the 25% aqueous solution of IP A
(2000 mL). To the suspended solution, 2-[(2S)-2-oxiranylmethyl]-lH-isoindole-l,3(2H)-dione
(126.86g) was added and temperature was raised to 60-65°C. At same temperature reaction
mass was stirred for about 20h. Reaction mass was cooled to 40-45 °C and stirred for lh. The
solid was collected by filtration at 40-45°C and dried, yielding 168.0g (81.67%) of the title
compound as white solid.
Example 1A
Purification of 2-((2R)-2-hydroxy-3-{[4-(3-oxo-4-morpholinyl)phenyl]amino}propyl-lHisoindole-
l,3(2H)-dione
IFO' DELHI. 2 3 . - 1 2 - 2 G 1 5 17 "• S-.A-
(i?)-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 2
Preparation of 2-({(5S)-2--oxo-3^[4-(3=oxo=4-morpholinyl)phenyl]=l,3=oxa2olidin-5-
yI}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 (140.0g) 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 140.0g (94.50 %)
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
4.0 g of (i?)-2-(2-hydroxy-3-((4-(3-oxomorpholino)phenyl)amino)propyl)isoindoline-l,3-
dione was suspended in DCM (40mL) at 25-30°C, followed by the addition of CDI (1.62 g).
Resulted suspension was stirred for 6h at 30-35°C, followed by addition of CDI (0.17 g). On
completion of the reaction mass , reaction mass was concentrated in vacuum, residual solid
was taken in ethyl acetate (40mL) and refluxed for 30 min. Reaction was cooled to 25-30°C,
stirred for 2h and filtered. Filtered solid was washed with ethyl acetate (14mL) and dried to
obtain titled compound 4.0g (94.50 %, Chiral Purity 99.93%).
XP O. D E L H 1 . 2 5 - I 2 - 2 8 1 5 ' I? '• 5-4'
Example 3
Preparation of (S)-N'-(2-hydroxyethyl)-N2-((2-oxo-3-(4-(3-oxomorpholino)phenyl)
oxazo!idin-5-yl)methyl)phthalamide
(5S)-2-((2-Oxo-3-(4-(3-oxomorpholino)phenyl) oxazolidin-5-yl)methyl)isoindoline-l,3-dione
(4.0g) was stirred with mixture of dichloromethane (8 mL) and ethanolamine (4 mL) at 25-
30°C for lh. Reaction mass was quenched with 25% brine solution followed by the extraction
with DCM (30 mL). Extracted solution was concentrated to obtain the entitled white solid (1.6
g). The isolated was further purified using flash chromatography to obtain amorphous solid
(IirLC purity 99.012%)
Mass (m/z): 483.12 [M+l], 505.25[M+23]; 'H-NMR (DMSO-d6, 400 MHz): 8.698-8.670 (t,
NH, 1H), 8.278 -8.252 (t, NH, 1H), 7.608-7.587(d, CH, 2H), 7.481-7.416(m, CH, 6H), 3.270-
3.241(m, CH2-N, 2H), 3.489-3.460(m, CH2-0, 2H), 3.626-3.504(m, CH2-N-CO-, 2H), 3.722-
3.699(m, CH2, 2H), 3.980-3.956(m, CH2, 2H), 4.139-4.117(m, CH2, 1H), 4.192-4.162(m,
CH2+CH2, 3H), 4.642-4.614(t, CH, 1H); 13C-NMR: 169.26 (CO-NH), 168.08 (CO-NH),
166.0(CO-NH cyclic), 154.26(CO-Oxazolidinone), 136.98 (C-C(O)N), 136.68 (C-C(O)N),
136.24(C-N), 136.12 (C-N), 129.42 (Ar-C), 129.37(Ar-C), 127.52(Ar-C), 125.96(Ar-C),
118.39 (C-O), 71.42 (C-C(O)), 67.74 (C-O,), 63.49 (C-O), 59.76 (C-N), 49.06 (C-N), 47.37(CO),
42.01 (C-N)
Example 4
Preparation of 4-[4-[(5S)-5-(aminomethyl)-2-oxo-l,3-oxazolidin-3-yl]phenyl]morpholin-
3-one
Ethanolamine (125 mL) was added to (S)-N'-(2-hydroxyethyl)-N2-((2-oxo-3-(4-(3-
oxomorpholino)phenyl) oxazolidin-5-yl)methyl)phthalamide (25.Og) at 25-30°C and stirred for
12-14h at same temperature. Reaction mass was quenched with 30% brine solution (125 mL)
followed by the extraction with DCM (375 mL). Extracted solution was concentrated and
crystallized in ethyl acetate (125 mL) to obtain solid residue.
