WO2005068456A1 - Herstellverfahren - Google Patents
Herstellverfahren Download PDFInfo
- Publication number
- WO2005068456A1 WO2005068456A1 PCT/EP2004/014870 EP2004014870W WO2005068456A1 WO 2005068456 A1 WO2005068456 A1 WO 2005068456A1 EP 2004014870 W EP2004014870 W EP 2004014870W WO 2005068456 A1 WO2005068456 A1 WO 2005068456A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- reaction
- oxo
- phenyl
- solvent
- carried out
- Prior art date
Links
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
- C07D413/14—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
-
- 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
- C07D413/12—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 chain containing hetero atoms as chain links
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
- A61K31/553—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having at least one nitrogen and one oxygen as ring hetero atoms, e.g. loxapine, staurosporine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
Definitions
- the present invention relates to a process for the preparation of 5-chloro-N - ( ⁇ (5S) -2-oxo-3- [4 ⁇ (3-oxo-4-morpholinyl) -phenyl] -1,3-oxazolidine-5 -yl ⁇ -methyl) -2-thiophenecarboxamide starting from 2 - [(2S) -2-oxiranylmethyl] -1H-isoindole-1,3, (2H) -dione, 4- (4-amino-phenyl) -3-orpholinone and 5 -Chlorthiophen-2-carbonyl chloride.
- the compound of formula (I) acts as an inhibitor of blood sclerosing factor Xa and may be used as an agent for the prophylaxis and / or treatment of thromboembolic disorders, especially myocardial infarction, angina pectoris (including unstable angina), reocclusions and restenosis after angioplasty or aortocoronary bypass, stroke, transitory ischemic attacks, peripheral arterial occlusive diseases, pulmonary embolisms or deep venous thrombosis.
- myocardial infarction especially myocardial infarction, angina pectoris (including unstable angina), reocclusions and restenosis after angioplasty or aortocoronary bypass, stroke, transitory ischemic attacks, peripheral arterial occlusive diseases, pulmonary embolisms or deep venous thrombosis.
- angina pectoris including unstable angina
- WO-A 01/47919 is also a method for the preparation of the compound of formula (I) in the gram range, starting from the same starting compounds 2 - [(2S) -2-oxiranylmethyl] -1H-isoindole-1, 3 ( 2H) -dione (H), 4- (4-aminophenyl) -3-morpholinone (IH) and 5-chlorothiophene-2-carbonyl chloride (IV):
- (IX) is converted into 5-chlorothiophene-2-carboxylic acid - ((S) -3-bromo-2-hydroxy-propyl) -amide (X), which is then treated with 4- (4-aminophenyl) -3-morpholinone (ÜT) to 5-chlorothiophene-2-carboxylic acid - ⁇ (R) -2-hydroxy-3- [4- (3-oxomorpholm-4-yl) -phenylamino] -propyl ⁇ -amide (XI) is implemented.
- the compound of the formula (I) can also be prepared in relatively high amounts in good yield and purity.
- the present invention thus provides a process for preparing 5-chloro-N- ( ⁇ (5S) -2-oxo-3- [4- (3-oxo-4-morpholinyl) -phenyl] -1,3-oxazolidine -5-yl ⁇ -methyl) -2-thiophenecarboxamide of the formula (I) by reacting 4- ⁇ 4 - [(5S) -5- (aminomethyl) -2-oxo-1,3-oxazolidin-3-one yl] phenyl ⁇ morpholin-3-one (V1T) hydrochloride with 5-chlorothiophene-2-carbonyl chloride (TV), characterized in that the reaction in a solvent selected from the group consisting of ether, alcohol, ketone and water or in a Mixture thereof is carried out using an inorganic base.
- a solvent selected from the group consisting of ether, alcohol, ketone and water or in a Mixture thereof is carried out using an inorganic
- Suitable solvents are: ethers, such as tetrahydrofuran, dioxane, diisopropyl ether or methyl tert-butyl ether; Alcohols such as methanol, ethanol, isopropanol, n-propanol, n-butanol, isobutanol, sec-butanol or tert-butanol; Ketones such as methyl ethyl ketone, methyl isobutyl ketone or acetone or water or mixtures of two or more of the listed solvents.
- ethers such as tetrahydrofuran, dioxane, diisopropyl ether or methyl tert-butyl ether
- Alcohols such as methanol, ethanol, isopropanol, n-propanol, n-butanol, isobutanol, sec-butanol or tert-butanol
- Particularly preferred solvents are ketones or mixtures of ketones with water, in particular acetone or preferably mixtures of acetone with water.
- Suitable inorganic bases include, by way of example and by way of example: alkali (e.g., sodium and potassium) and alkaline earth (e.g., calcium and magnesium) hydroxides, alkali and alkaline earth carbonates, and alkali and alkaline earth bicarbonates.
- alkali e.g., sodium and potassium
- alkaline earth e.g., calcium and magnesium
- Particularly preferred inorganic bases are sodium hydroxide, sodium carbonate or sodium bicarbonate, especially sodium carbonate.
