CN102933562A - 通过dmf缩醛和n-甲基咪唑在一锅法中制备钆布醇 - Google Patents
通过dmf缩醛和n-甲基咪唑在一锅法中制备钆布醇 Download PDFInfo
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- MCTWTZJPVLRJOU-UHFFFAOYSA-N 1-methyl-1H-imidazole Chemical compound CN1C=CN=C1 MCTWTZJPVLRJOU-UHFFFAOYSA-N 0.000 title claims abstract description 10
- 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 abstract description 10
- 229960003411 gadobutrol Drugs 0.000 title abstract description 10
- 238000002360 preparation method Methods 0.000 title abstract description 6
- DHKHKXVYLBGOIT-UHFFFAOYSA-N acetaldehyde Diethyl Acetal Natural products CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 title abstract description 5
- 238000005580 one pot reaction Methods 0.000 title abstract description 4
- 125000002777 acetyl group Chemical class [H]C([H])([H])C(*)=O 0.000 title 1
- 238000000034 method Methods 0.000 claims abstract description 19
- 229910052688 Gadolinium Inorganic materials 0.000 claims abstract description 13
- UIWYJDYFSGRHKR-UHFFFAOYSA-N gadolinium atom Chemical compound [Gd] UIWYJDYFSGRHKR-UHFFFAOYSA-N 0.000 claims abstract description 13
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 39
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 30
- 235000019441 ethanol Nutrition 0.000 claims description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 13
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 12
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 claims description 10
- 239000004744 fabric Substances 0.000 claims description 9
- 125000003158 alcohol group Chemical group 0.000 claims description 8
- 238000006243 chemical reaction Methods 0.000 claims description 7
- FOCAUTSVDIKZOP-UHFFFAOYSA-N chloroacetic acid Chemical compound OC(=O)CCl FOCAUTSVDIKZOP-UHFFFAOYSA-N 0.000 claims description 7
- 230000000536 complexating effect Effects 0.000 claims description 6
- 238000004821 distillation Methods 0.000 claims description 6
- CMIHHWBVHJVIGI-UHFFFAOYSA-N gadolinium(iii) oxide Chemical compound [O-2].[O-2].[O-2].[Gd+3].[Gd+3] CMIHHWBVHJVIGI-UHFFFAOYSA-N 0.000 claims description 6
- WBJINCZRORDGAQ-UHFFFAOYSA-N ethyl formate Chemical compound CCOC=O WBJINCZRORDGAQ-UHFFFAOYSA-N 0.000 claims description 5
- 229910000042 hydrogen bromide Inorganic materials 0.000 claims description 5
- CFHIDWOYWUOIHU-UHFFFAOYSA-N oxomethyl Chemical compound O=[CH] CFHIDWOYWUOIHU-UHFFFAOYSA-N 0.000 claims description 5
- 150000000921 Gadolinium Chemical class 0.000 claims description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 3
