RIVAROXABAN
5-Chloro-N-{[(5S)-2-oxo-3-[4-(3-oxo-4-morpholinophenyl]oxazolidin-5-yl]methyl} thiophene-2-carboxamide
5-Chloro-N-({(5S)-2-oxo-3-[4-(3-oxomorpholin-4-yl)phenyl]-1,3-oxazolidin-5-yl}methyl)thiophene-2-carboxamide
Molecular formula: C19H18ClN3O5S, MW435.9
CAS 366789-02-8
BAY 59-7939, XARELTO
Patent Expiration Date:
Feb 8, 2021(US7157456),
Dec 11, 2020(US7585860 and US7592339)
Originator and Manufacturer:Bayer
Marketer in the US: Johnson & Johnson
Sales: $1.3 billion (2013)
Rivaroxaban (BAY 59-7939) is an
oral anticoagulant invented and manufactured by
Bayer;
[3][4] in a number of countries it is marketed as
Xarelto.
[1] In the United States, it is marketed by
Janssen Pharmaceutica.
[5] It is the first available orally active
direct factor Xa inhibitor. Rivaroxaban is well absorbed from the gut and maximum inhibition of
factor Xa
occurs four hours after a dose. The effects last approximately 8–12
hours, but factor Xa activity does not return to normal within 24 hours
so once-daily dosing is possible.
In September 2008,
Health Canada granted marketing authorization for rivaroxaban for the prevention of
venous thromboembolism(VTE) in people who have undergone elective total
hip replacement or total
knee replacement surgery.
[8]
In September 2008, the
European Commission granted marketing authorization of rivaroxaban for the prevention of
venous thromboembolism in adults undergoing elective hip and knee replacement surgery.
[9]
On July 1, 2011, the
U.S. Food and Drug Administration (FDA) approved rivaroxaban for prophylaxis of
deep vein thrombosis (DVT), which may lead to
pulmonary embolism (PE), in adults undergoing hip and knee replacement surgery.
[5]
On November 4, 2011, the
U.S. FDA approved rivaroxaban for stroke prophylaxis in patients with non-valvular atrial fibrillation.
The
drug compound having the adopted name "Rivaroxaban" has chemical name,
5-chloro-N-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-l,3-oxazolidin-5-
yljmethyl)-2-thiophenecarboxamide; and has the structural formula I,
Formula I
The commercial pharmaceutical product XARELTO® tablets, contains
rivaroxaban as active ingredient. Rivaroxaban is a factor Xa inhibitor
useful as oral anticoagulant. Rivaroxaban can be used for the prevention
and treatment of various thromboembolic diseases, in particular of deep
vein thrombosis (DVT), pulmonary embolism (PE), myocardial infract,
angina pectoris and restenoses after angioplasty or aortocoronary
bypass, cerebral stroke,
transitory ischemic attacks, and peripheral arterial occlusive diseases.
U.S.
Patent No. 7, 157,456 describes Rivaroxaban and process for the
preparation thereof. The process of US '456 for rivaroxaban involves
reaction of 2-[(2S)-2-oxiranylmethyl]-lH-isoindole-l,3(2H)-dione with
4-(4-aminophenyl)-3-morpholinone to provide 2-((2R)-2-hydroxy-3- {
[4-(3-oxo-4-morpholiny)phenyl]amino Jpropyl)- lH-isoindole- 1
,3(2H)-dione, which on cyclization using Ν,Ν-carbonyl diimidazole to
afford
2-({5S)-2-Oxo-3-[4-(3-oxo-4-morpholiny)phenyl]-l,3-oxazolidin-5-yl}methyl)-lH-isoindole-l,3(2H)-dione,
which on reacted with methylamine followed by reaction with
5-chlorothiophene-2-carbonyl chloride to provide Rivaroxaban.
