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.

13 C NMR…..http://www.nmrdb.org/13c/index.shtml?v=v2.14.1

CLICK TO PREDICT..ALLOW SOME TIME TO LOAD ON NMRDB SITE…..CHECK JAVA AND FLASH SETTINGS

ABOVE PICTURES ARE THE ONES YOU WILL GET

· 1H NMR prediction……http://www.nmrdb.org/new_predictor/index.shtml?v=v2.12.1

· 13C NMR prediction

· COSY prediction

· HSQC/HMBC prediction

· All predictions

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.

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

…………..

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).

…………………

WO2013120465

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, 2×1 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%)

References

“Xarelto: Summary of Product Characteristics”. Bayer Schering Pharma AG. 2008. Retrieved 2009-02-11.
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.
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.
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.
“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.
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.
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.
“Bayer’s Xarelto Approved in Canada” (Press release). Bayer. 2008-09-16. Retrieved2010-01-31.
“Bayer’s Novel Anticoagulant Xarelto now also Approved in the EU” (Press release).Bayer. 2008-02-10. Retrieved 2010-01-31.
“Medication Guide–Xarelto” (PDF). http://www.fda.gov/. U.S. Food and Drug Administration. Retrieved 1 September 2014.
“Xarelto Side Effects”. http://www.webmd.com/. WebMD. Retrieved 1 September2014.
“Xarelto Side Effects Center”. http://www.rxlist.com/. RxList. Retrieved 1 September2014.
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.
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.
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.
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.
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.
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.
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.
ClinicalTrials.gov. “MAGELLAN – Multicenter, Randomized, Parallel Group Efficacy Superiority Study in Hospitalized Medically Ill Patients Comparing Rivaroxaban with Enoxaparin”. Retrieved 2009-02-11.
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.
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.
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.
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.
“Venous Thromboembolic Event (VTE) Prophylaxis in Medically Ill Patients (MAGELLAN)”. ClinicalTrials.gov. 11 March 2011. Retrieved 15 April 2011.
Hughes, Sue (5 April 2011). “MAGELLAN: Rivaroxaban prevents VTE in medical patients, but bleeding an issue”. theheart.org. Retrieved 15 April 2011.
“About the MAGELLAN Study”. Bayer HealthCare. Retrieved 15 April 2011.
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.
“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.
European Medicines Agency (2008). “CHP Assessment Report for Xarelto (EMEA/543519/2008)” (PDF). Retrieved 2009-06-11.
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, 2013	Aug 22, 2013	Zentiva, K.S.	A process for the preparation of rivaroxaban based on the use of (s)-epichlorohydrin

WO2001047919A1	Dec 11, 2000	Jul 5, 2001	Bayer Ag	Substituted oxazolidinones and their use in the field of blood coagulation
WO2004060887A1	Dec 24, 2003	Jul 22, 2004	Bayer Healthcare Ag	Method for producing 5-chloro-n-({5s)-2-oxo-3-[4-(3-oxo-4-morpholinyl)-phenyl]-1,3-oxazolidin-5-yl}-methyl)-2-thiophene carboxamide
WO2007116284A1	Mar 26, 2007	Oct 18, 2007	Pfizer Prod Inc	Process for preparing linezolid
WO2009023233A1	Aug 14, 2008	Feb 19, 2009	Concert Pharmaceuticals Inc	Substituted oxazolidinone derivatives
WO2010043110A1	Oct 9, 2009	Apr 22, 2010	Changzhou Multiple Dimension Institute Of Industry Technology Co., Ltd.	A preparation method of high-purity l-carnitine
WO2010082627A1	Jan 15, 2010	Jul 22, 2010	Daiso Co., Ltd.	Process for producing 2-hydroxymethylmorpholine salt
WO2010124835A1	Apr 27, 2010	Nov 4, 2010	Belte Ag	Aluminium-silicon diecasting alloy for thin-walled structural components
WO2011080341A1	Jan 3, 2011	Jul 7, 2011	Enantia, S.L.	Process for the preparation of rivaroxaban and intermediates thereof
WO2011098501A1	Feb 10, 2011	Aug 18, 2011	Sandoz Ag	Method for the preparation of rivaroxaban
WO2011102640A2	Feb 16, 2011	Aug 25, 2011	Hanmi Holdings Co., Ltd.	Method for preparing sitagliptin and amine salt intermediates used therein
WO2012159992A1 *	May 18, 2012	Nov 29, 2012	Interquim, S.A.	Process for obtaining rivaroxaban and intermediate thereof
CN102786516A *	Aug 21, 2012	Nov 21, 2012	湖南师范大学	Method for synthesizing rivaroxaban
US7157456	Dec 11, 2000	Jan 2, 2007	Bayer Healthcare Ag	Substituted oxazolidinones and their use in the field of blood coagulation
US7816355 *	Apr 28, 2009	Oct 19, 2010	Apotex Pharmachem Inc	Processes for the preparation of rivaroxaban and intermediates thereof
US20110034465		Feb 10, 2011	Apotex Pharmachem Inc.	Processes for the preparation of rivaroxaban and intermediates thereof