- ZSXGLVDWWRXATF-UHFFFAOYSA-N N,N-dimethylformamide dimethyl acetal Chemical compound COC(OC)N(C)C ZSXGLVDWWRXATF-UHFFFAOYSA-N 0.000 claims description 3
- 229910003317 GdCl3 Inorganic materials 0.000 claims description 2
- MEANOSLIBWSCIT-UHFFFAOYSA-K gadolinium trichloride Chemical compound Cl[Gd](Cl)Cl MEANOSLIBWSCIT-UHFFFAOYSA-K 0.000 claims description 2
- RQXZRSYWGRRGCD-UHFFFAOYSA-H gadolinium(3+);tricarbonate Chemical compound [Gd+3].[Gd+3].[O-]C([O-])=O.[O-]C([O-])=O.[O-]C([O-])=O RQXZRSYWGRRGCD-UHFFFAOYSA-H 0.000 claims description 2
- 238000001953 recrystallisation Methods 0.000 claims description 2
- 230000000630 rising effect Effects 0.000 claims description 2
- 239000002253 acid Substances 0.000 claims 1
- -1 DMF acetal Chemical class 0.000 abstract description 5
- 239000002872 contrast media Substances 0.000 abstract description 4
- ZPDFIIGFYAHNSK-UHFFFAOYSA-K gadobutrol Chemical compound [Gd+3].OCC(O)C(CO)N1CCN(CC([O-])=O)CCN(CC([O-])=O)CCN(CC([O-])=O)CC1 ZPDFIIGFYAHNSK-UHFFFAOYSA-K 0.000 abstract description 3
- 238000003325 tomography Methods 0.000 abstract description 3
- 230000003321 amplification Effects 0.000 abstract description 2
- 238000003199 nucleic acid amplification method Methods 0.000 abstract description 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 abstract 1
- 239000000543 intermediate Substances 0.000 description 9
- 239000000203 mixture Substances 0.000 description 7
- 239000000047 product Substances 0.000 description 7
- 239000000243 solution Substances 0.000 description 7
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- PQVSTLUFSYVLTO-UHFFFAOYSA-N ethyl n-ethoxycarbonylcarbamate Chemical compound CCOC(=O)NC(=O)OCC PQVSTLUFSYVLTO-UHFFFAOYSA-N 0.000 description 5
- GLXDVVHUTZTUQK-UHFFFAOYSA-M lithium hydroxide monohydrate Substances [Li+].O.[OH-] GLXDVVHUTZTUQK-UHFFFAOYSA-M 0.000 description 5
- 229940040692 lithium hydroxide monohydrate Drugs 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- 239000013078 crystal Substances 0.000 description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 238000012937 correction Methods 0.000 description 3
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- 230000002349 favourable effect Effects 0.000 description 3
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- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 2
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 238000004140 cleaning Methods 0.000 description 2
- 238000003745 diagnosis Methods 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 229910052744 lithium Inorganic materials 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 238000001556 precipitation Methods 0.000 description 2