Various
processes for the preparation of rivaroxaban, its intermediates, and
related compounds are disclosed in U.S. Patent Nos. 7,585,860;
7,351,823, 7,816,355, and 8,101,609; patent application Nos. WO
2011/012321, WO 2012/156983, WO 2012/153155, WO 2013/053739, WO
2013/098833, WO 2013/156936, WO 2013/152168, WO 2013/120464, WO
2013/164833, US 2012/0283434 and US 2013/184457; and J. Med. Chem. 2005,
48, 5900-5908.
PAPER CONTAING SPECTRAL DATA
JOURNAL OF CHEMICAL RESEARCH v 35, issue 7, pg 400-4-1, 2011
An approach to the anticoagulant agent rivaroxaban via an isocyanate-oxirane cycloaddition promoted by MgI2.etherate
Chao Lia, Yingshuai Liua, Yongjun Zhangb and Xingxian Zhanga*
a College of Pharmaceutical Sciences, Zhejiang University of Technology, Hangzhou 310032, P. R. China
b Zhejiang Apeloa Medical Technology Co., Ltd, Dongyang 322118, P. R. China
A convergent and efficient synthesis of anticoagulant rivaroxaban was developed using the cycloaddition of commercially
available (R)-epichlorohydrin with 4-(morpholin-3-one)phenyl isocyanate catalysed by MgI2 etherate as the
key step, in 22% overall yield.
Keywords: (R)-epichlorohydrin, isocyanate, MgI2.etherate, rivaroxaban
* Correspondent. E-mail: mhmosslemin@yahoo.com
(Rivaroxaban) (1):1
rivaroxaban 1 (689 mg) in 88% yield, Rf = 0.30 (ethyl acetate), as a white solid,
m.p. 229.3–230.7 °C(lit.1, 230 °C).
[α]D20 = −37° (c = 0.5, DMSO) [lit.1, [α]D21 = –38°(c = 0.2985, DMSO)].
IR (KBr) (νmax /cm−1): 3343, 1724 (C=O), 1649(C=O), 1523, 1430, 808, 756
δH
3.60–3.62 (m, 2H), 3.71–3.73 (m,2H), 3.84–3.87 (dd, J = 6.5, 9.5 Hz,
1H), 3.96–3.98 (m, 2H), 4.20 (s,2H), 4.18–4.21 (m, 1H), 4.83–4.86 (m,
1H), 7.20 (d, J = 4.0 Hz, 1H),7.41 (d, J = 9.0 Hz, 2H), 7.56 (d, J = 9.0
Hz, 2H), 7.69 (d, J = 4.0 Hz,1H), 8.99 (t, J = 5.5 Hz, 1H).
δC 42.19, 47.43, 49.00, 63.46, 67.71,71.30, 118.35, 125.92, 128.11, 128.43, 133.24, 136.48, 137.08,138.43, 154.08, 160.79, 165.95.
LIT
REF 1=S. Roehrig, A. Straub, J. Pohlmann, T. Lampe, J. Pernerstorfer,
K.Schlemmer, P. Reinemer and E. Perzborn, J. Med. Chem., 2005, 48, 5900.
STRUCTURE
SIMILARITY
Chemical structures of
linezolid (top) and rivaroxaban (bottom). The shared structure is shown in blue.
Rivaroxaban bears a striking
structural similarity to the antibiotic
linezolid: both drugs share the same
oxazolidinone-derived core structure. Accordingly, rivaroxaban was studied for any possible antimicrobial effects and for the possibility of
mitochondrial toxicity,
which is a known complication of long-term linezolid use. Studies found
that neither rivaroxaban nor its metabolites have any antibiotic effect
against
Gram-positive bacteria. As for mitochondrial toxicity,
in vitro studies found the risk to be low
IH NMR PREDICT
13 C NMR PREDICT
COSY NMR.
CLICK TO PREDICT..ALLOW SOME TIME TO LOAD ON NMRDB SITE.....CHECK JAVA AND FLASH SETTINGS
ABOVE PICTURES ARE THE ONES YOU WILL GET
New patent WO-2015104605
Process
for preparing rivaroxaban - comprising the reaction of a thioester
compound and its salts with
4-{4-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl}morpholine-3-one.