Example 5
Preparation of 4-[4-[(5S)-5-(aminomethyl)-2-oxo-l,3-oxazolidin-3-yl]phenyl]morpholin-
3-one
f55/)-2-((2-Oxo-3-(4-(3-oxomorpholino)phenyl) oxazolidin-5-yl)methyl)isoindoline-l,3-dione
(120.0 g) and ethanolamine (480 mL) was added to the RB flask fitted with thermometer pocket
D'ELHX 2 3. - 12 - 2QJ. S 17 : 54
at 30-35°C for 14-16h. Reaction mass was quenched with 25% brine solution (240 mL)
followed by extraction with DCM (2400 mL) and combined organic layer was washed with
brine (240 mL). Extracted solution was concentrated and to this residue ethyl acea'te (600 mL)
was added. Reaction mass was heated to 80°C for 15 min, cooled to 25-30°C and stirred for 2h
followed by the filtration of solid. Solid was dried to obtain solid 74.4 g (88.41%, HPLC Purity
99.0%).
Example 6
Preparation of 4-[4-[(5S)-5-(aminomethyl)-2-oxo-l,3-oxazolidin-3-yl]phenyl]morpholin-
3-one
Suspended (5£])-2-((2-Oxo-3-(4-(3-oxomorpholino)phenyl) oxazolidin-5-yl)methyl)
isoindoline-l,3-dione (120.0 g) in ethanolamine (480.0 mL) followed by stirring at 30-35°C
for 14-16h. After completion of the reaction, DCM (2400 mL and 25% brine solution (240 mL)
was added to reaction mass. The organic layer was separated, washed with 25% brine solution
(240 mL), 50-60% solvent was distilled off and the solution was used for the further reaction.
Example 7
Preparation of Rivaroxaban
To the solution of 5-chloro thiophene-2-carboxylic acid (55.56g) in dichloromethane (540 mL),
catalytic amount of DMF was added to it and cooled to 10-15°C. Added drop-wise thionyl
chloride (60.95g), heated to 40-45°C and stirred at 40-45°C for 3-4h. Reaction mass was
concentrated under vacuum to the residual and residual oil was chased with dichloromethane.
Residual oil was dissolved in 240 mL dichloromethane and was added drop-wise to the cooled
solution (0-10°C) of (5)-4-(4-(5-(aminomethyl)-2-oxooxazolidin-3-yl)phenyl)morpholin-3-
one in DCM, followed by the addition of 51.86 g of triethylamine at same temperature. The
reaction was stirred at 10-15°C for lh, quenched with demineralized water (720 mL) and
filtered. Solid obtained was washed with DM water & DCM and dried under suction to
obtained titled compound 148.0g.
I P Q D E L H I . 2 . 5 - 1 2 - 2 . Q I 5 1 7 : 5 4 -
i
Example 7A
Preparation of Rivaroxaban
To the solution of 5-chloro thiophene-2-carboxylic acid (1.62 g) in dichloromethane (16 mL),
catalytic amount of DMF was added to it and cooled to 10-15°C. Added drop-wise thionyl
chloride (1.77), heated to 40-45°C and stirred at 40-45°C for 3-4h. Reaction mass was
concentrated under vacuum to the residual and residual oil was chased with dichloromethane.
Residual oil was dissolved in 7 mL dichloromethane and was added dropwise to the cooled
solution (0-10°C) of (S)-4-(4-(5-(aminomethyl)-2-oxooxazolidin-3-yl)phenyl)morpholin-3-
one in DCM, followed by the addition of 1.51 g of triethylamine at same temperature. The
reaction was stirred at 10-15°C for lh, quenched with demineralized water (20 mL) and
filtered. Solid obtained was washed with DM water & DCM and dried under suction. Solid
was charged to RB flask fitted with condenser, added MeOH (20 mL), refluxed for 30 min and
cooled to room temperature. Solid was filtered and dried to obtained titled compound 2.10g
(HPLC Purity 99.5%, Chiral Purity 99.90%)
Example 8
Purification of Rivaroxaban
Crude Rivaroxaban (148.0 g) was dissolved in 3600 mL of 20% methanol in dichloromethane
at reflux temperature and solution were 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 dried to get the title compound 109.0g
Example 9
Purification of Rivaroxaban
109 g of rivaroxaban and 1440 ml of acetic acid were charged in a flask and heated to 80-85°C
to obtain clear solution. To the clear hot solution water (1440 mL) was added slowly at a
XPO D E L H I 2 . 3 - 1 2 . - 2 8 1 5 1 7 : 5 * 1Q
temperature between 80 and 45 °C. Precipitated product was cooled to 10-15°C and stirred for
another 4-5 hours at the same temperature, then filtered, and the product was rinsed with 240
mL of demineralised water. The Solid obtained was charged in flask containing 1% aq. sodium
hydrogen carbonate solution (480 mL) and stirred for 30 min, filtered, washed with water (360
mL) and dried at 50-55°C to obtain pure Rivaroxaban free from dichloromethane and methanol.
