HRP20200336T1 - Priprava gadobutrola visoke čistoće - Google Patents
Priprava gadobutrola visoke čistoće Download PDFInfo
- Publication number
- HRP20200336T1 HRP20200336T1 HRP20200336TT HRP20200336T HRP20200336T1 HR P20200336 T1 HRP20200336 T1 HR P20200336T1 HR P20200336T T HRP20200336T T HR P20200336TT HR P20200336 T HRP20200336 T HR P20200336T HR P20200336 T1 HRP20200336 T1 HR P20200336T1
- Authority
- HR
- Croatia
- Prior art keywords
- water
- solution
- ethanol
- water content
- tetraazacyclododecane
- Prior art date
Links
- ZPDFIIGFYAHNSK-CTHHTMFSSA-K 2-[4,10-bis(carboxylatomethyl)-7-[(2r,3s)-1,3,4-trihydroxybutan-2-yl]-1,4,7,10-tetrazacyclododec-1-yl]acetate;gadolinium(3+) Chemical compound [Gd+3].OC[C@@H](O)[C@@H](CO)N1CCN(CC([O-])=O)CCN(CC([O-])=O)CCN(CC([O-])=O)CC1 ZPDFIIGFYAHNSK-CTHHTMFSSA-K 0.000 title claims 4
- 229960003411 gadobutrol Drugs 0.000 title claims 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims 11
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims 10
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims 4
- 239000012043 crude product Substances 0.000 claims 4
- 150000002500 ions Chemical class 0.000 claims 4
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 claims 4
- 238000000034 method Methods 0.000 claims 4
- 238000010992 reflux Methods 0.000 claims 4
- 239000003446 ligand Substances 0.000 claims 3
- QBPPRVHXOZRESW-UHFFFAOYSA-N 1,4,7,10-tetraazacyclododecane Chemical compound C1CNCCNCCNCCN1 QBPPRVHXOZRESW-UHFFFAOYSA-N 0.000 claims 2
- JZNZSKXIEDHOBD-UHFFFAOYSA-N 2-[4,10-bis(carboxymethyl)-7-(1,3,4-trihydroxybutan-2-yl)-1,4,7,10-tetrazacyclododec-1-yl]acetic acid Chemical compound OCC(O)C(CO)N1CCN(CC(O)=O)CCN(CC(O)=O)CCN(CC(O)=O)CC1 JZNZSKXIEDHOBD-UHFFFAOYSA-N 0.000 claims 2
- GEKNCWQQNMEIMS-UHFFFAOYSA-N 4,4-dimethyl-3,5,8-trioxabicyclo[5.1.0]octane Chemical compound C1OC(C)(C)OCC2OC21 GEKNCWQQNMEIMS-UHFFFAOYSA-N 0.000 claims 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims 2
- 230000002378 acidificating effect Effects 0.000 claims 2
- 238000009835 boiling Methods 0.000 claims 2
- 238000001816 cooling Methods 0.000 claims 2
- 229940075613 gadolinium oxide Drugs 0.000 claims 2
- 229910001938 gadolinium oxide Inorganic materials 0.000 claims 2
- CMIHHWBVHJVIGI-UHFFFAOYSA-N gadolinium(iii) oxide Chemical compound [O-2].[O-2].[O-2].[Gd+3].[Gd+3] CMIHHWBVHJVIGI-UHFFFAOYSA-N 0.000 claims 2
- 239000000203 mixture Substances 0.000 claims 2
- 239000000047 product Substances 0.000 claims 2
- 150000003839 salts Chemical class 0.000 claims 2
- FDRCDNZGSXJAFP-UHFFFAOYSA-M sodium chloroacetate Chemical compound [Na+].[O-]C(=O)CCl FDRCDNZGSXJAFP-UHFFFAOYSA-M 0.000 claims 2
- 239000007858 starting material Substances 0.000 claims 2
- 238000011146 sterile filtration Methods 0.000 claims 2
- RRBYUSWBLVXTQN-UHFFFAOYSA-N tricyclene Chemical compound C12CC3CC2C1(C)C3(C)C RRBYUSWBLVXTQN-UHFFFAOYSA-N 0.000 claims 2
- RRBYUSWBLVXTQN-VZCHMASFSA-N tricyclene Natural products C([C@@H]12)C3C[C@H]1C2(C)C3(C)C RRBYUSWBLVXTQN-VZCHMASFSA-N 0.000 claims 2
- JZNZSKXIEDHOBD-HUUCEWRRSA-N 2-[4,10-bis(carboxymethyl)-7-[(2r,3s)-1,3,4-trihydroxybutan-2-yl]-1,4,7,10-tetrazacyclododec-1-yl]acetic acid Chemical compound OC[C@@H](O)[C@@H](CO)N1CCN(CC(O)=O)CCN(CC(O)=O)CCN(CC(O)=O)CC1 JZNZSKXIEDHOBD-HUUCEWRRSA-N 0.000 claims 1
- 229910052688 Gadolinium Inorganic materials 0.000 claims 1
- 239000003610 charcoal Substances 0.000 claims 1
- -1 gadolinium (III) ions Chemical class 0.000 claims 1