Wockhardt Ltd
The synthesis of (II) via intermediate (I) is described (example 7, page 15)
4-{4-[(5S)-5-(Aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl}morpholine-3-one
(formula III) is (I) and rivaroxaban is (II) (claim 1, page 16).
The
present invention relates to a process for the preparation of
Rivaroxaban and its novel intermediates, or pharmaceutically acceptable
salts thereof. The present invention provides novel intermediates, which
may be useful for the preparation of Rivaroxaban or its
pharmaceutically acceptable salts thereof. The process of preparation by
using novel intermediate is very simple cost effective and may be
employed at commercial scale. The product obtained by using novel
intermediate yield the Rivaroxaban of purity 99% or more, when measured
by HPLC. The present invention especially relates to a process for the
preparation of Rivaroxaban from thioester of formula II, or a
pharmaceutically acceptable salt thereof, wherein R is leaving group.
process includes the step of , reacting thioester of formula IIA or pharmaceutically acceptable salt thereof
Formula IIA
with 4-{4-[(5S)-5-(aminomethyl)-2-oxo-l,3-oxazolidin-3-yl]phenyl}morpholine-3-one of formula III,
Formula III
Formula I
EXAMPLE 7: One pot process for Rivaroxaban
The
triphenylphosphine (11.5g) and mercaptobenzothiazole disulphide
(15.31g) were taken in methylene chloride and reaction mixture was
stirred at 28°C -30°C for 1 hr. The 5-chlorothiophene-2-carboxylic acid
(7.2g) and triethylamine (3.8 g) were added to the above reaction
mixture. The reaction mixture is stirred at 0°C -25 °C for 1 hr. after 1
hr
4-{4-[(5S)-5-(aminomethyl)-2-oxo-l,3-oxazolidin-3-yl]phenyl}morpholine-3-one
(lOg) and triethylamine (3.8g) were added. The resulting reaction
mixture further stirred for 2 hrs. After completion of the reaction,
water was added and stirred for 10 min. aqueous layer was separated and
washed with methylene chloride. The organic layer was acidified to pH
6-7 with 2N hydrochloric acid and finally the organic layer was
concentrated to get desired product. The product was purified and dried
to yield Rivaroxaban.
Yield: 10.0 gm
Purity: 99.3 %
EXAMPLE 8: One pot process for Rivaroxaban
Exemplified
procedure in example 7 with the replacement of solvent ethyl acetate
and base potassium hydroxide were used to get the rivaroxaban.
EXAMPLE 9: One pot process for Rivaroxaban
Exemplified
procedure in example 7 with the replacement of solvent acetonitile and
base potassium carbonate were used, methylene chloride was added in the
reaction mixture to extract the Rivaroxaban.
https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2015104605&recNum=7&maxRec=57790&office=&prevFilter=%26fq%3DOF%3AWO%26fq%3DICF_M%3A%22C07D%22&sortOption=Pub+Date+Desc&queryString=&tab=PCTDescription
..............
http://www.google.com/patents/WO2013120465A1?cl=en
Rivaroxaban,
chemically
(S)-5-chloro-N-({2-oxo-3-[4-(3-oxomorpholin-4-yl)phenyl]-l,3-
oxazolidin-5-yl}methyl)thiophene-2-carboxamide, described by formula
(1), was developed by the company Bayer Healthcare (WO 01/47919, 2001).
Rivaroxaban is applied in the clinical practice as the active ingredient
of an orally available anticoagulant that is commercially marketed as
Xarelto and is used in the prevention and treatment of arterial or
venous thromboembolic disorders. In its effect, rivaroxaban is
characterized by direct selective inhibition of the FXa coagulation
enzyme (Drugs of the Future 2006, 31(6): 484-493).
