HRP20161588T1 - Intermedijer rivaroksabana i njegova priprava - Google Patents
Intermedijer rivaroksabana i njegova priprava Download PDFInfo
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- HRP20161588T1 HRP20161588T1 HRP20161588TT HRP20161588T HRP20161588T1 HR P20161588 T1 HRP20161588 T1 HR P20161588T1 HR P20161588T T HRP20161588T T HR P20161588TT HR P20161588 T HRP20161588 T HR P20161588T HR P20161588 T1 HRP20161588 T1 HR P20161588T1
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- Prior art keywords
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Links
- DEXXSYVEWAYIGZ-LBPRGKRZSA-N 4-[4-[(5s)-5-(aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl]morpholin-3-one Chemical compound O=C1O[C@@H](CN)CN1C1=CC=C(N2C(COCC2)=O)C=C1 DEXXSYVEWAYIGZ-LBPRGKRZSA-N 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims 23
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims 12
- 239000002253 acid Substances 0.000 claims 10
- 239000002904 solvent Substances 0.000 claims 10
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims 9
- 238000000034 method Methods 0.000 claims 9
- 239000002585 base Substances 0.000 claims 7
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims 6
- 150000003839 salts Chemical class 0.000 claims 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims 4
- 239000012458 free base Substances 0.000 claims 4
- 239000000203 mixture Substances 0.000 claims 4
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims 3
- KGFYHTZWPPHNLQ-AWEZNQCLSA-N rivaroxaban Chemical compound S1C(Cl)=CC=C1C(=O)NC[C@@H]1OC(=O)N(C=2C=CC(=CC=2)N2C(COCC2)=O)C1 KGFYHTZWPPHNLQ-AWEZNQCLSA-N 0.000 claims 3
- 229960001148 rivaroxaban Drugs 0.000 claims 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims 2
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 claims 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims 2
- 125000003172 aldehyde group Chemical group 0.000 claims 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims 2
- BWEPHOKPIKTSCJ-ZDUSSCGKSA-N n-[[(5s)-2-oxo-3-[4-(3-oxomorpholin-4-yl)phenyl]-1,3-oxazolidin-5-yl]methyl]formamide Chemical compound O=C1O[C@@H](CNC=O)CN1C1=CC=C(N2C(COCC2)=O)C=C1 BWEPHOKPIKTSCJ-ZDUSSCGKSA-N 0.000 claims 2
- NAYYNDKKHOIIOD-UHFFFAOYSA-N phthalamide Chemical group NC(=O)C1=CC=CC=C1C(N)=O NAYYNDKKHOIIOD-UHFFFAOYSA-N 0.000 claims 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims 2
- -1 sulfonyloxy, imidazole Chemical group 0.000 claims 2
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims 1
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 claims 1
- DUILGEYLVHGSEE-ZETCQYMHSA-N 2-[[(2s)-oxiran-2-yl]methyl]isoindole-1,3-dione Chemical compound O=C1C2=CC=CC=C2C(=O)N1C[C@H]1CO1 DUILGEYLVHGSEE-ZETCQYMHSA-N 0.000 claims 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims 1
- MHCRLDZZHOVFEE-UHFFFAOYSA-N 4-(4-aminophenyl)morpholin-3-one Chemical compound C1=CC(N)=CC=C1N1C(=O)COCC1 MHCRLDZZHOVFEE-UHFFFAOYSA-N 0.000 claims 1
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 claims 1
- BTJIUGUIPKRLHP-UHFFFAOYSA-N 4-nitrophenol Chemical compound OC1=CC=C([N+]([O-])=O)C=C1 BTJIUGUIPKRLHP-UHFFFAOYSA-N 0.000 claims 1
- MZALEEOEVCTDJA-UHFFFAOYSA-N 5-chlorothiophene-2-carbonitrile Chemical compound ClC1=CC=C(C#N)S1 MZALEEOEVCTDJA-UHFFFAOYSA-N 0.000 claims 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims 1
- 125000003545 alkoxy group Chemical group 0.000 claims 1
- 239000012296 anti-solvent Substances 0.000 claims 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims 1
- 229910052794 bromium Inorganic materials 0.000 claims 1
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 claims 1
- 229910052801 chlorine Inorganic materials 0.000 claims 1
- 239000000460 chlorine Substances 0.000 claims 1
