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Showing posts with label 利伐沙班. Show all posts
Showing posts with label 利伐沙班. Show all posts

Monday, 27 July 2015

RIVAROXABAN 利伐沙班 ريفاروكسابان Ривароксабан


5-Chloro-N-{[(5S)-2-oxo-3-[4-(3-oxo-4-morpholinophenyl]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.


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.


ChemSpider 2D Image | Rivaroxaban | C19H18ClN3O5SFigure CN102786516AD00041



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





COSY NMR prediction 1
Predict 13C carbon NMR spectra

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
front page image
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.



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).
Figure imgf000002_0001
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.
Figure imgf000003_0001
(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.
Figure imgf000003_0002
Scheme 1
Figure imgf000004_0001
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.
Figure imgf000005_0001
Scheme 3
Figure imgf000005_0002
Scheme 4
Figure imgf000006_0001
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.
Figure imgf000007_0001
Scheme 6
Figure imgf000007_0002
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.
Figure imgf000008_0001

Figure imgf000016_0001



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:
Figure CN102786516AD00051





Preparation 6 rivaroxaban implementation
Figure CN102786516AD00111
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)
Figure imgf000038_0002
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)
Figure imgf000039_0001
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)

Figure CN102702186AD00041
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)

Figure CN102702186AD00051



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):

Figure CN102702186AD00052



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):

Figure CN102702186AD00053


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):
Figure CN102702186AD00061


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)..:

Figure CN102702186AD00062




Compound rivaroxaban Synthesis Example 7 formula (X), [0071] Example
[0072] Method One:

Figure CN102702186AD00112
[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:

Figure CN102702186AD00113
[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%)



BAYER HEALTHCARE AG Patent: WO2004/60887 A1, 2004 ; Location in patent: Page/Page column 8; 10-11 ;


MEDICHEM S.A.; MANGION, Bernardino; DURAN LOPEZ, Ernesto Patent: WO2012/35057 A2, 2012 ; Location in patent: Page/Page column 34 ;


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 ;


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 ;


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 ;


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 ;