H2
For
the preparation of rivaroxaban several key structures, referred to as
building blocks, can be used as advanced intermediates. Virtually all
the so far described syntheses are using two such building blocks. The
first one are derivatives of 4-(4-aminophenyl)morpholin-3-one, where it
may be the case of an unsubstituted amine (2, G means hydrogen), or a
derivative alkylated on nitrogen, or a carbamate derived from this
compound (2, G means an alkyl or COOalkyl group). The other general and
commonly used building block for the rivaroxaban molecule are
derivatives of 5-chlorothiophene-2-carboxylic acid (3, X means -OH), or
its functional derivatives such as the chloride and amide (3, X means
-CI or -NH2). Various synthetic approaches used for synthesis
of rivaroxaban differ from each other mainly as regards the chiral
building block, which is the source for the construction of the central
heterocycle, i.e., 2-oxo-l,3-oxazolidine, wherein the chirality centre
is also located. For pharmaceutical purposes one optical isomer derived
from rivaroxaban is only used, in particular the target molecule with
the absolute configuration (5)-. The selection of a suitable chiral
building block must be subjected to this fact.
(4) (5) (6) (7) (8)
Chiral
building blocks that have been successfully used for synthesis of
rivaroxaban include (5)-glycidyl phthalimide (4),
(S)-3-aminopropane-l,2-diol (5), ( ?)-epichlorohydrin (6) and
(i?)-glycidyl butyrate (7). (S)-glycidol (8) was used as a starting
material for the preparation of (5)-glycidyl phthalimide (4)
(Tetrahedron: Asymmetry, Vol. 7, No. 6, pp. 1641-1648, 1996).
The
known methods of chemical synthesis of rivaroxaban (1) are described in
Schemes 1 to 7. The first one is the process according to Scheme 1 (WO
01/47919 Bayer, US 7 157 456 B2, J.MedChem. (2005), 48(19), 5900-5908),
which starts from 4-(4-aminophenyl)morpholin-3- one and (5)-glycidyl
phthalimide (4). The second synthetic process follows Scheme 2 (WO
2004/060887, Bayer) and starts from 5-chlorothiophene-2-carboxylic acid
(3, X means -OH) and (5)-3-aminopropane-l,2-diol (5).
4-(4-aminophenyl)morpholin-3-one only engages in the synthesis in the
penultimate stage in case of the process according to Scheme 2.
Scheme 1
The
third synthetic process, which proceeds according to Scheme 3, was
mainly used for preparation of deuterated analogs of rivaroxaban (WO
2009/023233 Al, Concert Pharm.). It also represents the first synthetic
process in which (i?)-epichlorohydrin (6) was used as the chiral
building block. The other key starting material for the third process
was 4-(4- aminophenyl)morpholin-3-one. The fourth synthetic process,
which proceeds according to Scheme 4 (WO 2010/124835 Al, Apotex), again
uses (i?)-epichlorohydrin as the chiral building block, which reacts
with the alkyl carbamate derived from 4-(4- aminophenyl)morpholin-3-one
in the key stage. The fifth synthetic process, which proceeds according
to Scheme 5 (US 20110034465 Al), also uses (i?)-epichlorohydrin as the
chiral building block, which directly reacts with
4-(4-aminophenyl)morpholin-3-one in the key stage, which is the same
reaction as in the third process. The differences between the third and
fifth processes consist in the preparation method of the
2-oxo-l,3-oxazolidine cycle and in the carbonylation agent used. While
the third process uses Ι,Γ-carbonyldiimidazol (CDI) as the carbonylation
agent, the fifth process uses more available and cheaper alkyl
chloroformates.
