RIVAROXABAN 利伐沙班 ريفاروكسابان Ривароксабан

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

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

 

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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:

 

 

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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).

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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, 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.
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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)

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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)

 

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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):

 

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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):

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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):

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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)..:

 

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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 ;

 

 

 

References

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.
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20.  ClinicalTrials.gov. "MAGELLAN - Multicenter, Randomized, Parallel Group Efficacy Superiority Study in Hospitalized Medically Ill Patients Comparing Rivaroxaban with Enoxaparin". Retrieved 2009-02-11.
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WO2013120465A1 *

Feb 18, 2013

Aug 22, 2013

Zentiva, K.S.

A process for the preparation of rivaroxaban based on the use of (s)-epichlorohydrin

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FROM THE NET

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

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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 ...

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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	C19H18ClN3O5S
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:
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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