- UIWYJDYFSGRHKR-UHFFFAOYSA-N gadolinium atom Chemical compound [Gd] UIWYJDYFSGRHKR-UHFFFAOYSA-N 0.000 claims 1
- 238000004128 high performance liquid chromatography Methods 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 claims 1
- 239000002904 solvent Substances 0.000 claims 1
Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/06—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations
- A61K49/08—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by the carrier
- A61K49/10—Organic compounds
- A61K49/101—Organic compounds the carrier being a complex-forming compound able to form MRI-active complexes with paramagnetic metals
- A61K49/106—Organic compounds the carrier being a complex-forming compound able to form MRI-active complexes with paramagnetic metals the complex-forming compound being cyclic, e.g. DOTA
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/06—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations
- A61K49/08—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by the carrier
- A61K49/10—Organic compounds
- A61K49/101—Organic compounds the carrier being a complex-forming compound able to form MRI-active complexes with paramagnetic metals
- A61K49/106—Organic compounds the carrier being a complex-forming compound able to form MRI-active complexes with paramagnetic metals the complex-forming compound being cyclic, e.g. DOTA
- A61K49/108—Organic compounds the carrier being a complex-forming compound able to form MRI-active complexes with paramagnetic metals the complex-forming compound being cyclic, e.g. DOTA the metal complex being Gd-DOTA
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
- C07D257/02—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic System
- C07F5/003—Compounds containing elements of Groups 3 or 13 of the Periodic System without C-Metal linkages
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2123/00—Preparations for testing in vivo
Landscapes
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Radiology & Medical Imaging (AREA)
- Epidemiology (AREA)
- Pharmacology & Pharmacy (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Claims (4)
1. Postupak za proizvodnju gadobutrola visoke čistoće (= kompleks gadolinija N-(1 -hidroksimetil-2,3-dihidroksipropil)-1,4,7-triskarboksimetil-1,4,7,10-tetraazaciklododekana), naznačen time što polazni materijal ciklen (1,4,7,10-tetraazaciklododekan) reagira s 4,4-dimetil-3,5,8-trioksabiciklo[5,1,0]oktanom i litijevim kloridom u izopropanolu na povišenim temperaturama, zatim se destilira u vodi i alkilira s natrijevim monokloracetatom u alkalnom mediju, obrađuje se u klorovodičnim uvjetima, soli se uklanjaju dodavanjem metanola i sirovi ligand reagira s gadolinijevim oksidom u vodi pri povišenim temperaturama, zatim se pH podešava s litijevim hidroksidom na 7,1-7,4, otopina se koncentrira i dodaje se etanol u takvoj količini da se postigne sadržaj vode od 7,0-9,5%, smjesa se zatim zagrijava pod refluksom tijekom najmanje 60 minuta i sirovi proizvod se, nakon hlađenja, izolira i suši pri 46°-48°C, sirovi produkt se zatim otapa u vodi i pročišćava na kaskadi ionskog izmjenjivača, gdje se otopina najprije propušta kroz kiseli, a zatim kroz bazični ionski izmjenjivač, pročišćena otopina, koja ima provodljivost < 20 µS/cm, je zatim koncentrirana, obrađuje se s aktivnim ugljenom, podvrgava se sterilnoj filtraciji, te se odmjerenim dodavanjem etanola, prilagođava na sadržaj vode u rasponu od 10 - 12%, zatim se zagrijava do vrenja pod refluksom i hladi, a produkt se izolira i suši pri 53-55°C.