  1.  "Xarelto: Summary of Product Characteristics". Bayer Schering Pharma AG. 2008. Retrieved 2009-02-11.
  2.  Abdulsattar, Y; Bhambri, R; Nogid, A (May 2009). "Rivaroxaban (xarelto) for the prevention of thromboembolic disease: an inside look at the oral direct factor xa inhibitor.".P & T : a peer-reviewed journal for formulary management 34 (5): 238–44.PMID 19561868.
  3.  Roehrig S, Straub A, Pohlmann J et al. (September 2005). "Discovery of the novel antithrombotic agent 5-chloro-N-({(5S)-2-oxo-3- [4-(3-oxomorpholin-4-yl)phenyl]-1,3-oxazolidin-5-yl}methyl)thiophene- 2-carboxamide (BAY 59-7939): an oral, direct factor Xa inhibitor". Journal of Medicinal Chemistry 48 (19): 5900–8. doi:10.1021/jm050101d.PMID 16161994.
  4.  Perzborn, Elisabeth; Roehrig, Susanne; Straub, Alexander; Kubitza, Dagmar; Misselwitz, Frank (17 December 2010). "The discovery and development of rivaroxaban, an oral, direct factor Xa inhibitor". Nature Reviews Drug Discovery 10 (1): 61–75. doi:10.1038/nrd3185.
  5.  "FDA Approves XARELTO® (rivaroxaban tablets) to Help Prevent Deep Vein Thrombosis in Patients Undergoing Knee or Hip Replacement Surgery" (Press release).Janssen Pharmaceutica. 2011-07-01. Retrieved 2011-07-01.
  6.  Gómez-Outes, A; Terleira-Fernández, AI; Calvo-Rojas, G; Suárez-Gea, ML; Vargas-Castrillón, E (2013). "Dabigatran, Rivaroxaban, or Apixaban versus Warfarin in Patients with Nonvalvular Atrial Fibrillation: A Systematic Review and Meta-Analysis of Subgroups.". Thrombosis 2013: 640723. doi:10.1155/2013/640723. PMC 3885278.PMID 24455237.
  7.  Brown DG, Wilkerson EC, Love WE (March 2015). "A review of traditional and novel oral anticoagulant and antiplatelet therapy for dermatologists and dermatologic surgeons".Journal of the American Academy of Dermatology 72 (3): 524–34.doi:10.1016/j.jaad.2014.10.027. PMID 25486915.
  8.  "Bayer's Xarelto Approved in Canada" (Press release). Bayer. 2008-09-16. Retrieved2010-01-31.
  9.  "Bayer’s Novel Anticoagulant Xarelto now also Approved in the EU" (Press release).Bayer. 2008-02-10. Retrieved 2010-01-31.
  10.  "Medication Guide--Xarelto" (PDF). http://www.fda.gov/. U.S. Food and Drug Administration. Retrieved 1 September 2014.
  11.  "Xarelto Side Effects". http://www.webmd.com/. WebMD. Retrieved 1 September2014.
  12. "Xarelto Side Effects Center". http://www.rxlist.com/. RxList. Retrieved 1 September2014.
  13.  Eriksson BI, Borris LC, Dahl OE et al. (November 2006). "A once-daily, oral, direct Factor Xa inhibitor, rivaroxaban (BAY 59-7939), for thromboprophylaxis after total hip replacement". Circulation 114 (22): 2374–81.doi:10.1161/CIRCULATIONAHA.106.642074. PMID 17116766.
  14.  Eriksson BI, Borris LC, Friedman RJ et al. (June 2008). "Rivaroxaban versus enoxaparin for thromboprophylaxis after hip arthroplasty". The New England Journal of Medicine 358(26): 2765–75. doi:10.1056/NEJMoa0800374. PMID 18579811.
  15. Kakkar AK, Brenner B, Dahl OE et al. (July 2008). "Extended duration rivaroxaban versus short-term enoxaparin for the prevention of venous thromboembolism after total hip arthroplasty: a double-blind, randomised controlled trial". Lancet 372 (9632): 31–9.doi:10.1016/S0140-6736(08)60880-6. PMID 18582928.
  16. Lassen MR, Ageno W, Borris LC et al. (June 2008). "Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty". The New England Journal of Medicine358 (26): 2776–86. doi:10.1056/NEJMoa076016. PMID 18579812.
  17.  Turpie A, Bauer K, Davidson B et al. "Comparison of rivaroxaban – an oral, direct factor Xa inhibitor – and subcutaneous enoxaparin for thromboprophylaxis after total knee replacement (RECORD4: a phase 3 study) / European Federation of National Associations of Orthopaedics and Traumatology Annual Meeting; May 29 – June 1, 2008; Nice, France, Abstract F85". Journal of Bone & Joint Surgery, British Volume 92–B (SUPP II): 329.
  18.  Turpie AG, Lassen MR, Davidson BL et al. (May 2009). "Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty (RECORD4): a randomised trial".Lancet 373 (9676): 1673–80. doi:10.1016/S0140-6736(09)60734-0. PMID 19411100.
  19.  ClinicalTrials.gov. "Randomized, Double-Blind Study Comparing Once Daily Oral Rivaroxaban With Adjusted-Dose Oral Warfarin for the Prevention of Stroke in Subjects With Non-Valvular Atrial Fibrillation". Retrieved 2009-02-11.
  20.  ClinicalTrials.gov. "MAGELLAN - Multicenter, Randomized, Parallel Group Efficacy Superiority Study in Hospitalized Medically Ill Patients Comparing Rivaroxaban with Enoxaparin". Retrieved 2009-02-11.
  21.  ClinicalTrials.gov. "Once-Daily Oral Direct Factor Xa Inhibitor Rivaroxaban in the Long-Term Prevention of Recurrent Symptomatic Venous Thromboembolism in Patients With Symptomatic Deep-Vein Thrombosis or Pulmonary Embolism. The Einstein-Extension Study". Retrieved 2009-02-11.
  22.  ClinicalTrials.gov. "Oral Direct Factor Xa Inhibitor Rivaroxaban In Patients With Acute Symptomatic Deep-Vein Thrombosis (DVT) Without Symptomatic Pulmonary Embolism: Einstein-DVT Evaluation". Retrieved 2009-02-11.
  23.  ClinicalTrials.gov. "Oral Direct Factor Xa Inhibitor Rivaroxaban In Patients With Acute Symptomatic Pulmonary Embolism (PE) With Or Without Symptomatic Deep-Vein Thrombosis: Einstein-PE Evaluation". Retrieved 2009-02-11.
  24.  ClinicalTrials.gov. "A Randomized, Double-Blind, Placebo-Controlled, Event-Driven Multicenter Study to Evaluate the Efficacy and Safety of Rivaroxaban in Subjects With a Recent Acute Coronary Syndrome". Retrieved 2009-02-11.
  25.  "Venous Thromboembolic Event (VTE) Prophylaxis in Medically Ill Patients (MAGELLAN)". ClinicalTrials.gov. 11 March 2011. Retrieved 15 April 2011.
  26.  Hughes, Sue (5 April 2011). "MAGELLAN: Rivaroxaban prevents VTE in medical patients, but bleeding an issue". theheart.org. Retrieved 15 April 2011.
  27.  "About the MAGELLAN Study". Bayer HealthCare. Retrieved 15 April 2011.
  28. Bauersachs, M.D., Rupert; The EINSTEIN Investigators (December 23, 2010). "Oral Rivaroxaban for Symptomatic Venous Thromboembolism". The New England Journal of Medecine 363 (26): 2499–2510. doi:10.1056/NEJMoa1007903. PMID 21128814. Retrieved 4 April 2011.
  29.  "Oral Direct Factor Xa Inhibitor Rivaroxaban In Patients With Acute Symptomatic Deep-Vein Thrombosis Without Symptomatic Pulmonary Embolism: Einstein-DVT Evaluation". clinicaltrials.gov. Retrieved 15 April 2011.
  30.  European Medicines Agency (2008). "CHP Assessment Report for Xarelto (EMEA/543519/2008)" (PDF). Retrieved 2009-06-11.
  31. Turpie AG (January 2008). "New oral anticoagulants in atrial fibrillation". European Heart Journal 29 (2): 155–65. doi:10.1093/eurheartj/ehm575. PMID 18096568.