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- QBPPRVHXOZRESW-UHFFFAOYSA-N 1,4,7,10-tetraazacyclododecane Chemical compound C1CNCCNCCNCCN1 QBPPRVHXOZRESW-UHFFFAOYSA-N 0.000 description 1
- 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 description 1
- 206010008190 Cerebrovascular accident Diseases 0.000 description 1
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- 239000002585 base Substances 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 150000004696 coordination complex Chemical class 0.000 description 1
- 235000013399 edible fruits Nutrition 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- RJOJUSXNYCILHH-UHFFFAOYSA-N gadolinium(3+) Chemical compound [Gd+3] RJOJUSXNYCILHH-UHFFFAOYSA-N 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
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- 229910003002 lithium salt Inorganic materials 0.000 description 1
- 159000000002 lithium salts Chemical class 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 150000002739 metals Chemical class 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- TVMXDCGIABBOFY-UHFFFAOYSA-N octane Chemical compound CCCCCCCC TVMXDCGIABBOFY-UHFFFAOYSA-N 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
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Classifications
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- 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 Table
-
- C—CHEMISTRY; METALLURGY
- C01—INORGANIC CHEMISTRY
- C01F—COMPOUNDS OF THE METALS BERYLLIUM, MAGNESIUM, ALUMINIUM, CALCIUM, STRONTIUM, BARIUM, RADIUM, THORIUM, OR OF THE RARE-EARTH METALS
- C01F17/00—Compounds of rare earth metals
-
- 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
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- Chemical & Material Sciences (AREA)
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- Life Sciences & Earth Sciences (AREA)
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- Inorganic Chemistry (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
Abstract
本发明涉及一种通过DMF缩醛和N-甲基咪唑在一锅法中制备N-(1-羟基甲基-2,3-二羟基丙基)-1,4,7-三羧基甲基-1,4,7,10-四氮杂环十二烷“钆布醇=Gadovist
Description
技术领域
本发明涉及一种通过DMF缩醛和N-甲基咪唑在一锅(one-pot)法中制备N-(1-羟基甲基-2,3-二羟基丙基)-1,4,7-三羧基甲基-1,4,7,10-四氮杂环十二烷的钆络合物的方法。
背景技术
Gadovist是一种用于核自旋断层成像的含钆造影剂，并且自2000年以来在德国于适应证“颅和脊椎磁共振断层成像中的对比放大(contrastamplification in cranial and spinal magnetic resonance tomography)”中得到批准。
MRT造影剂
1.0是含钆的MR造影剂领域中最新成果之一(EP 0448191 B1)。其用于要求高浓度的造影剂的研究(如用于诊断中风)或者用于例如肿瘤中的血管的研究。
形成对比的效果基于钆布醇，一种非离子络合物，其由钆(III)和大环配体二羟基(羟基甲基)丙基四氮杂环十二烷三乙酸(布醇(butrol))组成。
