CN1481371A - 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 - Google Patents
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 Download PDFInfo
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- 150000002641 lithium Chemical class 0.000 title abstract 2
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 15
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 claims description 13
- 150000001875 compounds Chemical class 0.000 claims description 10
- 238000000034 method Methods 0.000 claims description 9
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- 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 claims description 8
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 8
- 229960003411 gadobutrol Drugs 0.000 claims description 8
- AMXOYNBUYSYVKV-UHFFFAOYSA-M lithium bromide Chemical compound [Li+].[Br-] AMXOYNBUYSYVKV-UHFFFAOYSA-M 0.000 claims description 8
- 239000000460 chlorine Substances 0.000 claims description 7
- FOCAUTSVDIKZOP-UHFFFAOYSA-N chloroacetic acid Chemical compound OC(=O)CCl FOCAUTSVDIKZOP-UHFFFAOYSA-N 0.000 claims description 5
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 4
- HBBGRARXTFLTSG-UHFFFAOYSA-N Lithium ion Chemical compound [Li+] HBBGRARXTFLTSG-UHFFFAOYSA-N 0.000 claims description 4
- 229910052801 chlorine Inorganic materials 0.000 claims description 4
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 4
- 229940059936 lithium bromide Drugs 0.000 claims description 4
- 229910001416 lithium ion Inorganic materials 0.000 claims description 4
- WBJINCZRORDGAQ-UHFFFAOYSA-N ethyl formate Chemical compound CCOC=O WBJINCZRORDGAQ-UHFFFAOYSA-N 0.000 claims description 3
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 2
- 229910052794 bromium Inorganic materials 0.000 claims description 2
- 239000002798 polar solvent Substances 0.000 claims description 2
- 229910052688 Gadolinium Inorganic materials 0.000 abstract description 10
- UIWYJDYFSGRHKR-UHFFFAOYSA-N gadolinium atom Chemical compound [Gd] UIWYJDYFSGRHKR-UHFFFAOYSA-N 0.000 abstract description 10
- 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 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 33
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 21
- 238000002425 crystallisation Methods 0.000 description 11
- 230000008025 crystallization Effects 0.000 description 11
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 8
- 229910052744 lithium Inorganic materials 0.000 description 8
- AIDLAEPHWROGFI-UHFFFAOYSA-N 2-methylbenzene-1,3-dicarboxylic acid Chemical compound CC1=C(C(O)=O)C=CC=C1C(O)=O AIDLAEPHWROGFI-UHFFFAOYSA-N 0.000 description 7
- 239000000725 suspension Substances 0.000 description 7
- 239000000203 mixture Substances 0.000 description 5
- 150000003839 salts Chemical class 0.000 description 5
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 4
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 3
- 230000000536 complexating effect Effects 0.000 description 3
- PQVSTLUFSYVLTO-UHFFFAOYSA-N ethyl n-ethoxycarbonylcarbamate Chemical compound CCOC(=O)NC(=O)OCC PQVSTLUFSYVLTO-UHFFFAOYSA-N 0.000 description 3