WO2013120465A1 *Feb 18, 2013Aug 22, 2013Zentiva, K.S.A process for the preparation of rivaroxaban based on the use of (s)-epichlorohydrin
WO2001047919A1Dec 11, 2000Jul 5, 2001Bayer AgSubstituted oxazolidinones and their use in the field of blood coagulation
WO2004060887A1Dec 24, 2003Jul 22, 2004Bayer Healthcare AgMethod for producing 5-chloro-n-({5s)-2-oxo-3-[4-(3-oxo-4-morpholinyl)-phenyl]-1,3-oxazolidin-5-yl}-methyl)-2-thiophene carboxamide
WO2007116284A1Mar 26, 2007Oct 18, 2007Pfizer Prod IncProcess for preparing linezolid
WO2009023233A1Aug 14, 2008Feb 19, 2009Concert Pharmaceuticals IncSubstituted oxazolidinone derivatives
WO2010043110A1Oct 9, 2009Apr 22, 2010Changzhou Multiple Dimension Institute Of Industry Technology Co., Ltd.A preparation method of high-purity l-carnitine
WO2010082627A1Jan 15, 2010Jul 22, 2010Daiso Co., Ltd.Process for producing 2-hydroxymethylmorpholine salt
WO2010124835A1Apr 27, 2010Nov 4, 2010Belte AgAluminium-silicon diecasting alloy for thin-walled structural components
WO2011080341A1Jan 3, 2011Jul 7, 2011Enantia, S.L.Process for the preparation of rivaroxaban and intermediates thereof
WO2011098501A1Feb 10, 2011Aug 18, 2011Sandoz AgMethod for the preparation of rivaroxaban
WO2011102640A2Feb 16, 2011Aug 25, 2011Hanmi Holdings Co., Ltd.Method for preparing sitagliptin and amine salt intermediates used therein
WO2012159992A1 *May 18, 2012Nov 29, 2012Interquim, S.A.Process for obtaining rivaroxaban and intermediate thereof
CN102786516A *Aug 21, 2012Nov 21, 2012湖南师范大学Method for synthesizing rivaroxaban
US7157456Dec 11, 2000Jan 2, 2007Bayer Healthcare AgSubstituted oxazolidinones and their use in the field of blood coagulation
US7816355 *Apr 28, 2009Oct 19, 2010Apotex Pharmachem IncProcesses for the preparation of rivaroxaban and intermediates thereof
US20110034465Feb 10, 2011Apotex Pharmachem Inc.Processes for the preparation of rivaroxaban and intermediates thereof
CN101560209A *Apr 15, 2008Oct 21, 2009Shenyang, one hundred million Leo Pharmaceutical Co., Ltd.Pyrimidine oxazolidinone compound and preparation method comprising
CN101619061A *Aug 11, 2009Jan 6, 2010Shenyang Pharmaceutical UniversityCyanopyridyl substituted oxazolidinone compounds
CN101821260A *Aug 14, 2008Sep 1, 2010Consett Pharmaceuticals Ltd.Substituted oxazolidinone derivatives
CN102250076A *May 27, 2011Nov 23, 2011Hengdian Group homes Chemical Co., Ltd.One kind of rivaroxaban Rivaroxaban intermediates and preparation methods
CN102250077A *Jun 15, 2011Nov 23, 2011Zhejiang UniversityA method for intermediate and rivaroxaban Rivaroxaban for the synthesis of
CN102311400A *Jun 29, 2010Jan 11, 2012Xiang really Biotechnology Co., Ltd.Aminomethyl-3-aryl-2-oxazolidinone class method - Preparation of L-5-
CN102320988A *Jun 3, 2011Jan 18, 2012Shanghai Institute of Organic Chemistry4- (4-aminophenyl) -3-morpholinone intermediate amide, the synthesis method and uses
EP2354128A1 *Feb 10, 2010Aug 10, 2011Sandoz AgMethod for the preparation of rivaroxaban
WO2010124385A1 *Apr 28, 2010Nov 4, 2010Apotex Pharmachem Inc.Processes for the preparation of rivaroxaban and intermediates thereof