Scheme 3
Scheme 4
Scheme 5
The
sixths synthetic process, which proceeds according to Scheme 6 (WO
2011/080341 Al), uses (7?)-glycidyl butyrate (7) as the chiral building
block, which in the key stage reacts with the alkyl carbamate derived
from 4-(4-aminophenyl)morpholin-3-one. The last, seventh synthetic
process leading to rivaroxaban proceeds according to Scheme 7 (WO 201
1/098501 Al) and, like process 2, uses (S)-3-aminopropane-l,2-diol (5)
as the chiral building block. The differences between the second and
seventh processes consist in the preparation process of the
2-oxo-l,3-oxazolidine cycle and the carbonylation agent used. While the
second process uses Ι,Γ-carbonyldiimidazol (CDI) as the carbonylation
agent, the fifth process uses the cheaper, but very toxic phosgene.
Scheme 6
Scheme
7 The processes used for the synthesis of rivaroxaban differ from each
other especially in the chiral building block (compounds 4 to 7) and in
the carbonylation agents (CDI, alkyl chloroformates, phosgene) used.
Another difference can be found in the method of performing deprotection
reactions, i.e. such reactions that lead to elimination of the
protecting groups, initially bound to the nitrogen atom of the advanced
intermediates and which had the initial purpose of protecting these
intermediates from undesired chemical transformations. No deprotection
reactions were necessary in the case of the processes according to
Schemes 2, 4 and 7, as the protecting groups bound to the nitrogen atom
eventually became part of the final product. In the case of process 6 it
was necessary to deprotect the fert-butyl group bound to the nitrogen.
The reaction used was an acid catalyzed reaction of the tert-butyl
group, releasing isobutylene according to Scheme 8. In normal conditions
isobutylene is a gas and thus can be very easily separated from the
final product.
isobutylen
.................
WO 01/47919 discloses ー species from 4_ (4_ aminophenyl) -3_ morpholinone (I) Preparation of rivaroxaban approach:
..............
US 07/149522 discloses ー kind to 5_ chlorothiophenes _2_ carbonyl chloride (IV) is a method for preparing raw rivaroxaban in:
.............
http://www.google.com/patents/CN102786516A?cl=en
Preparation 6 rivaroxaban implementation
The
12.5 g (76.9 mmol) 5- chloro-thiophene-2-carboxylic acid was suspended
in 35 g of toluene was heated to 80 で, at this temperature, a solution
of 11.0 g (92.5 mmol) of thionyl chloride, reaction was continued for 30
min; then warmed to the boiling point of toluene was 120 ° C, and
stirring was continued under reflux until cessation of gas; cooled to
room temperature, the reaction mixture was concentrated under reduced
pressure to remove excess thionyl chloride and toluene to give
5-chloro-thiophene-2-carbonyl chloride;
The
11.6 g (37.0 mmol) 4- {4 - [(5S) -5- (aminomethyl)
-2-oxo-1,3-oxazolidin-3-yl] phenyl} morpholin-3 -one hydrochloride was
added 40ml of water, was added 4. 64 g (43 8 mmol.) Na2CO3 stirred and
dissolved; then added 50 ml of toluene, was added dropwise at 10 ° C
under the mixture, the mixture is 8. 0 g ( 44. 4 mmol) 5-
chloro-thiophene-2-carbonyl chloride was dissolved in 15 ml of toluene,
20 min the addition was complete, then stirring was continued at room
temperature, TLC monitoring progress of the reaction, 2 h after
completion of the reaction; and the filter cake washed with water and
washed with acetone to give a pale yellow solid 19. 6 g, used directly
ko acid recrystallization, as a white solid 15. 2 g,
mp 227. 2 - 228. 1 ° C, [a] D21 = -38 2 ° (. c = 0. 30, DMS0), rivaroxaban yield of 94%, the total yield of 87.5% 0
1H-NMR
(DMSO) 8: 3. 61 (. 2 H, t, / = 5 4 Hz), 3. 71 (2 H, t, / = 5 4 Hz.),
3.85 (IH, m ), 3.97 (2 H, t, J = 4. 5 Hz), 4. 19 (3 H, t, / = 7. 5
Hz), 4.84 (IH, m), 7. 19 (IH, d, / = 4. 2Hz), 7.40 (2 H, d, /=9.0 Hz),
7. 57 (2 H, t, /=9.0 Hz), 7. 69 (IH, d, J = 4. 19 Hz), 8. 96 (IH, t, / =
5. 7 Hz).