2. Postupak prema patentnom zahtjevu 1, naznačen time što polazni materijal ciklen (1,4,7,10-tetraazaciklododekan) reagira s 4,4-dimetil-3,5,8-trioksabiciklo[5,1,0]oktanom i LiCl u izopropanolu na povišenim temperaturama, zatim se destilira u vodi i alkilira s natrijevim monokloracetatom u alkalnom mediju i obrađuje se u klorovodičnim uvjetima, soli se uklanjaju dodavanjem metanola i sirovi ligand reagira s gadolinijevim oksidom u vodi pri povišenim temperaturama, zatim se pH podešava s litijevim hidroksidom na 7,1-7,4, otopina se koncentrira i dodaje se etanol u takvoj količini da se postigne sadržaj vode od poželjno 8,5%, smjesa se zatim zagrijava pod refluksom tijekom najmanje 60 minuta i sirovi proizvod se, nakon hlađenja, izolira i suši pri 46°-48°C, sirovi produkt se otapa u vodi i pročišćava na kaskadi ionskog izmjenjivača, gdje se otopina prvo propušta kroz kiseli ionski izmjenjivač, pročišćena otopina, koja ima provodljivost < 20 µS/cm, je koncentrirana, obrađuje se s aktivnim ugljenom, zatim se podvrgava sterilnoj filtraciji, te se odmjerenim dodavanjem etanola u razdoblju od 120 minuta, prilagođava na sadržaj vode u rasponu od 10 - 12%, zatim se zagrijava do vrenja pod refluksom i hladi, a produkt se izolira i suši pri 53-55°C.
3. Postupak prema patentnom zahtjevu 1 ili 2, naznačen time što dobiveni Gadobutrol ima čistoću (prema HPLC) veću od 99,7% koji sadrži manje od 0,01% slobodnih iona gadolinija (III), koji sadrži zaostali sadržaj otapala etanola od manje od 200 ppm i sadrži udio liganda butrola (= N-(1-hidroksimetil-2,3-dihidroksipropil)-1,4,7-triskarboksimetil-1,4,7,10-tetraazaciklododekan) manji od 0,03%.
4. Postupak prema patentnom zahtjevu 3, naznačen time što dobiveni Gadobutrol ima sadržaj vode od 3,0 do 3,5%.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE102011100128 | 2011-04-21 | ||
| EP14172784.2A EP2896405B1 (en) | 2011-04-21 | 2012-04-17 | Preparation of high-purity gadobutrol |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| HRP20200336T1 true HRP20200336T1 (hr) | 2020-06-12 |
Family
ID=46208435
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| HRP20200336TT HRP20200336T1 (hr) | 2011-04-21 | 2020-02-27 | Priprava gadobutrola visoke čistoće |
Country Status (34)
| Country | Link |
|---|---|
| US (2) | US10072027B2 (hr) |
| EP (2) | EP2896405B1 (hr) |
| JP (3) | JP6096757B2 (hr) |
| KR (3) | KR20190079682A (hr) |
| CN (1) | CN103547573B (hr) |
| AR (1) | AR086190A1 (hr) |
| AU (2) | AU2012244791B2 (hr) |
| BR (1) | BR112013027028B1 (hr) |
| CA (1) | CA2833659C (hr) |
| CL (1) | CL2013003045A1 (hr) |
| CO (1) | CO6801752A2 (hr) |
| CU (2) | CU24439B1 (hr) |
| DK (1) | DK2896405T3 (hr) |
| DO (1) | DOP2013000245A (hr) |
| EA (2) | EA026572B1 (hr) |
| EC (1) | ECSP13013010A (hr) |
| ES (1) | ES2780599T3 (hr) |
| GT (1) | GT201300253A (hr) |
| HK (1) | HK1193817A1 (hr) |
| HR (1) | HRP20200336T1 (hr) |
| IL (1) | IL228885A (hr) |
| LT (1) | LT2896405T (hr) |
| MX (1) | MX362133B (hr) |
| MY (1) | MY163709A (hr) |
| NZ (1) | NZ616637A (hr) |
| PE (1) | PE20141325A1 (hr) |
| PL (1) | PL2896405T3 (hr) |
| PT (1) | PT2896405T (hr) |