临床上推荐剂量的钆布醇使得组织水中质子的释放时间减少。
由于其作为诊断显像剂特别是在MRI诊断中的重要性，已有各种用于制备金属络合物的方法，特别是N-(1-羟基甲基-2,3-二羟基丙基)-1,4,7-三羧基甲基-1,4,7,10-四氮杂环十二烷“钆布醇”的钆络合物(DE 4009119)。尽管与原始方法相比已经获得了进展，但是仍然亟需环境有利并且更经济的合成选择，特别是可以用于工业规模。
发明内容
令人惊讶地发现，从目前在非常有利的条件下购买的式1的轮环藤宁(cyclen，1,4,7,10-四氮杂环十二烷)(DE19608307)开始，可以高收率制备满足规格要求的钆布醇而无需分离中间体，因而明显优于涉及中间体分离或中间体纯化的方法，特别是对于生产能力和生产时间而言。本发明的方法明显优于最接近的现有技术(Inorg.Chem.1997,36,6086-6093和DE19724186.7)和EP 1343770 B1中所述的方法，其中布醇配体分离为锂络合物。
EP 0596586 B1描述了将作为起始原料的轮环藤宁与4,4-二甲基-3,5,8-三氧杂二环[5.1.0]辛烷反应；随后通过添加水和氢氧化锂将甲酰基中间体水解；然后与氯乙酸或溴乙酸反应，其中碱氢氧化锂或N-甲基咪唑充当清除剂；然后在相同的锅中用盐酸或氢溴酸酸化并与钆络合。钆络合物在通过蒸馏除去溶剂并添加乙醇或异丙醇时沉淀，并被滤出，并且在简单地暂时清理反应搅拌器后从滤器直接溶于水(仍然是湿润的)，并且被漂洗回搅拌器以最后从乙醇结晶。如EP 1343770 B1所述，该方法不使用离子交换剂并且也避免游离形式或作为锂络合物的布醇配体的中间体分离。
通过使用诸如氢氧化锂或N-甲基咪唑的弱碱，这种方法的优势在于高生产能力而无需分离和中间纯化中间体。在所述方法中，可以有利地回收锂盐并随后再次供回生产循环。与现有技术方法相比，废物产生是更有利的，因为所有的步骤在一“锅”中进行，从而省去母液的后处理、滤器装置的清理等。通过在钆络合之前精确地测定配体含量，可以成功地避免废水中的钆，因为可以所有金属被布醇配体络合的方式来调节钆的量。所述方法可以用搅拌器和过滤装置进行管理。仅用水进行中间体清理，无需干燥，并且可以直接进行后续的制备。这确保最优的设备使用，并允许半连续操作。本发明的新方法成功地再次显著降低钆布醇的制备成本。
本发明的新方法如下进行：
通过以下步骤制备钆布醇：如EP 0596586所述，将轮环藤宁与4,4-二甲基-3,5,8-三氧杂二环[5.1.0]辛烷，在80-200°C、优选100-140°C的温度下反应8-40小时、优选12-30小时；然后加入水中，并通过添加1-5当量的氢氧化锂在50-100°C、优选100°C下将甲酰基中间体水解2-24小时、优选8-16小时；然后添加氯乙酸或溴乙酸、优选氯乙酸，并在40-150°C、优选40-90°C的温度下，于8-14、优选9-13的pH下，与氢氧化锂反应0.5-24小时、优选1-6小时。随后用盐酸或氢溴酸调节至1-4.5、优选2.0-4.0的pH，在20-100°C、优选30-70°C下搅拌0.5-24小时、优选0.5-5小时；然后测定布醇配体含量，随后添加化学计量量的钆盐如氧化钆、碳酸钆或氯化钆、但优选氧化钆；随后在50-100°C、优选70-100°C下搅拌1-12小时、优选1-5小时。络合完成后，通过添加氢氧化锂(作为固体或水溶液)将pH调节至4-8、但优选6-7.5。随后，在减压下充分浓缩，并且任选地于70-80°C的升高的温度下，在添加乙醇或异丙醇、优选乙醇后，共沸蒸馏除去水。合适地继续蒸馏，直至达到1-20%、优选5-10%的水含量。在这些条件下，沉淀出钆布醇产物，即使仍然是热的。然后冷却至0-30°C、优选5-20°C，并且滤出产物。在20-60°C、优选20-40°C下用少量水从滤器溶解仍然在滤器上的潮湿产物，并且最后从乙醇重结晶。为此目的，任选地将水大量共沸，在这种情况下，产物在沸腾温度下沉淀。将混合物冷却至0-20°C，将产物滤出，用少量冷乙醇(优选0-20°C)洗涤，然后干燥。
由此获得的产物的特征在于高质量和纯度，并且满足规格的期望要求。
实施例
在氮气下，将20l二甲基甲酰胺二甲基缩醛(DMF缩醛)加入200l甲苯中的24.0kg(139.34mol)轮环藤宁(=1,4,7,10-四氮杂环十二烷)。缓慢地升高温度，并将甲醇/二甲胺/甲苯的共沸物蒸馏。随后在减压下将溶剂完全蒸馏。将留下的油冷却至50°C，然后加入22.44kg(147.86mol)的4,4-二甲基-3,5,8-三氧杂二环[5.1.0]辛烷(含量约95%)(也在氮气下)，然后在130°C的夹套温度下搅拌12小时。然后将混合物冷却至40°C，并添加200l水和17.53kg(418.0mol)氢氧化锂一水合物。将混合物在回流下加热8小时，然后在减压下蒸馏除去约140l水，然后冷却至室温并进一步处理。
将46.66kg(493.83mol)氯乙酸溶于50kg水并冷却至5°C。向该溶液添加20.73kg(494.1mol)氢氧化锂一水合物。然后将由此制备的溶液加入上述溶液。使混合物升温至约65°C的内部温度，并在这一温度下，在2小时内添加总共12.0kg(286.1mol)氢氧化锂一水合物(约5-6份)或等量的N-甲基咪唑。然后将混合物在65°C下搅拌1小时。用浓盐酸将pH调节至1，并在65°C下继续搅拌30分钟。冷却至20°C后，用氢氧化锂一水合物将pH调节至3.5，随后通过HPLC针对外部标准品测定布醇配体(=N-(1-羟基甲基-2,3-二羟基丙基)-1,4,7-三羧基甲基-1,4,7,10-四氮杂环十二烷)含量。这获得94.7%的修正含量。随后添加23.92kg(65.97mol)氧化钆，并将混合物在90°C下搅拌1小时。络合完成(初始悬浮液变为澄清溶液)后，通过添加氢氧化锂一水合物将pH调节至7.0。在减压下蒸馏除去水，直至搅拌器中剩下仍然可以搅拌的粘性溶液。在升高的温度下(约80°C)，向该溶液加入1350l乙醇，将其在回流下沸腾5小时。将混合物冷却至10°C，并将沉淀的晶体悬浮液滤出，然后用100l乙醇洗涤两次。将滤器上仍然被乙醇湿润的滤饼溶于75l水，并将溶液通过滤芯过滤。然后，添加750l乙醇，并将溶液在回流下加热5小时。冷却至10°C并滤出沉淀的晶体悬浮液后，将后者用75kg乙醇洗涤两次，并且在60°C下减压干燥。