- GLXDVVHUTZTUQK-UHFFFAOYSA-M lithium hydroxide monohydrate Substances [Li+].O.[OH-] GLXDVVHUTZTUQK-UHFFFAOYSA-M 0.000 description 3
- 229940040692 lithium hydroxide monohydrate Drugs 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- DPDMMXDBJGCCQC-UHFFFAOYSA-N [Na].[Cl] Chemical compound [Na].[Cl] DPDMMXDBJGCCQC-UHFFFAOYSA-N 0.000 description 2
- 230000001476 alcoholic effect Effects 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 238000004992 fast atom bombardment mass spectroscopy Methods 0.000 description 2
- CMIHHWBVHJVIGI-UHFFFAOYSA-N gadolinium(iii) oxide Chemical compound [O-2].[O-2].[O-2].[Gd+3].[Gd+3] CMIHHWBVHJVIGI-UHFFFAOYSA-N 0.000 description 2
- 229910000042 hydrogen bromide Inorganic materials 0.000 description 2
- 239000011159 matrix material Substances 0.000 description 2
- 239000012452 mother liquor Substances 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N DMSO Substances CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 1
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 1
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 150000004696 coordination complex Chemical class 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 238000010612 desalination reaction Methods 0.000 description 1
- SBZXBUIDTXKZTM-UHFFFAOYSA-N diglyme Chemical compound COCCOCCOC SBZXBUIDTXKZTM-UHFFFAOYSA-N 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- IDGUHHHQCWSQLU-UHFFFAOYSA-N ethanol;hydrate Chemical compound O.CCO IDGUHHHQCWSQLU-UHFFFAOYSA-N 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- GBMDVOWEEQVZKZ-UHFFFAOYSA-N methanol;hydrate Chemical compound O.OC GBMDVOWEEQVZKZ-UHFFFAOYSA-N 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 150000003333 secondary alcohols Chemical class 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000000967 suction filtration Methods 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
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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
- C07F1/00—Compounds containing elements of Groups 1 or 11 of the Periodic Table
- C07F1/02—Lithium compounds
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- 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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- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
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- Epoxy Compounds (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
Abstract
本发明涉及以下式(I)之结晶的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，其中3个X一起代表n个锂离子和m个氢原子，而n和m分别为0－3的数，优选为0.8－2.2，并且n与m的和为3，而Y代表氯或溴。本发明还涉及该络合物的制备方法由该化合物制备无盐的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钆络合物的方法，其中无需使用离子交换剂。
Description
技术领域
本发明涉及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。
背景技术
由于可作为形成图象的诊断剂、特别是MRI诊断剂，已通过不同的方法研究了制备金属络合物、特别是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钆络合物(GADOBUTROL)的方法(DE 4009119)。尽管相对于原始的方法取得了进展，但仍需要特别是在工业规模上可实施、对环境友善而且成本低的合成方法。
该任务是通过本发明解决的。
发明内容
令人惊奇地发现根据本发明之通式I的结晶络合物形成体(Complexbildner)非常适合于制备钆络合物GADOBUTROL，其方法明显优于最简单的现有技术(Inorg.Chem.1997，36，6086-6093以及DE19724186.7)：
其中：3个X一起代表n个锂离子和m个氢原子，而n和m分别为0-3的数，优选为0.8-2.2，并且n与m的和为3，Y代表氯或溴，即、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。