XP © ttELHI 2 3 - 12 - 2-01.5' 1.7': 54.

Claims:
1. A process for the preparation of Rivaroxaban (I) comprising the steps of:
(i) reacting compound of formula (V) with ethanolamine to obtain (S)-N'-(2-
hydroxyethyl)-N2-((2-oxo-3-(4-(3-oxomorpholino)phenyl)oxazolidin-5-
yl)methyl)phthalamide (XVIII);
(ii) conversion of compound of formula (XVIII) to 4-[4-[(5S)-5-(aminomethyl)-2-
oxo-l,3-oxazolidin-3-yl]phenyl]morpholine-3-one (VI);
(iii)reacting 4-[4-[(5S)-5-(aminomethyl)-2-oxo-l,3-oxazolidin-3-yl]phenyl]
morpholine-3-one (VI) with 5-chlorothiophene-2-carbonyl chloride in presence
of a suitable base to obtain Rivaroxaban and
(iv)ptionally, purifying Rivaroxaban in presence of a suitable solvent or mixture
thereof
wherein, steps 'i'-'iii' can be carried out with or without isolation of respective
intermediates.
2. A process according to claim 1, wherein compound of formula (V) can be prepared
from the compound of formula (II) comprising the steps of:
(i) 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-1 H-isoindolel,
3(2H)-dione(IV);
(ii) optionally, purifying 2-((2R)-2-hydroxy-3-{[4-(3-oxo-4-
morpholinyl)phenyl] amino} propyl-lH-isoindole-1,3 (2H)-dione (IV) in
presence of a suitable solvent or mixture thereof;
TPQ D'ELMX 2:5 - 1 2 - 2 8 1 . S 1.7 • 5 A(
iii) compound of formula (IV) is cyclized in the presence of 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), which can
further be used for the next reaction step with or without isolation.
3. A process for the preparation of Rivaroxaban (I) comprising the steps of:
(i) reacting 4-(4-amiiiuphenyl)-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-1 H-isoindole-1,3(2H)-dione (IV);
(ii) optionally, purifying 2-((2R)-2-hydroxy-3-{[4-(3-oxo-4-
morpholinyl)phenyl]amino} propyl-1 H-isoindole-1,3 (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-( {(5 S)-2-oxo-3 -[4-(3 -oxo-4-morpholinyl)phenyl] -1,3 -oxazolidin-5 -
yl}methyl)-lH-isoindole-l,3(2H)-dione (V);
(iv) reacting compound of formula (V) with ethanolamine to obtain (S)-N'-(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]morpholine-3-one (VI); •
(vi) reacting 4-[4-[(5S)-5-(aminomethyl)-2-oxo-l,3-oxazolidin-3-yl]phenyl]
morpholine-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.
Dt:E-LHX 2 . 3 f - l Z - 2 . D r 5 1 7 : 54 22
wherein, steps 'iii'-'vi' can be carried out with or without isolation of the respective
intermediates.
4. A process according to any of the preceding claims, wherein the solvent used is selected
from the group comprising of nitriles, alcohols, ketones, esters, halogenated hydrocarbons,
ethers, amides, dialkylsulfoxides, water and mixtures thereof.
5. The process according to claim 4, wherein the solvent is selected from the group
comprising of acetonitrile, propionitrile, butyronitrile, valeronitrile, methanol, ethanol, npropanol,
isopropanol, rc-butanol, acetone, methyl ethyl ketone, methyl isobutyl ketone,
ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate, dichloromethane (DCM),
chloroform, dichloroethane, chlorobenzene, diethyl ether, methyl tert-bx\\y\ ether (MTBE),
diisopropyl ether, tetrahydrofuran (THF), dioxane, N,N-dimethylformamide (DMF), N,Ndimethylacetamide
(DMA), N-methylformamide, N-methylpyrrolidone,
dimethylsulfoxide, diethylsulfoxide, dibutylsulfoxide, pentane, hexane, heptane, octane,
cyclohexane, cyclopentane, toluene and xylene.
6. The process according to any of the preceding claims, wherein the base used is selected
from the organic or inorganic bases selected from the group comprising of amines,
carbonate, bicarbonate and hydroxides of alkali or alkaline earth metals.
7. A process for purification of Rivaroxaban which comprises the steps of:
a) providing mixture of Rivaroxaban in an organic acid;
b) optionally, heating the mixture of step (a);
c) optionally, stirring the reaction mixture of step (b);
d) adding water to the reaction mixture;
e) optionally, cooling the reaction mixture and
f) isolation of rivaroxaban.
8. A compound of formula (XVIII)
XFO DELHI 2 3 - 12 - 2 0 1 B 1 7 : 5 4, 23
(XVIII)
9. Use of compound of formula (XVIII) for the preparation of Rivaroxaban.
10. Rivaroxaban substantially free of residual solvent.