CN106220580A - 钆特酸葡胺的提纯方法 - Google Patents
钆特酸葡胺的提纯方法 Download PDFInfo
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- CN106220580A CN106220580A CN201610650121.XA CN201610650121A CN106220580A CN 106220580 A CN106220580 A CN 106220580A CN 201610650121 A CN201610650121 A CN 201610650121A CN 106220580 A CN106220580 A CN 106220580A
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- acid meglumine
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- MBBZMMPHUWSWHV-BDVNFPICSA-N N-methylglucamine Chemical compound CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO MBBZMMPHUWSWHV-BDVNFPICSA-N 0.000 title claims abstract description 43
- 229960003194 meglumine Drugs 0.000 title claims abstract description 43
- 239000002253 acid Substances 0.000 title claims abstract description 41
- 238000000034 method Methods 0.000 title claims abstract description 16
- 238000000746 purification Methods 0.000 title claims abstract description 14
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims abstract description 42
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims abstract description 36
- 239000012043 crude product Substances 0.000 claims abstract description 17
- 239000002244 precipitate Substances 0.000 claims abstract description 3
- 238000003756 stirring Methods 0.000 claims description 10
- 238000003556 assay Methods 0.000 claims description 8
- 238000004128 high performance liquid chromatography Methods 0.000 claims description 8
- 238000001556 precipitation Methods 0.000 claims description 5
- 238000005406 washing Methods 0.000 claims description 5
- 239000002872 contrast media Substances 0.000 abstract description 5
- 238000003384 imaging method Methods 0.000 abstract description 5
- 238000004458 analytical method Methods 0.000 abstract description 2
- 229940079593 drug Drugs 0.000 abstract description 2
- 239000003814 drug Substances 0.000 abstract description 2
- 239000007791 liquid phase Substances 0.000 abstract description 2
- 238000004519 manufacturing process Methods 0.000 abstract description 2
- 238000002595 magnetic resonance imaging Methods 0.000 description 3
- 238000005516 engineering process 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
- 238000010189 synthetic method Methods 0.000 description 2
- 229910052688 Gadolinium Inorganic materials 0.000 description 1
- 206010054949 Metaplasia Diseases 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 208000019155 Radiation injury Diseases 0.000 description 1
- WDLRUFUQRNWCPK-UHFFFAOYSA-N Tetraxetan Chemical compound OC(=O)CN1CCN(CC(O)=O)CCN(CC(O)=O)CCN(CC(O)=O)CC1 WDLRUFUQRNWCPK-UHFFFAOYSA-N 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000003745 diagnosis Methods 0.000 description 1