特别优选的是，Y为氯，一个X代表锂离子，而其余的两个代表氢原子。
在水中使用氯乙酸或溴乙酸、氢氧化锂和氢氯酸或氢溴酸，由N-(6-羟基-2，2-二甲基-1，3-二氧环庚烷(dioxepan)-5-基)-1，4，7，10-四氮杂环十二烷-氯化锂或溴化锂络合物(DE19724186.7)可制备根据本发明的化合物，然后由乙醇-水混合物中结晶。该结晶的络合物形成体在水中与钆络合，然后该络合物通过在乙醇/水中的结晶被无盐地分离出来，无需使用离子交换剂。
本发明的优点是：该络合物形成体以晶体形式分离，并因此以非常纯的形式得到。
通过用氢氧化锂替换氢氧化钠(DE19724186.7)，制备结晶络合物形成体的方法避免了昂贵的由强酸性甲醇-水溶液中分离设备腐蚀性的氯化钠。在本发明的方法中替代氯化钠形成氯化锂或溴化锂，它们在结晶络合物形成体时存留在弱酸性乙醇-水母液中。用阴离子交换剂处理，可以氢氧化锂的形式由母液中回收锂。该制备方法成本的下降是非常经济的。
具体实施方式
为制备GADOBUTROL，在络合期间精确计量加入钆。这样可减少包含钆的产品的沉淀量。
为从钆络合物中除去盐以及其他副产物，与现有技术的方法相反，不需要使用离子交换剂。因此，取消了相应工艺装置的运行以及与此相关的沉淀产物。
这也取消了离子交换剂的水洗脱物的蒸发能量。
根据本发明的方法是如下实现的：N-(6-羟基-2，2-二甲基-1，3-二氧环庚烷-5-基)-1，4，7，10-四氮杂环十二烷的氯化锂或溴化锂络合物，在极性溶剂如水、伯醇和仲醇(如乙醇或异丙醇)、DMF、二甲氧基乙烷、二乙二醇二甲醚或这些溶剂的混合物中，优选在水中，与氯乙酸或溴乙酸(优选氯乙酸)、以及氢氧化锂在40-150℃(优选40-90℃)的温度、8-14的pH值(优选9-13)下反应0.5-24小时，优选1-6小时。
为分离产物，用氢氯酸、氢溴酸、乙酸、三氟乙酸或对甲苯磺酸(优选用氢氯酸)将pH值调节为3.5-4.5，优选调节为3.8-4.2，然后由水和乙醇的混合物中结晶。
为将通式I的络合物形成体转化为通式II的钆络合物，将所述络合物形成体溶解在水中，通过添加氢氯酸将pH值调节为约3.6，加入经过计算量的氧化钆，在50-100℃、优选70-100℃下络合，然后通过添加乙醇使钆络合物结晶。
以下将通过实施例更为详细地说明本发明。实施例1制备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
预先准备38.5g氯乙酸，溶解在40g水中，然后将该溶液冷却至0-10℃。在该溶液中添加17.1g氢氧化锂单水合物。将该溶液添加至41.25g(114.95mmol)N-(6-羟基-2，2-二甲基-1，3-二氧环庚烷-5-基)-1，4，7，10-四氮杂环十二烷的氯化锂络合物在约45ml水中的溶液内。该混合物温热至65℃，然后在该温度下于2小时的时间内分批地添加总共14.6g的氢氧化锂单水合物。之后在65℃下搅拌1小时。该溶液接着用盐酸酸化至pH为4。在65-75℃的温度内，该溶液在75分钟的时间中添加500ml乙醇。相对于乙醇的添加结束，自发地形成锂络合物的结晶。乙醇添加结束后，加热回流2小时，然后冷却至室温，过滤出结晶，用2×20ml 80％和2×20ml 90％乙醇洗涤，最后在50℃下干燥。
产量：51.6g＝93.67mmol(包括水含量)＝81.5％理论值
H-NMR(D2O)：在3.0-3.9ppm之间多重峰，N-CH2-CH2-N(4×)，N-CH2-COOH(3×)，N-CH(1×)，CH-OH(1×)，以及CH2-OH(2×)
IR(KBr，cm-1)：3440，3360，3300，1675，1650，1590，1400
FAB-MS(基质NBA-甘油-DMSO)：451(M+H)，45(M+Li)，473(M+Na)
FAB-MS(基质Magic Bullet)：451(M+H)，457(M+7)
水含量：9.45％，乙醇含量：0.0％混合物的元素分析：锂络合物+9.45％＝2.89mol水
实施例2制备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钆络合物(GADOBUTROL)
| ％ | C | H | Cl | Li | N | 水 | EtOH |
| 理论值 | 39.25 | 7.1 | 6.44 | 2.52 | 10.17 | 9.45 | 0 |
| 实测值 | 38.82 | 6.86 | 6.83 | 2.64 | 10.17 | 9.45 | 0 |
| 差异 | -0.43 | -0.24 | 0.39 | 0.12 | 0 | 0 | 0 |
将51.6g(93.67mmol，包含9.45％的水)结晶的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(实施例1)溶解在51g完全脱除盐的水中，然后用浓盐酸将该溶液的pH值调节为3.5。在该溶液中添加16.9g的Gd2O3，并在90℃下搅拌该悬浮液1小时。悬浮液转变为溶液。该溶液的pH值任选用固体氢氧化锂单水合物调节为7。在约78℃的温度下，该溶液在2小时的时间中缓慢地与960ml的乙醇混合，形成一悬浮液。在乙醇添加完成后，加热回流该悬浮液5小时。接着将该悬浮液冷却至室温，过滤出结晶，用100ml乙醇洗涤，然后在50℃下干燥。
产量：51.02g＝80.3mmol(包括水含量)＝85.73％理论值
干燥丢失量：1.06％，水含量：4.74％
GADOBUTROL的元素分析(包含1.7mol水＝4.82％和0.53mol的LiCl)：
为完全脱盐的重结晶
| ％ | C | H | N | Cl | Li | Gd | 水 | EtOH |
| 理论值 | 32.87 | 5.27 | 8.52 | 2.86 | 0.56 | 23.91 | 4.82 | 0 |
| 实测值 | 32.96 | 5.25 | 8.49 | 2.91 | 0.53 | 23.85 | 4.74 | 0 |
| 差异 | 0.09 | -0.02 | -0.03 | 0.05 | -0.03 | -0.06 | -0.08 | 0 |
在约75℃下将51.02g的GADOBUTROL(粗)＝80.3mmol(包含水)溶解在47ml的水中，然后在该溶液中于1小时的时间内缓慢地添加470ml的乙醇，形成一悬浮液。在乙醇添加完成后，该悬浮液加热回流2小时，然后冷却至20℃，并在该温度下搅拌1小时，抽滤结晶，用66ml的乙醇洗涤，最后在50℃下干燥。
产量：47.08g＝74.84mmol(包括水含量)＝93.2％理论值
水含量：3.92％，乙醇含量0.16％
GADOBUTROL的元素分析(包含1.35mol水＝3.86％、0.02mol的乙醇＝0.15％以及0mol LiCl)：
| ％ | C | H | N | Cl | Li | Gd | 水 | EtOH |
| 理论值 | 34.4 | 5.4 | 8.89 | 0 | 0 | 24.96 | 3.86 | 0.15 |
| 实测值 | 34.48 | 5.01 | 8.76 | 0 | ＜0.01 | 24.96 | 3.92 | 0.16 |
| 差异 | 0.08 | -0.39 | -0.13 | 0 | ＜0.01 | 0.09 | 0.06 | 0.01 |