CN101560209A *	Apr 15, 2008	Oct 21, 2009	Shenyang, one hundred million Leo Pharmaceutical Co., Ltd.	Pyrimidine oxazolidinone compound and preparation method comprising
CN101619061A *	Aug 11, 2009	Jan 6, 2010	Shenyang Pharmaceutical University	Cyanopyridyl substituted oxazolidinone compounds
CN101821260A *	Aug 14, 2008	Sep 1, 2010	Consett Pharmaceuticals Ltd.	Substituted oxazolidinone derivatives
CN102250076A *	May 27, 2011	Nov 23, 2011	Hengdian Group homes Chemical Co., Ltd.	One kind of rivaroxaban Rivaroxaban intermediates and preparation methods
CN102250077A *	Jun 15, 2011	Nov 23, 2011	Zhejiang University	A method for intermediate and rivaroxaban Rivaroxaban for the synthesis of
CN102311400A *	Jun 29, 2010	Jan 11, 2012	Xiang really Biotechnology Co., Ltd.	Aminomethyl-3-aryl-2-oxazolidinone class method – Preparation of L-5-
CN102320988A *	Jun 3, 2011	Jan 18, 2012	Shanghai Institute of Organic Chemistry	4- (4-aminophenyl) -3-morpholinone intermediate amide, the synthesis method and uses
EP2354128A1 *	Feb 10, 2010	Aug 10, 2011	Sandoz Ag	Method for the preparation of rivaroxaban
WO2010124385A1 *	Apr 28, 2010	Nov 4, 2010	Apotex Pharmachem Inc.	Processes for the preparation of rivaroxaban and intermediates thereof

FROM THE NET

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

https://plus.google.com/…/posts/EeEveU8xvUd

ANTHONY MELVIN CRASTO

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 …

https://plus.google.com/…/posts/g4TXSPBA4YV

ANTHONY MELVIN CRASTO

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
Systematic (IUPAC) name


(S)-5-chloro-N-{[2-oxo-3-[4-(3-oxomorpholin-4-yl) phenyl]oxazolidin-5-yl]methyl} thiophene-2-carboxamide
Clinical data
Trade names	Xarelto
AHFS/Drugs.com	Micromedex Detailed Consumer Information
Licence data	EMA:Link, US FDA:link
Pregnancy category	AU:C US:C (Risk not ruled out)
Legal status	AU:Prescription Only (S4) CA: ℞-only UK:Prescription-only (POM) US:℞-only
Routes of administration	oral
Pharmacokinetic data
Bioavailability	80% to 100%; Cmax = 2 – 4 hours (10 mg oral)^[1]
Metabolism	CYP3A4 , CYP2J2 and CYP-independent mechanisms^[1]
Biological half-life	5 – 9 hours in healthy subjects aged 20 to 45^[1]^[2]
Excretion	2/3 metabolized in liver and 1/3 eliminated unchanged^[1]
Identifiers
CAS Registry Number	366789-02-8
ATC code	B01AX06
PubChem	CID: 6433119
IUPHAR/BPS	6388
DrugBank	DB06228
ChemSpider	8051086
UNII	9NDF7JZ4M3
ChEMBL	CHEMBL198362
Synonyms	Xarelto, BAY 59-7939
Chemical data
Formula	C₁₉H₁₈Cl N₃O₅S
Molecular mass	435.882 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.