| RS (1) | RS60001B1 (hr) |
| SG (1) | SG194511A1 (hr) |
| SI (1) | SI2896405T1 (hr) |
| TW (1) | TW201249818A (hr) |
| WO (1) | WO2012143355A1 (hr) |
| ZA (1) | ZA201308706B (hr) |
Families Citing this family (24)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| RS60001B1 (sr) * | 2011-04-21 | 2020-04-30 | Bayer Ip Gmbh | Pripremanje gadobutrola visoke čistoće |
| US10195295B2 (en) * | 2014-02-06 | 2019-02-05 | T2Pharma Gmbh | Process for purifying 1,4,7,10-tetra-azacyclododecane-1,4,7,10-tetraacetic acid |
| KR101693400B1 (ko) * | 2014-09-17 | 2017-01-05 | 에스티팜 주식회사 | 칼코부트롤의 제조방법 |
| KR101646211B1 (ko) * | 2014-11-12 | 2016-08-05 | (주)디아이테크 | 자기공명영상용 조영제의 제조방법 |
| KR101653064B1 (ko) | 2014-12-26 | 2016-09-09 | 에스티팜 주식회사 | 가도부트롤의 제조방법 |
| PL3519394T3 (pl) | 2016-09-27 | 2020-11-30 | Bayer Pharma Aktiengesellschaft | Sposób wytwarzania krystalicznej postaci o modyfikacji a kalkobutrolu |
| CN106543094A (zh) * | 2016-11-04 | 2017-03-29 | 嘉实（湖南）医药科技有限公司 | 高纯度钆布醇的制备方法 |
| EP3544964B1 (en) | 2016-11-28 | 2020-06-17 | Bayer Pharma Aktiengesellschaft | High relaxivity gadolinium chelate compounds for use in magnetic resonance imaging |
| CN109293592A (zh) * | 2017-07-24 | 2019-02-01 | 天津科伦药物研究有限公司 | 一种制备钆布醇的方法 |
| KR101971435B1 (ko) * | 2017-08-29 | 2019-04-24 | 주식회사 엔지켐생명과학 | 가도부트롤 중간체 및 이를 이용한 가도부트롤의 제조 방법 |
| CN108840832A (zh) * | 2018-06-29 | 2018-11-20 | 广州康瑞泰药业有限公司 | 一种钆布醇中间体的制备方法 |
| EP3820853A4 (en) * | 2018-07-10 | 2022-08-17 | Biophore India Pharmaceuticals Pvt. Ltd. | PROCESS FOR THE PREPARATION OF 2,2',2''-( 10-((2R,3S)-1,3,4-TRIHYDROXY BUTAN-2-YL)-1,4,7,10-TETRAAZACYCLODODECAN-1,4 ,7-TRIYL)-TRIACETIC ACID AND THEIR COMPLEXES |
| KR102167614B1 (ko) * | 2018-08-23 | 2020-10-19 | 에스티팜 주식회사 | 가도부트롤의 제조방법 |
| AU2019382881A1 (en) | 2018-11-23 | 2021-05-20 | Bayer Aktiengesellschaft | Formulation of contrast media and process of preparation thereof |
| JP2022513195A (ja) * | 2018-12-12 | 2022-02-07 | メディビーコン，インク． | 持続的腎代替療法における経皮的糸球体濾過量測定の使用 |
| GB201919073D0 (en) * | 2019-12-20 | 2020-02-05 | Ge Healthcare As | Novel manufacturing process |
| CN113087680A (zh) * | 2020-01-08 | 2021-07-09 | 威智医药有限公司 | Dota晶型及其制备方法 |
| CN113105407A (zh) * | 2020-01-13 | 2021-07-13 | 北京北陆药业股份有限公司 | 一种钆布醇新型晶型及其制备方法 |
| KR20210114742A (ko) * | 2020-03-11 | 2021-09-24 | 주식회사 엔지켐생명과학 | 칼테리돌의 제조방법 |
| CN114539178B (zh) * | 2020-11-26 | 2024-03-15 | 江苏恒瑞医药股份有限公司 | 一种钆布醇的纯化方法 |
| CN114573522A (zh) * | 2020-11-30 | 2022-06-03 | 江苏恒瑞医药股份有限公司 | 一种考布曲钙的新晶型及其制备方法 |
| CN112939806B (zh) * | 2021-03-08 | 2023-05-16 | 山东新华制药股份有限公司 | 一种卡比多巴的精制方法 |
| CN113527223B (zh) * | 2021-06-22 | 2023-05-09 | 安徽普利药业有限公司 | 一种钆布醇的精制方法 |
| CN114105897B (zh) * | 2021-07-29 | 2023-04-04 | 安徽普利药业有限公司 | 一种钆特醇的制备方法 |
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| US4957939A (en) | 1981-07-24 | 1990-09-18 | Schering Aktiengesellschaft | Sterile pharmaceutical compositions of gadolinium chelates useful enhancing NMR imaging |
| NL194579C (nl) | 1983-01-21 | 2002-08-05 | Schering Ag | Diagnostisch middel. |
| US4885363A (en) | 1987-04-24 | 1989-12-05 | E. R. Squibb & Sons, Inc. | 1-substituted-1,4,7-triscarboxymethyl-1,4,7,10-tetraazacyclododecane and analogs |