- the acetone water ratio is variable over a wide range, preferably 0.5 to 1.5 (v / v), especially 0.9 to 1.1 (v / v).
- an aqueous sodium carbonate solution is preferably initially charged, in which first acetone and then aminomethyloxazolidinone (VH) hydrochloride and then chlorothiophenecarbonyl chloride (TV) are introduced.
- VH aminomethyloxazolidinone
- TV chlorothiophenecarbonyl chloride
- the addition of the reactants is preferably carried out at a temperature between 0 and 20 ° C, in particular between 10 and 15 ° C.
- the reaction mixture is then stirred at a temperature between 40 and 55 ° C, preferably at about 50 ° C.
- the product can then be isolated in a simple manner by filtration.
- the crude product of the compound of the formula (I) obtained by the above-described filtration is recrystallized from acetic acid in a subsequent step for further purification.
- the preparation of the hydroxyamine (V) is carried out, as already disclosed in WO-A 01/47919, by reacting (S) -epoxyphthalimide (H) with anilinomorpholinone (HJ) in aqueous ethanol as solvent at a reaction temperature of 60 ° C.
- the ethanol / water ratio (v / v) but instead of 9: 1 erf ⁇ ndungshunt is 1: 1 to 1: 3, preferably 1: 2 (v / v) and it is no longer necessary to top up the educt (H).
- the reaction mixture between 24 and 48 hours, preferably about 36 hours, stirred at a temperature between 55 and 65 ° C.
- reaction mixture is treated with seed crystals of the reaction product (V) so that the reaction product begins to crystallize out.
- the reaction mixture is heated to reflux at the end of the reaction time, wherein the suspension is maintained, and then cooled again to the reaction temperature between 55 and 65 ° C.
- This heating to reflux is optionally repeated, preferably is heated a total of twice.
- anilinomorpholinone HI
- WO-A 01/47919 pages 55 to 57 or in DE 10342570.5.
- the individual stages of the process according to the invention can be carried out at normal, elevated or reduced pressure (for example from 0.5 to 5 bar). Unless otherwise stated, it is generally carried out at atmospheric pressure.
- reaction mixture is then heated to 50 ° C, treated with 2700 ml of acetone and stirred at 50 to 53 ° C for a further 30 minutes. After cooling to 26 ° C, the precipitated reaction product is filtered off with suction and washed with water and acetone.
- the determined residual moisture content is 24.3%, which gives a calculated dry weight of 1505 g or 98.7% d. Th. Corresponds.
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Heart & Thoracic Surgery (AREA)
- Cardiology (AREA)
- Diabetes (AREA)
- Urology & Nephrology (AREA)
- Vascular Medicine (AREA)
- Hematology (AREA)
- Epidemiology (AREA)
- Plural Heterocyclic Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
Description
Claims
Priority Applications (17)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DK04804455.6T DK1720866T3 (da) | 2004-01-15 | 2004-12-31 | Fremgangsmåde |
KR1020067014193A KR101206598B1 (ko) | 2004-01-15 | 2004-12-31 | 제조 방법 |
CA2553237A CA2553237C (en) | 2004-01-15 | 2004-12-31 | Production method |
NZ548506A NZ548506A (en) | 2004-01-15 | 2004-12-31 | Process for preparing 5-chloro-N-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)-phenyl]-1,3-oxazolidin-5-yl}methyl)-2-thiophenecarboxamide |
CN200480040552XA CN1906191B (zh) | 2004-01-15 | 2004-12-31 | 制备方法 |
PL04804455T PL1720866T3 (pl) | 2004-01-15 | 2004-12-31 | Sposób wytwarzania |
SI200431764T SI1720866T1 (sl) | 2004-01-15 | 2004-12-31 | Postopek izdelave |
KR1020127018712A KR20130004257A (ko) | 2004-01-15 | 2004-12-31 | 제조 방법 |
AT04804455T ATE518856T1 (de) | 2004-01-15 | 2004-12-31 | Herstellverfahren |
BRPI0418405A BRPI0418405B8 (pt) | 2004-01-15 | 2004-12-31 | processo para preparação de 5-cloro- n -({(5 s )-2-oxo-3-[4-(3-oxo-4-morfolinil)-fenil]-1,3-oxazolidin-5-il}-metil)-2-tiofenocarboxamida |
AU2004313694A AU2004313694B2 (en) | 2004-01-15 | 2004-12-31 | Production method |
JP2006548182A JP5311742B2 (ja) | 2004-01-15 | 2004-12-31 | 製造方法 |