基于使用的1,4,7,10-四氮杂环十二烷的无色晶体粉末，收率为78.89kg=130.46mol，对应于理论的84.6%(对水和残留溶剂修正)。
水含量(Karl-Fischer)：4.12%
干燥损失：1.15%
元素分析(对水修正)：
| 元素 | C | H | N | O | Gd |
| 计算 | 35.75 | 5.17 | 9.26 | 23.81 | 26.00 |
| 实测 | 35.80 | 5.25 | 9.16 | 23.73 | 25.92 |
HPLC(100%方法)：>99%
Claims (3)
1.一种通过以下步骤制备N-(1-羟基甲基-2,3-二羟基丙基)-1,4,7-三羧基甲基-1,4,7,10-四氮杂环十二烷的钆络合物的方法：将轮环藤宁与4,4-二甲基-3,5,8-三氧杂二环[5.1.0]辛烷和二甲基甲酰胺二甲基缩醛反应，通过添加氢氧化锂将甲酰基中间体水解，添加氯乙酸或溴乙酸并与氢氧化锂或N-甲基咪唑反应，用盐酸或氢溴酸调节至酸性pH，随后测定布醇配体含量并添加化学计量量的钆盐。
2.如权利要求1所述的方法，其包括将轮环藤宁与4,4-二甲基-3,5,8-三氧杂二环[5.1.0]辛烷和二甲基甲酰胺二甲基缩醛在80-200°C的温度下反应，并且通过添加1-5当量的氢氧化锂将甲酰基中间体在50-100°C下水解2-24小时，添加氯乙酸或溴乙酸并在40-150°C的温度下与氢氧化锂或N-甲基咪唑反应，随后用盐酸或氢溴酸调节至1-4.5的pH，然后测定布醇配体含量并添加化学计量量的氧化钆、碳酸钆或氯化钆，并且在50-100°C下搅拌1-12小时。
3.如权利要求1或2所述的方法，其包括与4,4-二甲基-3,5,8-三氧杂二环[5.1.0]辛烷在80-200°C的温度下反应8-40小时、优选12-30小时；溶于水中并通过添加1-5当量的氢氧化锂在50-100°C、优选100°C下将甲酰基中间体反应2-24小时；然后添加氯乙酸或溴乙酸并在40-150°C、优选40-90°C的温度下于8-14、优选9-13的pH下与氢氧化锂或N-甲基咪唑反应0.5-24小时、优选1-6小时；用盐酸或氢溴酸调节至1-4.5、优选2.0-4.0的pH；在20-100°C下搅拌0.5-24小时、优选0.5-5小时；然后测定布醇配体含量并添加化学计量量的钆盐并在50-100°C、优选70-100°C下搅拌1-12小时；络合完成后，通过添加氢氧化锂将pH调节至4-8、但优选6-7.5；随后在减压下浓缩，并且任选地在添加乙醇或异丙醇后于70-80°C的升高的温度下共沸蒸馏除去水至水含量为1-20%、优选5-10%；冷却至0-30°C、优选5-20°C；滤出产物并从乙醇重结晶。
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE102010023105A DE102010023105A1 (de) | 2010-06-04 | 2010-06-04 | Gadobutrolherstellung im Eintopfverfahren mittels DMF-acetal und N-Methylimidazol |
| DE102010023105.3 | 2010-06-04 | ||
| PCT/EP2011/058988 WO2011151347A1 (de) | 2010-06-04 | 2011-05-31 | Gadobutrolherstellung im eintopfverfahren mittels dmf-acetal und n-methylimidazol |
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| CN102933562A true CN102933562A (zh) | 2013-02-13 |
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| CN2011800273535A Pending CN102933562A (zh) | 2010-06-04 | 2011-05-31 | 通过dmf缩醛和n-甲基咪唑在一锅法中制备钆布醇 |
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| US (1) | US20130116429A1 (zh) |
| EP (1) | EP2576521A1 (zh) |
| JP (1) | JP2013527212A (zh) |
| KR (1) | KR20130089229A (zh) |
| CN (1) | CN102933562A (zh) |
| AU (1) | AU2011260310A1 (zh) |
| BR (1) | BR112012030902A2 (zh) |
| CA (1) | CA2801255A1 (zh) |
| DE (1) | DE102010023105A1 (zh) |
| MX (1) | MX2012014161A (zh) |
| RU (1) | RU2012157538A (zh) |
| WO (1) | WO2011151347A1 (zh) |
| ZA (1) | ZA201209037B (zh) |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107001294A (zh) * | 2014-12-26 | 2017-08-01 | St制药株式会社 | 一种用于制备钆布醇的方法 |
| 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 |