.....................
EXAMPLE 28 (preparation of rivaroxaban)
10
g of the salt prepared according to Example 18 were suspended in 75 ml
of N- methylpyrolidone, the suspension was heated at 50°C, then 14 ml of
triethylamine was added and the mixture was heated at 60°C. This was
followed by addition of 15.7 ml of a solution of
5-chlorothiophene-2-carboxylic acid chloride in toluene (2.46 M) and the
reaction mixture was stirred and heated at 55°C for 15 minutes, then
slowly cooled below 30°C, 75 ml were added and the turbid solution was
filtered. The clear filtrate was stirred at 50°C, which was followed by
addition of 15 ml of water and 75 ml of ethanol and stirring for 1 hour
under slow cooling. The separated product was filtered off, washed with
water (15 ml, 60°C), ethanol (2 x 25 ml) and dried in vacuo. 9.1 g
(yield 81%) of rivaroxaban in the form of an off-white powder with the
melt, point of 229.5-231°C was obtained, HPLC 99.95%, content of the (
)-isomer below 0.03%.
1H NMR (250 MHz, DMSO-D6), δ (ppm): 3.61 (t, 2H, CH2); 3.71 (m, 2H, CH2); 3.85 and 4.19 (m, 2x1 H, CH2); 3.97 (m, 2H, CH2); 4.19 (s, 2H, CH2); 4.84 (pent, 1H, CH); 7.18 (d, 1H); 7.40 (m, 2H); 7.56 (m, 2H); 7.68 (d, 1H); 8.95 (bt, 1H, NH).
13C NMR (250 MHz, DMSO-D6), δ (ppm): 42.2; 47.4; 49.0; 63.4; 67.7; 71.3; 1 18.3; 125.9; 128.1 ; 128.4; 133.2; 136.4; 137.0; 138.4; 154.0; 160.8; 165.9.
MS (m/z): 436.0729 (M+H)+. ation)
The
optical isomer of rivaroxaban with the (R)- configuration was obtained
by a process analogous to Example 28 starting from the salt prepared
according to Example 19. The yield was 76%, HPLC 99.90%, content of the
(5)-isomer below 0.03%. The NMR and MS spectra were in accordance with
Example 28.
..........................
........................
5-
chloro-thiophene-2-chloride by condensation, bromide, with 4-
(4-amino-phenyl) -3-morpholinone cyclization reaction rivaroxaban, the
following reaction scheme :( References : W02005068456, US20070149522,
DE10300111)
...........................
5-
chloro-thiophene-2-chloride by condensation, oxidation, and 4-
(4-amino-phenyl) -3-morpholinone cyclization reaction racemic
rivaroxaban, since the epoxidation step is not give any
stereoselectivity, the final chiral separation need to get rivaroxaban,
the reaction scheme is as follows :( References: W0-0147919)
............
4-
(4- amino-phenyl) -3-morpholinone by condensation, cyclization, and
potassium phthalimide after reaction with methyl chloroformate to give
(S) -2 - hydroxy -3- (I, 3- dioxo - isoindoline-2-yl) propyl-4- (3-oxo
--morpholino) phenyl carbamate, by condensation, methylamine and Ethanol
action under profit rivaroxaban, the following reaction scheme (Ref:
US20110034465):
..........
4-
(4- amino-phenyl) -3-morpholinone (R) and - epichlorohydrin, in the DMF
solvent phthalimide potassium salt was reacted with ammonia solution
and then prepared to succeed amino compound, and
5-chloro-thiophene-2-chloride in pyridine catalyzed system benefit
rivaroxaban, the following reaction scheme (Ref: W02009023233):
.............