- 239000012351 deprotecting agent Substances 0.000 claims 1
- 230000008030 elimination Effects 0.000 claims 1
- 238000003379 elimination reaction Methods 0.000 claims 1
- 150000002148 esters Chemical class 0.000 claims 1
- 229910052731 fluorine Inorganic materials 0.000 claims 1
- 239000011737 fluorine Substances 0.000 claims 1
- 235000019253 formic acid Nutrition 0.000 claims 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims 1
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 claims 1
- 229910052740 iodine Inorganic materials 0.000 claims 1
- 239000011630 iodine Substances 0.000 claims 1
- 229940098779 methanesulfonic acid Drugs 0.000 claims 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims 1
- 229910000027 potassium carbonate Inorganic materials 0.000 claims 1
- 150000003141 primary amines Chemical class 0.000 claims 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims 1
- 238000007363 ring formation reaction Methods 0.000 claims 1
- 125000000467 secondary amino group Chemical class [H]N([*:1])[*:2] 0.000 claims 1
- 239000007787 solid Substances 0.000 claims 1
- 125000005415 substituted alkoxy group Chemical group 0.000 claims 1
- 150000003536 tetrazoles Chemical group 0.000 claims 1
- 150000003852 triazoles Chemical group 0.000 claims 1
- 125000004951 trihalomethoxy group Chemical group 0.000 claims 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
- C07D265/28—1,4-Oxazines; Hydrogenated 1,4-oxazines
- C07D265/30—1,4-Oxazines; Hydrogenated 1,4-oxazines not condensed with other rings
- C07D265/32—1,4-Oxazines; Hydrogenated 1,4-oxazines not condensed with other rings with oxygen atoms directly attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
Claims (10)
1. Spoj, naznačen time, da je formula (A):
[image]
2. Postupak za pripravu rivaroksabana uporabom spoja formule (A), kako je u patentnom zahtjevu 1, naznačen time, da sadrži:
(a) tretiranje, 4-(4-aminofenil)morfolin-3-ona formule (II) s 2-[(2S)-oksiran-2-ilmetil]-1H-izoindol-1,3(2H)-diona formule (III) u prikladnom otapalu kako bi se dobio 2-[(2R)-2-hidroksi-3-{[4-(3- oksomorfolin-4-il) fenil]amino (propil]-1H-izoindol-1,3(2H)-dion formule (IV);
[image]
(b) reagiranje spoja formule (IV) s di-1H-imidazol-1-ilmetanonom formule (V);
[image]
u prikladnom otapalu u nazočnosti baze kako bi se dobio spoj formule (VI);
[image]
(c) uklanjanja skupine ptalamida iz spoja formule (VI) u prikladnom otapalu korištenjem prikladnog sredstva za skidanje zaštite kako bi se dobio spoj formule (VII), kao slobodna baza, koja se dalje tretira s kiselinom kako bi se dobila kisela adicijska sol spoja formule (VII);
[image]
A je kisela adicijska sol
(d) tretiranje spoja formule (VII) s kiselinom u prikladnom otapalu(otapalima) kako bi se dobio novi intermedijer formule (A), N-({(5S)-2-okso-3-[4-(3-oksomorfolin-4-il)fenil]-1,3-oksazolidin-5-il}metil)formamid;
[image]
(c) tretiranja kisele adicijske soli spoja formule (VII) s bazom u prikladnom otapalu(otapalima) kako bi se dobila baza spoja formule (VII) koja se dalje tretira s kiselinom u prikladnom otapalu kako bi se dobio novi intermedijer formule (A),N-({(5S)-2-okso-3-[4-(3-oksomorfolin-4-il)fenil]-1,3-oksazolidin-5-il]metil)formamid;
[image]
A je kisela adicijska sol;
(f) tretiranja spoja formule (A) sa spojem formule (VIII) ili 5-klorotiofen-2-karbonitrilom u prikladnim otapalima odabranim od metilen diklorida, acetona, toluena i ili njihov smjesa u nazočnosti baze kako bi se dobio spoj formule (B),
[image]
pri čemu;
Y je sulfoniloksi, imidazol, triazol, tetrazol, alkoksi, supstituirani alkoksi, tri-halometoksi, N-hidroskisukcinamid,
hidroksi, esteri, primarni amin, sekundarni amin p-nitrofenol, N-hidroksitalamid, N-hidroksibenzotriazol, klor, fluor, brom i jod.