| CN109384737A (zh) * | 2017-08-04 | 2019-02-26 | 天津科伦药物研究有限公司 | 一种四氮杂环钇络合物及其制备方法和应用 |
| CN111039885A (zh) * | 2019-12-06 | 2020-04-21 | 广州康瑞泰药业有限公司 | 一种制备高纯度考布曲钙的方法 |
| CN112585121A (zh) * | 2018-08-23 | 2021-03-30 | St制药株式会社 | 制备钆布醇的方法 |
| 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 |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| PE20141325A1 (es) | 2011-04-21 | 2014-10-08 | Bayer Ip Gmbh | Preparacion de gadobutrol de alta pureza |
| KR101971435B1 (ko) | 2017-08-29 | 2019-04-24 | 주식회사 엔지켐생명과학 | 가도부트롤 중간체 및 이를 이용한 가도부트롤의 제조 방법 |
| KR20190088793A (ko) | 2018-01-19 | 2019-07-29 | 주식회사 엔지켐생명과학 | 칼코부트롤의 제조방법 |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0596586A1 (de) * | 1992-11-06 | 1994-05-11 | Schering Aktiengesellschaft | Verfahren zur Herstellung von Metallkomplexen der N-beta-Hydroxy-alkyl-tri-N-carboxyalkyl-1,4,7,10-tetraazacyclododecan- und N-beta-Hydroxyalkyl-tri-N-carboxyalkyl-1,4,8,11-tetraazacyclotetradecan-Derivate |
| US5994536A (en) * | 1997-06-02 | 1999-11-30 | Schering Aktiengesellschaft | Process for mono- and 1,7-bis-N-β-hydroxyalkylation of cyclene; N-β-hydroxyalkyl-1,4,7,10-tetraazacyclododecane-lithium-salt complexes and the use of the complexes for the production of gadobutrol and analogs |
| CN1481371A (zh) * | 2000-12-15 | 2004-03-10 | ���ֹɷݹ�˾ | N-(1-羟甲基-2,3-二羟丙基)-1,4,7-三羧甲基-1,4,7,10-四氮杂环十二烷的锂络合物、其制备方法及应用 |
| CN1494435A (zh) * | 2001-03-26 | 2004-05-05 | �����ڶ���ϣ | 预防再狭窄的制剂 |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4369099A (en) * | 1981-01-08 | 1983-01-18 | Bell Telephone Laboratories, Incorporated | Photoelectrochemical etching of semiconductors |
| 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 |
| DE19608307C1 (de) | 1996-02-26 | 1997-08-28 | Schering Ag | Verfahren zur Herstellung von 1,4,7,10-Tetraazacyclododecan und dessen Derivaten |
-
2010
- 2010-06-04 DE DE102010023105A patent/DE102010023105A1/de not_active Ceased
-
2011
- 2011-05-31 CN CN2011800273535A patent/CN102933562A/zh active Pending
- 2011-05-31 KR KR1020137000141A patent/KR20130089229A/ko not_active Application Discontinuation
- 2011-05-31 WO PCT/EP2011/058988 patent/WO2011151347A1/de active Application Filing
- 2011-05-31 CA CA2801255A patent/CA2801255A1/en not_active Abandoned
- 2011-05-31 EP EP11724601.7A patent/EP2576521A1/de not_active Withdrawn
- 2011-05-31 RU RU2012157538/04A patent/RU2012157538A/ru not_active Application Discontinuation
- 2011-05-31 JP JP2013512876A patent/JP2013527212A/ja not_active Withdrawn
- 2011-05-31 AU AU2011260310A patent/AU2011260310A1/en not_active Abandoned
- 2011-05-31 US US13/701,914 patent/US20130116429A1/en not_active Abandoned