4-
(4- amino-phenyl) -3-morpholinone after condensation with (R) -
epichlorohydrin, then the 5-chloro-thiophene-2-amide lithium chloride
and tert-butyl the reaction of an alcohol potassium enrichment
rivaroxaban, the following reaction scheme (Ref: US7816355):
...................
3-chloro-1,2-propanediol
by cyclization, the reaction with phthalimide, then with 4-
(4-aminophenyl) -3-morpholinone reaction, CDI and hydrazine to give 4-
{4- [(5S) -5- (aminomethyl) -2-oxo-1,3-oxazolidin-3-yl] phenyl}
morpholin-3-one under the influence, in pyridine and under the action of
tetrahydrofuran and 5-chloro-thiophene-2-chloride benefit rivaroxaban,
the following reaction scheme (Reference: Gutcait, A. et al
Tetrahedron:.. Asymmetry 1996, 7 (6), 1641-1648 Roehrig, .. S. et al J.
Med Chem 2005,48 (19), 5900-5908)..:
..............
http://www.google.com/patents/CN102702186A?cl=zh
Compound rivaroxaban Synthesis Example 7 formula (X), [0071] Example
[0072] Method One:
[0074] The compound of formula (VIII) of (180mg, 0. 618mmol), Ni chloride (5mL) and tris ko amine (187mg,
I.
85mmol) added to the reaction flask, stirred at room temperature for 10
minutes, cooled to 0 ° C, a solution of 5-chloro-2-thiophene chloride
(224mg, 1.24mm0l), stirred at room temperature overnight; after the
completion of the reaction, spin dry, rinse with anhydrous alcohol ko,
filtered, washed ko anhydrous alcohol three times to obtain a white
solid product rivaroxaban (215mg, embodiments of the total yield of 7,8
80%).
[0075]
1H-Mffi (DMSC) JOOMHz, δ d m):.... 3 61 (t, 2H, J = 5 6Hz), 3. 71 (t,
2H, J = 5 2Hz), 3 89 ( m, 1H), 3. 97 (t, 2H, J = 4. 4Hz), 4. 20 (m, 3H),
4. 85 (m, 1H), 7. 18 (d, 1H, J = 4. 0Hz), 7. 40 (d, 2H, J = 8. 8Hz), 7.
56 (d, 2H, J = 8. 8Hz), 7. 73 (d, 1H, J = 4. 0Hz).
The method of writing is:
[0078]
The compound 5_ gas - oh -I- thiophene carboxylic acid (500mg, 3.
08mmol), MsCl (702mg, 6. 1 Bmmol) and sodium bicarbonate (. 517mg, 6
16mmol) was suspended in THF (20ml) in , heated to 60 ° C with stirring
45min, a large white suspension washed out; the reaction mixture was
cooled to room temperature, the compound of formula VIII was added
portionwise (800mg, 2 75mmol.), stirred for 5 hours, after completion of
the reaction distilled THF, was added after the residue was cooled to
room temperature, water (IOOml), at room temperature embrace Cheung
30min, filtered, and the filter cake washed with cold water, dried and
added to a ko-ol (5ml) was heated at reflux for I hour. After cooling,
stirred for 5 hours at room temperature After filtration to give the
product of formula (X) of the compound rivaroxaban (719mg, 60%)
SYNTHESIS
SYN 1
BAYER HEALTHCARE AG Patent: WO2004/60887 A1, 2004 ; Location in patent: Page/Page column 8; 10-11 ;
SYN 2
MEDICHEM
S.A.; MANGION, Bernardino; DURAN LOPEZ, Ernesto Patent: WO2012/35057
A2, 2012 ; Location in patent: Page/Page column 34 ;
SYN 3
EGIS
GYOGYSZERGYAR NYILVANOSAN MUeKOeDOe RESZVENY-TARSASAG; SIPOS, Eva;