RIVAROXABAN 5-Chloro-N-{[(5S) 2-oxo-3 [4-(3-oxo-4 ...

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 ...

WO 2015104605.new patent on Rivaroxaban, Wockhardt ...

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 xtal 2005.png
Systematic (IUPAC) name
phenyl]oxazolidin-5-yl]methyl} thiophene-2-carboxamide
Clinical data
Trade namesXarelto
AHFS/Drugs.comMicromedex Detailed Consumer Information
Licence dataEMA:Link, US FDA:link
  • AU:C
  • US:C (Risk not ruled out)
Legal status
Routes of
Pharmacokinetic data
Bioavailability80% to 100%; Cmax = 2 – 4 hours (10 mg oral)[1]
MetabolismCYP3A4 , CYP2J2 and CYP-independent mechanisms[1]
Biological half-life5 – 9 hours in healthy subjects aged 20 to 45[1][2]
Excretion2/3 metabolized in liver and 1/3 eliminated unchanged[1]
CAS Registry Number366789-02-8 
ATC codeB01AX06
PubChemCID: 6433119
DrugBankDB06228 Yes
ChemSpider8051086 Yes
SynonymsXarelto, BAY 59-7939
Chemical data
Molecular mass435.882 g/mol
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 C19H18ClN3O5S and the molecular weight is 435.89. The structural formula is:
XARELTO (rivaroxaban) Structural Formula Illustration
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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