- 239000000032 diagnostic agent Substances 0.000 description 1
- 229940039227 diagnostic agent Drugs 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- UIWYJDYFSGRHKR-UHFFFAOYSA-N gadolinium atom Chemical compound [Gd] UIWYJDYFSGRHKR-UHFFFAOYSA-N 0.000 description 1
- GFSTXYOTEVLASN-UHFFFAOYSA-K gadoteric acid Chemical compound [Gd+3].OC(=O)CN1CCN(CC([O-])=O)CCN(CC([O-])=O)CCN(CC([O-])=O)CC1 GFSTXYOTEVLASN-UHFFFAOYSA-K 0.000 description 1
- 229960003823 gadoteric acid Drugs 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 230000015689 metaplastic ossification Effects 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Classifications
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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
-
- 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
- C07F5/003—Compounds containing elements of Groups 3 or 13 of the Periodic Table without C-Metal linkages
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
Abstract
本发明是关于磁共振成像技术造影剂，特别是造影剂钆特酸葡胺的提纯方法。本发明提供一种钆特酸葡胺的提纯方法，通过将钆特酸葡胺粗品溶于50～60℃的甲醇溶液中，加入丙酮并冷却至0～5℃，将沉淀物过滤即得钆特酸葡胺纯品。通过本发明方法对钆特酸葡胺粗品进行提纯后，经高效液相分析，所得钆特酸葡胺的纯度＞99.6％，可直接用于相应的药物生产。
Description
技术领域
本发明是关于磁共振成像技术造影剂，特别是造影剂钆特酸葡胺的提纯方法。
背景技术
磁共振成像(MRI)以其空间分辨率高、对人体无电离辐射损伤、多参数成像等优点而得到迅速发展和广泛应用。目前，MRI已从单一形态学向分子影像学的深度发展，对医学临床和医学研究产生了巨大影像。为了提高病变部位与正常组织间信号的对比度，超过35％的诊断需要使用磁共振成像造影剂。它是一类能缩短成像时间、提高成像对比度和清晰度、显示组织器官功能状态的诊断用药。
钆特酸葡胺(化学名称：2-[4,7,10-三(羧甲基)-1,4,7,10-四氮杂环十二-1-基]乙酸钆葡甲胺)具有极高的动力学稳定性及热力学稳定性，是到目前为止稳定性最高的造影剂，因此，当需要造影剂在体内滞留时间较长时，它便更具吸引力，因此，对钆特酸葡胺进行有效的精制提纯，以满足药用原料的纯度要求，成为急需解决的问题。钆特酸葡胺的化学结构式如下：
经检索相关文献，目前钆特酸葡胺的合成方法如下：
专利WO2009/103744，通过DOTA和氧化钆在注射等级的水中反应，再用葡甲胺调PH至6.8～7.4，通过过滤，然后放置在典型的通过高压灭菌器灭菌的瓶子中，直接制成制剂，期间也未对钆特酸葡胺进行纯化，这势必造成钆特酸葡胺质量的不可控性。合成路线如下：
目前尚无文献报道对钆特酸葡胺的纯化工艺。
发明内容
本发明的目的在于提供一种操作简便，适合工业化大化生产的钆特酸葡胺的纯化工艺。
本发明的主要技术方案如下：
通过将钆特酸葡胺粗品溶于50～60℃的甲醇溶液中，加入丙酮并冷却至0～5℃，将沉淀物过滤即得钆特酸葡胺纯品。
优选的，钆特酸葡胺粗品、甲醇和丙酮的重量比为1:2～3:6～9。
优选的，甲醇和丙酮的重量比为1:3。
更优选的，钆特酸葡胺粗品、甲醇和丙酮的重量比为1:3:9。
所述的钆特酸葡胺粗品，HPLC分析纯度95％以下。
优选的，钆特酸葡胺粗品先用甲醇混合，搅拌加热至50～55℃，搅拌溶清，加入丙酮，冷却至0～5℃，保温搅拌结晶2小时，过滤析出的沉淀，用丙酮洗涤，60℃真空干燥即得。
本发明的有益效果：
通过本发明方法对钆特酸葡胺粗品进行提纯后，经高效液相分析，所得钆特酸葡胺的纯度＞99.6％，可直接用于相应的药物生产。
具体实施方式
为了更好地理解本发明，下面结合实施例进一步阐明本发明的内容。但本发明的内容不仅仅限于下面的实施例。
本实施例中使用的钆特酸葡胺粗品，可参考背景技术的合成方法制备得到。
实施例1
10g钆特酸葡胺粗品(HPLC分析纯度90.1％)，30g甲醇混合，搅拌加热至50℃，搅拌溶清，加入丙酮90g，冷却至0～5℃，保温搅拌结晶2小时，过滤析出的沉淀，用丙酮洗涤，60℃真空干燥得8.6g，收率86％，HPLC分析纯度99.8％。
实施例2
10g钆特酸葡胺粗品(HPLC分析纯度94.2％)，25g甲醇混合，搅拌加热至55℃，搅拌溶清，加入丙酮75g，冷却至0～5℃，保温搅拌结晶2小时，过滤析出的沉淀，用丙酮洗涤，60℃真空干燥得9.1g，收率91％，HPLC分析纯度99.7％。
实施例3
10g钆特酸葡胺粗品(HPLC分析纯度93.5％)，20g甲醇混合，搅拌加热至50℃，搅拌溶清，加入丙酮60g，冷却至0～5℃，保温搅拌结晶2小时，过滤析出的沉淀，用丙酮洗涤，60℃真空干燥得8.9g，收率89％，HPLC分析纯度99.6％。