KOVANYINE LAX, Gyoergyi; HAVASI, Balazs; VOLK, Balazs; KRASZNAI,
Gyoergy; RUZSICS, Gyoergy; BARKOCZY, Jozsef; TOTHNE LAURITZ, Maria;
LUKACS, Gyula; BOZA, Andras; HEGEDUeS, Laszlo Jozsef; TABORINE TOTH,
Maria Julia; PECSI, Eva Patent: WO2012/153155 A1, 2012 ; Location in
patent: Page/Page column 49 ;
SYN4
EGIS
GYOGYSZERGYAR NYILVANOSAN MUeKOeDOe RESZVENY-TARSASAG; SIPOS, Eva;
KOVANYINE LAX, Gyoergyi; HAVASI, Balazs; VOLK, Balazs; KRASZNAI,
Gyoergy; RUZSICS, Gyoergy; BARKOCZY, Jozsef; TOTHNE LAURITZ, Maria;
LUKACS, Gyula; BOZA, Andras; HEGEDUeS, Laszlo Jozsef; TABORINE TOTH,
Maria Julia; PECSI, Eva Patent: WO2012/153155 A1, 2012 ; Location in
patent: Page/Page column 68 ;
SYN 5
INTERQUIM,
S.A.; Berzosa Rodríguez, Xavier; Marquillas Olondriz, Francisco;
Llebaria Soldevilla, Amadeo; Serra Comas, Carme Patent: US2014/128601
A1, 2014 ; Location in patent: Paragraph 0068 ;
SYN 6
MEGAFINE
PHARMA (P) LTD; MATHAD Vijayavitthal Thippannachar; PATIL NILESH
SUDHIR, Nilesh; NIPHADE NAVNATH CHINTAMAN, Navnath; MALI ANIL CHATURLAL,
Anil; BODAKE MAHENDRA BHAGIRATH, Mahendra; IPPAR SHARAD SUBHASH,
Sharad; TALLA RAJESH, Rajesh Patent: WO2013/121436 A2, 2013 ; Location
in patent: Page/Page column 31 ;
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FROM THE NET
https://plus.google.com/.../posts/EeEveU8xvUd
32 mins ago - RIVAROXABAN 5-Chloro-N-{[(5S) 2-oxo-3 [4-(3-oxo-4-morpholinophenyl]oxazolidin-5-yl]methyl} thiophene-2-carboxamide (Rivaroxaban) (1):1 rivaroxaban 1 ...
https://plus.google.com/.../posts/g4TXSPBA4YV
1 hour ago - WO 2015104605.new patent on Rivaroxaban, Wockhardt Ltd Process for preparing rivaroxaban - comprising the reaction of a thioester compound and its salts ...
Rivaroxaban,
a FXa inhibitor, is the active ingredient in XARELTO Tablets with the
chemical name
5-Chloro-N-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-1,3-oxazolidin-5yl}methyl)-2-thiophenecarboxamide.
The molecular formula of rivaroxaban is C
19H
18ClN
3O
5S and the molecular weight is 435.89. The structural formula is:
Rivaroxaban
is a pure (S)-enantiomer. It is an odorless, non-hygroscopic, white to
yellowish powder. Rivaroxaban is only slightly soluble in organic
solvents (e.g.,
acetone, polyethylene glycol 400) and is practically insoluble in water and aqueous media.
Each
XARELTO tablet contains 10 mg, 15 mg, or 20 mg of rivaroxaban. The
inactive ingredients of XARELTO are: croscarmellose sodium,
hypromellose, lactose monohydrate, magnesium stearate, microcrystalline
cellulose, and sodium lauryl sulfate. Additionally, the proprietary film
coating mixture used for XARELTO 10 mg tablets is Opadry® Pink and for
XARELTO 15 mg tablets is Opadry® Red, both containing ferric oxide red,
hypromellose, polyethylene glycol 3350, and titanium dioxide, and for
XARELTO 20 mg tablets is Opadry® II Dark Red, containing ferric oxide
red, polyethylene glycol 3350, polyvinyl alcohol (partially hydrolyzed),
talc, and titanium dioxide.
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