Claims (4)
1、通式I的化合物：其中：3个X一起代表n个锂离子和m个氢原子，而n和m分别为0-3的数，
优选为0.8-2.2，并且n与m的和为3，Y代表氯或溴。
2、制备如权利要求1所述的通式I化合物的方法，其特征在于，N-(6-羟基-2，2-二甲基-1，3-二氧环庚烷-5-基)-1，4，7，10-四氮杂环十二烷或其与氯化锂或溴化锂的络合物，在极性溶剂中与氯乙酸或溴乙酸以及氢氧化锂在40-150℃的温度、8-14的pH值下反应。
3、如权利要求1所述的通式I化合物在制备通式II的GADOBUTROL中的应用：
4、如权利要求1所述的通式I的化合物，其特征在于，Y为氯，一个X代表锂离子，而其余的两个X代表氢原子。
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| Application Number | Priority Date | Filing Date | Title |
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| DE10064467A DE10064467C2 (de) | 2000-12-15 | 2000-12-15 | Lithium-Komplexe von N-(1-Hydroxymethyl-2,3-dihydroxypropyl)-1,4,7-triscarboxymethyl-1,4,7,10-tetraazacyclododecan, deren Herstellung und Verwendung |
| DE10064467.8 | 2000-12-15 |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102933562A (zh) * | 2010-06-04 | 2013-02-13 | 拜耳知识产权有限责任公司 | 通过dmf缩醛和n-甲基咪唑在一锅法中制备钆布醇 |
| CN103547573A (zh) * | 2011-04-21 | 2014-01-29 | 拜耳知识产权有限责任公司 | 高纯度钆布醇的制备 |
| 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 |
| 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 |
Families Citing this family (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2007521254A (ja) * | 2003-06-25 | 2007-08-02 | ゲルベ | 診断画像用化合物 |
| FR2867473B1 (fr) | 2004-03-12 | 2006-06-23 | Guerbet Sa | Compose de porphyrines et utilisation a haut champ en irm |
| WO2006002875A1 (en) * | 2004-07-02 | 2006-01-12 | Bracco Imaging Spa | Contrast agents endowed with high relaxivity for use in magnetic resonance imaging (mri) which contain a chelating moiety with polyhydroxylated substituents |
| JP5518465B2 (ja) | 2006-03-14 | 2014-06-11 | マリンクロッド エルエルシー | テトラアザ大員環誘導体の金属錯体 |
| US7777029B2 (en) * | 2006-05-02 | 2010-08-17 | San Diego State University (Sdsu) Foundation | Bifunctional chelators for sequestering lanthanides |
| DE102009057274B4 (de) | 2009-12-02 | 2011-09-01 | Bayer Schering Pharma Aktiengesellschaft | Gadobutrolherstellung mittels Trioxobicyclo-octan |
| WO2011054480A1 (de) | 2009-11-09 | 2011-05-12 | Bayer Schering Pharma Aktiengesellschaft | Gadobutrolherstellung mittels keramischer membran |
| DE102009053252B3 (de) * | 2009-11-09 | 2011-09-01 | 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 |
| KR101971435B1 (ko) * | 2017-08-29 | 2019-04-24 | 주식회사 엔지켐생명과학 | 가도부트롤 중간체 및 이를 이용한 가도부트롤의 제조 방법 |
| KR102033964B1 (ko) * | 2018-01-19 | 2019-10-18 | 주식회사 엔지켐생명과학 | 가도테리돌 중간체 및 이를 이용한 가도테리돌 제조방법 |
| KR20210112910A (ko) * | 2020-03-06 | 2021-09-15 | 주식회사 엔지켐생명과학 | 가도부트롤 주사제 제조를 위한 부형제인 칼코부트롤의 제조 방법 |
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| 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 |
| 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 |
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102933562A (zh) * | 2010-06-04 | 2013-02-13 | 拜耳知识产权有限责任公司 | 通过dmf缩醛和n-甲基咪唑在一锅法中制备钆布醇 |
| CN103547573A (zh) * | 2011-04-21 | 2014-01-29 | 拜耳知识产权有限责任公司 | 高纯度钆布醇的制备 |
| CN103547573B (zh) * | 2011-04-21 | 2016-08-17 | 拜耳知识产权有限责任公司 | 高纯度钆布醇的制备 |
| 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 |
| 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 |
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