(g) spoj formule (B) dobiveno u koraku (c) se spaja s metanolom i filtrira, dobivena krutina se pere metanolom i suši kako bi se dobio pročišćeni spoj formule (B).
(h) tretiranja spoja formule (B) s kiselinom u prikladnom otapalu tako da aledhidna skupina napusti spoj formule (B) kako bi se dobio rivaroksaban formule (1).
[image]
3. Postupak iz patentnog zahtjeva 2, naznačen time, da se korak (a) izvodi u prikladnim otapalima koji su neovisno odabrani od izopropil alkohola i vode ili smjese istih.
4. Postupak iz patentnog zahtjeva 2, naznačen time, da se cikliranje u koraku (b) izvodi u metilen dikloridu s kalijevim karbonatom kao bazom.
5. Postupak iz patentnog zahtjeva 2, naznačen time, da se eliminacija skupine ptalamida u koraku (c) izvodi u metanolu s metilaminom kao bazom kako bi se dobila slobodna baza spoja formule (VII).
6. Postupak iz patentnog zahtjeva 2, naznačen time, daje spoj formule (VII), dobiven u koraku (c), tretiran s klorovodičnom kiselinom kako bi se dobila klorovodična sol spoja formule (VII).
7. Postupak iz patentnog zahtjeva 2, naznačen time, da se u koraku (d), treatira slobodna baza spoja formule (VII) s mravljom kiselinom u prikladnom otapalu (s) koji je odabran od metilen diklorida, etilen diklorida, etera i toluena ili smjesa istih, ali je poželjno s toluenom.
8. Postupak iz patentnog zahtjeva 2, naznačen time, da se u koraku (c), kisela adicijska sol spoja formule (VII) tretira s bazom kako bi se dobila slobodna baza spoja formule (VII), a sljedeći korak se izvodi sukladno patentnom zahtjevu 6.
9. Postupak iz patentnog zahtjeva 2, naznačen time, da se napuštanje aldehidne skupine u koraku (f) izvodi u kiselini koja je odabrana od metan sulfonske kiseline, klorovodične kiseline i sumporne kiseline ili smjesi istih.
10. Postupak iz patentnog zahtjeva 2, naznačen time, da u korak (h), rivaroksaban se istaloži dodavanjem metanola kao protuotapala.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IN3358MU2012 | 2012-12-26 | ||
| PCT/IN2013/000799 WO2014102820A2 (en) | 2012-12-26 | 2013-12-24 | Rivaroxaban intermediate and preparation thereof |
| EP13866539.3A EP2895176B1 (en) | 2012-12-26 | 2013-12-24 | Rivaroxaban intermediate and preparation thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| HRP20161588T1 true HRP20161588T1 (hr) | 2017-01-13 |
Family
ID=51022156
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| HRP20161588TT HRP20161588T1 (hr) | 2012-12-26 | 2016-11-29 | Intermedijer rivaroksabana i njegova priprava |
Country Status (9)
| Country | Link |
|---|---|
| US (1) | US9394292B2 (hr) |
| EP (1) | EP2895176B1 (hr) |
| DK (1) | DK2895176T3 (hr) |
| ES (1) | ES2610020T3 (hr) |
| HR (1) | HRP20161588T1 (hr) |
| HU (1) | HUE032850T2 (hr) |
| PL (1) | PL2895176T3 (hr) |
| PT (1) | PT2895176T (hr) |
| WO (1) | WO2014102820A2 (hr) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2014102822A2 (en) * | 2012-12-26 | 2014-07-03 | Wanbury Ltd. | Aldehyde derivative of substitute oxazolidinones |
| CN104098558B (zh) * | 2014-07-22 | 2016-07-06 | 常州市第四制药厂有限公司 | 酰胺类化合物及其制备方法 |
Family Cites Families (16)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE19962924A1 (de) | 1999-12-24 | 2001-07-05 | Bayer Ag | Substituierte Oxazolidinone und ihre Verwendung |