以上已对本发明创造的较佳实施例进行了具体说明，但本发明创造并不限于所述实施例，熟悉本领域的技术人员在不违背本发明创造精神的前提下还可作出种种等同的变型或替换，这些等同的变型或替换均包含在本申请权利要求所限定的范围内。
Claims (6)
1.一种钆特酸葡胺的提纯方法，其特征在于，该提纯方法是将钆特酸葡胺粗品溶于50～60℃的甲醇溶液中，加入丙酮并冷却至0～5℃，将沉淀物过滤即得钆特酸葡胺纯品。
2.根据权利要求1所述的一种钆特酸葡胺的提纯方法，其特征在于，钆特酸葡胺粗品、甲醇和丙酮的重量比为1:2～3:6～9。
3.根据权利要求1所述的一种钆特酸葡胺的提纯方法，其特征在于，甲醇和丙酮的重量比为1:3。
4.根据权利要求1所述的一种钆特酸葡胺的提纯方法，其特征在于，钆特酸葡胺粗品、甲醇和丙酮的重量比为1:3:9。
5.根据权利要求1所述的一种钆特酸葡胺的提纯方法，其特征在于，所述的钆特酸葡胺粗品，HPLC分析纯度95％以下。
6.根据权利要求1所述的一种钆特酸葡胺的提纯方法，其特征在于，钆特酸葡胺粗品先用甲醇混合，搅拌加热至50～55℃，搅拌溶清，加入丙酮，冷却至0～5℃，保温搅拌结晶2小时，过滤析出的沉淀，用丙酮洗涤，60℃真空干燥即得钆特酸葡胺纯品。
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113801071A (zh) * | 2021-09-14 | 2021-12-17 | 安徽普利药业有限公司 | 一种钆特酸葡甲胺的精制方法 |
| CN113925976A (zh) * | 2020-07-13 | 2022-01-14 | 山东威智百科药业有限公司 | 一种钆特酸葡甲胺注射液及其制备方法 |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4647447A (en) * | 1981-07-24 | 1987-03-03 | Schering Aktiengesellschaft | Diagnostic media |
| CN1130189A (zh) * | 1995-11-14 | 1996-09-04 | 武汉大学 | 合成环状多氨多羧酸螯合物造影剂的新方法 |
| WO2002062397A2 (en) * | 2001-02-05 | 2002-08-15 | Biophysics Assay Laboratory, Inc. | Chelates of metals which can be activated by neutrons and their use for the measurement of labeled specimens |
| WO2014055504A1 (en) * | 2012-10-02 | 2014-04-10 | Mallinckrodt Llc | Process for the preparation of macrocyclic polyazacarboxylate ligands and chelates |
| CN104955822A (zh) * | 2013-01-28 | 2015-09-30 | 爱克发医疗保健公司 | 制备1,4,7,10-四氮杂环十二烷-1,4,7,10-四乙酸及其络合物的方法 |
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- 2016-08-10 CN CN201610650121.XA patent/CN106220580B/zh active Active
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4647447A (en) * | 1981-07-24 | 1987-03-03 | Schering Aktiengesellschaft | Diagnostic media |
| CN1130189A (zh) * | 1995-11-14 | 1996-09-04 | 武汉大学 | 合成环状多氨多羧酸螯合物造影剂的新方法 |
| WO2002062397A2 (en) * | 2001-02-05 | 2002-08-15 | Biophysics Assay Laboratory, Inc. | Chelates of metals which can be activated by neutrons and their use for the measurement of labeled specimens |
| WO2014055504A1 (en) * | 2012-10-02 | 2014-04-10 | Mallinckrodt Llc | Process for the preparation of macrocyclic polyazacarboxylate ligands and chelates |
| CN104955822A (zh) * | 2013-01-28 | 2015-09-30 | 爱克发医疗保健公司 | 制备1,4,7,10-四氮杂环十二烷-1,4,7,10-四乙酸及其络合物的方法 |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113925976A (zh) * | 2020-07-13 | 2022-01-14 | 山东威智百科药业有限公司 | 一种钆特酸葡甲胺注射液及其制备方法 |
| CN113801071A (zh) * | 2021-09-14 | 2021-12-17 | 安徽普利药业有限公司 | 一种钆特酸葡甲胺的精制方法 |
| CN113801071B (zh) * | 2021-09-14 | 2023-04-07 | 安徽普利药业有限公司 | 一种钆特酸葡甲胺的精制方法 |
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