| DE3625417C2 (de) | 1986-07-28 | 1998-10-08 | Schering Ag | Tetraazacyclododecan-Derivate |
| DE3640708C2 (de) | 1986-11-28 | 1995-05-18 | Schering Ag | Verbesserte metallhaltige Pharmazeutika |
| DE4009119A1 (de) | 1990-03-19 | 1991-09-26 | Schering Ag | 1,4,7,10-tetraazacyclododecan-butyltriole, verfahren zu ihrer herstellung und diese enthaltende pharmazeutische mittel |
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| DE4035760A1 (de) | 1990-11-08 | 1992-05-14 | Schering Ag | Mono-n-substituierte 1,4,7,10-tetraazacyclododecan-derivate, verfahren zu ihrer herstellung und diese enthaltende pharmazeutische mittel |
| US5410043A (en) | 1991-12-06 | 1995-04-25 | Schering Aktiengesellschaft | Process for the production of mono-N-substituted tetraaza macrocycles |
| DE4237943C2 (de) | 1992-11-06 | 1997-10-23 | Schering Ag | Verfahren zur Herstellung von Metallkomplexen der N-beta-Hydroxyalkyl-tri-N-carboxyalkyl-1,4,7,10-tetraazacyclododecan- und N-beta-Hydroxyalkyl-tri-N-carboxyalkyl-1,4,8,11-tetraazacyclotetradecan-Derivate |
| DE4140779A1 (de) | 1991-12-06 | 1993-06-09 | Schering Ag Berlin Und Bergkamen, 1000 Berlin, De | Verfahren zur herstellung von mono-n-substituierten tetraazamakrocyclen |
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| DE19724186C2 (de) | 1997-06-02 | 2002-07-18 | Schering Ag | Verfahren zur Mono- und 1,7-Bis-N-ß-Hydroxyalkylierung von Cyclen und die entsprechenden N-ß-Hydroxyalkyl-1,4,7,10-tetraazacyclododecan-Li-Salz-Komplexe |
| IT1292127B1 (it) | 1997-06-11 | 1999-01-25 | Bracco Spa | Processo per la dissalazione di sostanze instabili a ph acidi |
| IT1292128B1 (it) * | 1997-06-11 | 1999-01-25 | Bracco Spa | Processo per la preparazione di chelanti macrociclici e loro chelati con ioni metallici paramagnetici |
| DE69903603T2 (de) | 1998-09-08 | 2003-08-14 | Kba Giori Sa | Sicherheitsdruckmaschine für Wertpapiere |
| DE10064467C2 (de) * | 2000-12-15 | 2002-10-31 | Schering Ag | Lithium-Komplexe von N-(1-Hydroxymethyl-2,3-dihydroxypropyl)-1,4,7-triscarboxymethyl-1,4,7,10-tetraazacyclododecan, deren Herstellung und Verwendung |
| DE102009053171B4 (de) | 2009-11-04 | 2011-07-21 | Bayer Schering Pharma Aktiengesellschaft, 13353 | Verfahren zur Herstellung des Calcium-Komplexes von Dihydroxy-hydroxy-methylpropyl-tetraazacyclododecan-triessigsäure (Calcobutrol) |
| WO2011054480A1 (de) | 2009-11-09 | 2011-05-12 | Bayer Schering Pharma Aktiengesellschaft | Gadobutrolherstellung mittels keramischer membran |
| DE102010013833A1 (de) | 2010-03-29 | 2011-09-29 | Bayer Schering Pharma Aktiengesellschaft | Herstellung von Gadobutrol mittels Dimethylformamiddimethylacetal |
| DE102010023105A1 (de) | 2010-06-04 | 2011-12-08 | Bayer Schering Pharma Aktiengesellschaft | Gadobutrolherstellung im Eintopfverfahren mittels DMF-acetal und N-Methylimidazol |
| RS60001B1 (sr) * | 2011-04-21 | 2020-04-30 | Bayer Ip Gmbh | Pripremanje gadobutrola visoke čistoće |
| KR101653064B1 (ko) | 2014-12-26 | 2016-09-09 | 에스티팜 주식회사 | 가도부트롤의 제조방법 |
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