| DE10300111A1 (de) | 2003-01-07 | 2004-07-15 | Bayer Healthcare Ag | Verfahren zur Herstellung von 5-Chlor-N-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)-phenyl]-1,3-oxazolidin-5-yl}-methyl)-2-thiophencarboxamid |
| DE102004002044A1 (de) | 2004-01-15 | 2005-08-04 | Bayer Healthcare Ag | Herstellverfahren |
| DE102005045518A1 (de) | 2005-09-23 | 2007-03-29 | Bayer Healthcare Ag | 2-Aminoethoxyessigsäure-Derivate und ihre Verwendung |
| NZ567092A (en) | 2005-10-04 | 2011-05-27 | Bayer Schering Pharma Ag | Novel polymorphous form and the amorphous form of 5-chloro-N-({ (5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)-phenyl]-1,3-oxazolidine-5-yl}-methyl)-2-thiophene carboxamide |
| DE102006007146A1 (de) | 2006-02-16 | 2007-08-23 | Bayer Healthcare Ag | Aminoacyl-Prodrugs |
| JP5389028B2 (ja) | 2007-08-14 | 2014-01-15 | コンサート ファーマシューティカルズ インコーポレイテッド | 置換オキサゾリジノン誘導体 |
| US7816355B1 (en) | 2009-04-28 | 2010-10-19 | Apotex Pharmachem Inc | Processes for the preparation of rivaroxaban and intermediates thereof |
| SI2459555T1 (sl) | 2009-07-31 | 2022-03-31 | Krka, D.D., Novo Mesto | Postopek kristalizacije rivaroksabana |
| EP2521723A1 (en) * | 2010-01-04 | 2012-11-14 | Enantia, S.L. | Process for the preparation of rivaroxaban and intermediates thereof |
| EP2354128A1 (en) | 2010-02-10 | 2011-08-10 | Sandoz Ag | Method for the preparation of rivaroxaban |
| EP2697209B1 (en) * | 2011-04-11 | 2015-09-23 | Sandoz AG | Method for the preparation of substituted oxazolidinones |
| MD4557C1 (ro) * | 2011-05-06 | 2018-10-31 | Egis Gyogysszegyar Nyilvanosan Mukodo Reszvenytarsasag | Procedeu de obţinere a rivaroxabanului şi un compus intermediar utilizat în acest procedeu |
| ES2395304B1 (es) | 2011-05-20 | 2014-01-16 | Interquim, S.A. | Procedimiento de obtención de una tiofen-2-carboxamida. |
| CN103288814B (zh) * | 2012-02-24 | 2016-07-06 | 国药集团国瑞药业有限公司 | 一种利伐沙班中间体的制备方法 |
| WO2014102822A2 (en) * | 2012-12-26 | 2014-07-03 | Wanbury Ltd. | Aldehyde derivative of substitute oxazolidinones |
-
2013
- 2013-12-24 DK DK13866539.3T patent/DK2895176T3/en active
- 2013-12-24 WO PCT/IN2013/000799 patent/WO2014102820A2/en active Application Filing
- 2013-12-24 EP EP13866539.3A patent/EP2895176B1/en not_active Not-in-force
- 2013-12-24 PT PT13866539T patent/PT2895176T/pt unknown
- 2013-12-24 HU HUE13866539A patent/HUE032850T2/en unknown
- 2013-12-24 US US14/436,035 patent/US9394292B2/en not_active Expired - Fee Related
- 2013-12-24 PL PL13866539T patent/PL2895176T3/pl unknown
- 2013-12-24 ES ES13866539.3T patent/ES2610020T3/es active Active
-
2016
- 2016-11-29 HR HRP20161588TT patent/HRP20161588T1/hr unknown
Also Published As
| Publication number | Publication date |
|---|---|
| US9394292B2 (en) | 2016-07-19 |
| PL2895176T3 (pl) | 2017-05-31 |
| WO2014102820A3 (en) | 2015-02-19 |
| EP2895176A4 (en) | 2015-09-02 |
| HUE032850T2 (en) | 2017-11-28 |
| DK2895176T3 (en) | 2017-01-30 |
| US20150299175A1 (en) | 2015-10-22 |
| EP2895176A2 (en) | 2015-07-22 |
| ES2610020T3 (es) | 2017-04-25 |
| EP2895176B1 (en) | 2016-10-19 |
| WO2014102820A2 (en) | 2014-07-03 |
| PT2895176T (pt) | 2017-01-27 |
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