- 2011-05-31 BR BR112012030902A patent/BR112012030902A2/pt not_active IP Right Cessation
- 2011-05-31 MX MX2012014161A patent/MX2012014161A/es not_active Application Discontinuation
-
2012
- 2012-11-29 ZA ZA2012/09037A patent/ZA201209037B/en unknown
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0596586A1 (de) * | 1992-11-06 | 1994-05-11 | Schering Aktiengesellschaft | Verfahren zur Herstellung von Metallkomplexen der N-beta-Hydroxy-alkyl-tri-N-carboxyalkyl-1,4,7,10-tetraazacyclododecan- und N-beta-Hydroxyalkyl-tri-N-carboxyalkyl-1,4,8,11-tetraazacyclotetradecan-Derivate |
| US5994536A (en) * | 1997-06-02 | 1999-11-30 | Schering Aktiengesellschaft | Process for mono- and 1,7-bis-N-β-hydroxyalkylation of cyclene; N-β-hydroxyalkyl-1,4,7,10-tetraazacyclododecane-lithium-salt complexes and the use of the complexes for the production of gadobutrol and analogs |
| CN1481371A (zh) * | 2000-12-15 | 2004-03-10 | ���ֹɷݹ�˾ | N-(1-羟甲基-2,3-二羟丙基)-1,4,7-三羧甲基-1,4,7,10-四氮杂环十二烷的锂络合物、其制备方法及应用 |
| CN1494435A (zh) * | 2001-03-26 | 2004-05-05 | �����ڶ���ϣ | 预防再狭窄的制剂 |
Non-Patent Citations (1)
| Title |
|---|
| J. PLATZEK等: "Synthesis and structure of a new macrocyclic polyhydroxylated gadolinium chelate used as contrast agent for magnetic resonance imaging", 《INORGANIC CHEMISTRY》 * |
Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107001294A (zh) * | 2014-12-26 | 2017-08-01 | St制药株式会社 | 一种用于制备钆布醇的方法 |
| CN107001294B (zh) * | 2014-12-26 | 2020-02-28 | St制药株式会社 | 一种用于制备钆布醇的方法 |
| 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 |
| CN109384737A (zh) * | 2017-08-04 | 2019-02-26 | 天津科伦药物研究有限公司 | 一种四氮杂环钇络合物及其制备方法和应用 |
| CN112585121A (zh) * | 2018-08-23 | 2021-03-30 | St制药株式会社 | 制备钆布醇的方法 |
| CN112585121B (zh) * | 2018-08-23 | 2023-11-21 | St制药株式会社 | 制备钆布醇的方法 |
| CN111039885A (zh) * | 2019-12-06 | 2020-04-21 | 广州康瑞泰药业有限公司 | 一种制备高纯度考布曲钙的方法 |
| CN111039885B (zh) * | 2019-12-06 | 2021-03-05 | 广州康瑞泰药业有限公司 | 一种制备高纯度考布曲钙的方法 |
| 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 |
Also Published As
| Publication number | Publication date |
|---|---|
| WO2011151347A1 (de) | 2011-12-08 |
| KR20130089229A (ko) | 2013-08-09 |
| RU2012157538A (ru) | 2014-07-20 |
| DE102010023105A1 (de) | 2011-12-08 |
| EP2576521A1 (de) | 2013-04-10 |
| AU2011260310A1 (en) | 2013-01-10 |
| ZA201209037B (en) | 2014-02-26 |
| JP2013527212A (ja) | 2013-06-27 |
| MX2012014161A (es) | 2013-02-27 |
| CA2801255A1 (en) | 2011-12-08 |
| US20130116429A1 (en) | 2013-05-09 |
| BR112012030902A2 (pt) | 2015-09-22 |
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