EP04804455A EP1720866B1 (de) | 2004-01-15 | 2004-12-31 | Herstellverfahren |
IL176767A IL176767A (en) | 2004-01-15 | 2006-07-10 | Process for the production of ribaroxaban and the use of ribaroxaban produced by its preparation for the preparation of a drug for the treatment / prevention of thermo-embolic disorders |
NO20063677A NO335553B1 (no) | 2004-01-15 | 2006-08-15 | Fremgangsmåte for fremstilling av 5-klor-N-({(5S)-2-okso-3-[4-(3-okso-4-morfolinyl)fenyl]-1,3-oksazolidin-5-yl}metyl)-2-tiofenkarboksamid |
HK07107855.2A HK1103722A1 (en) | 2004-01-15 | 2007-07-20 | Production method |
HR20110796T HRP20110796T1 (hr) | 2004-01-15 | 2011-11-02 | Postupak dobivanja |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE102004002044.2 | 2004-01-15 | ||
DE102004002044A DE102004002044A1 (de) | 2004-01-15 | 2004-01-15 | Herstellverfahren |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2005068456A1 true WO2005068456A1 (de) | 2005-07-28 |
Family
ID=34716548
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/EP2004/014870 WO2005068456A1 (de) | 2004-01-15 | 2004-12-31 | Herstellverfahren |
Country Status (33)
Country | Link |
---|---|
US (1) | US7351823B2 (de) |
EP (1) | EP1720866B1 (de) |
JP (2) | JP5311742B2 (de) |
KR (1) | KR20130004257A (de) |
CN (1) | CN1906191B (de) |
AR (1) | AR047389A1 (de) |
AT (1) | ATE518856T1 (de) |
AU (1) | AU2004313694B2 (de) |
BR (1) | BRPI0418405B8 (de) |
CA (1) | CA2553237C (de) |
CY (1) | CY1112565T1 (de) |
DE (1) | DE102004002044A1 (de) |
DK (1) | DK1720866T3 (de) |
EC (1) | ECSP066703A (de) |
ES (1) | ES2369140T3 (de) |
GT (1) | GT200400277A (de) |
HK (1) | HK1103722A1 (de) |
HN (1) | HN2005000016A (de) |
HR (1) | HRP20110796T1 (de) |
IL (1) | IL176767A (de) |
MA (1) | MA28290A1 (de) |
MY (1) | MY138944A (de) |
NO (1) | NO335553B1 (de) |
NZ (1) | NZ548506A (de) |
PE (1) | PE20050763A1 (de) |
PL (1) | PL1720866T3 (de) |
PT (1) | PT1720866E (de) |
RU (1) | RU2383540C2 (de) |
SI (1) | SI1720866T1 (de) |
TW (1) | TWI340137B (de) |
UY (1) | UY28718A1 (de) |
WO (1) | WO2005068456A1 (de) |
ZA (1) | ZA200605747B (de) |
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WO2007039132A1 (de) * | 2005-10-04 | 2007-04-12 | Bayer Healthcare Ag | Neue polymorphe form und die amorphe form von 5-chlor-n- ( { ( 5s ) -2-0x0-3-[4-( 3-oxo-4-morpholinyl) - phenyl] -1,3-oxazolidin-5-yl} -methyl) -2- thiophencarboxamid |
EP1928867A1 (de) | 2005-09-23 | 2008-06-11 | Bayer HealthCare AG | 2-aminoethoxyessigsäure-derivate und ihre verwendung zur behandlung thromboembolischer erkrankungen |
WO2009018807A1 (de) * | 2007-08-06 | 2009-02-12 | Schebo Biotech Ag | Oxazolidinone als faktor xa- inhibitoren, verfahren zu ihrer herstellung und ihre verwendung in der therapie |
WO2009149851A1 (de) * | 2008-06-12 | 2009-12-17 | Bayer Schering Pharma Aktiengesellschaft | Neue cokristall-verbindung von rivaroxaban und malonsäure |
US7767702B2 (en) | 2001-06-20 | 2010-08-03 | Bayer Schering Pharma Aktiengesellschaft | Substituted oxazolidinones for combinational therapy |
WO2011012321A1 (en) | 2009-07-31 | 2011-02-03 | Krka, D.D., Novo Mesto | Processes for crystallization of rivaroxaban |
EP2292616A1 (de) * | 2005-10-04 | 2011-03-09 | Bayer Schering Pharma Aktiengesellschaft | Neue polymorphe Form und die amorphe Form von 5-Chlor-N-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)-phenyl]-1,3-oxazolidin-5-yl}-methyl)-2-thiophencarboxamid |
EP2382209A1 (de) * | 2008-12-31 | 2011-11-02 | Apotex Pharmachem Inc. | Polymorphe form von 5-chlor-n-{ý(5s)-2-oxo-3-ý4-(3-oxomorpholin-4-yl)phenyl¨oxazolidin-5-yl¨methyl} thiophen-2-carbonsäureamid |
EP2388260A1 (de) | 2010-05-21 | 2011-11-23 | Archimica GmbH | Herstellungsverfahren für einen Inhibitor eines Blutgerinnungsfaktors |
EP2404920A1 (de) | 2010-07-06 | 2012-01-11 | Sandoz AG | Kristalline Form von Rivaroxaban-Dihydrat |
US8106192B2 (en) | 2003-01-07 | 2012-01-31 | Bayer Pharma Aktiengesellschaft | Method for producing 5-chloro-N-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-1,3-oxazolidin-5-yl}methyl)-2-thiophenecarboxamide |
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