CN104169252A - 用于纯化聚氨基羧酸酯的工艺 - Google Patents

用于纯化聚氨基羧酸酯的工艺 Download PDF

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CN104169252A
CN104169252A CN201280057802.5A CN201280057802A CN104169252A CN 104169252 A CN104169252 A CN 104169252A CN 201280057802 A CN201280057802 A CN 201280057802A CN 104169252 A CN104169252 A CN 104169252A
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polyaminocarboxylic
resin
acid ester
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CN104169252B (zh
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亚加迪什·巴布·兰吉塞提
马尼克·雷迪·普拉古尔拉
拉杰什·布德提
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Pharmaceutical Co Ltd Of Bai Oufu India
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C227/38—Separation; Purification; Stabilisation; Use of additives
    • C07C227/40—Separation; Purification
    • C07C227/42—Crystallisation
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C227/38—Separation; Purification; Stabilisation; Use of additives
    • C07C227/40—Separation; Purification
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C229/04—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C229/26—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having more than one amino group bound to the carbon skeleton, e.g. lysine
    • 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
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C229/04—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C229/06—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton
    • C07C229/10—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton the nitrogen atom of the amino group being further bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings
    • C07C229/16—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton the nitrogen atom of the amino group being further bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings to carbon atoms of hydrocarbon radicals substituted by amino or carboxyl groups, e.g. ethylenediamine-tetra-acetic acid, iminodiacetic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C229/04—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C229/24—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having more than one carboxyl group bound to the carbon skeleton, e.g. aspartic acid

Abstract

本发明涉及一种用于纯化聚氨基羧酸酯的改进工艺，所述聚氨基羧酸酯比如DOTA、DTPA、DO3A-butrol、BOPTA。

Description

用于纯化聚氨基羧酸酯的工艺
背景
本发明涉及聚氨基羧酸酯螯合物的纯化，所述聚氨基羧酸酯螯合物可以用作MRI造影剂。聚氨基羧酸酯是若干药品的一部分，所述药品包括钆特酸、钆布醇、钆贝酸、钆喷酸盐、钆弗塞胺、钆双胺。所有基于钆的药品的关键成分是与钆键合的螯合物。具有不含任何盐和金属的高度纯的螯合物是用于制备纯的基于钆的MRI剂的基础。
螯合物中的一些包括用于钆特酸的1,4,7,10-四氮杂环十二烷-1,4,7,10-四乙酸(DOTA)，用于钆喷酸盐的三胺五乙酸(DTPA)，用于钆贝酸的BOPTA，用于钆布醇的10-(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(DO3A-butrol)。
技术状态
文献中报告的螯合物中的一些涉及络合物和涉及到各种类型的树脂的高成本的纯化方法。
US5922862描述了用于纯化DOTA和其他cyclen取代的衍生物的程序。其描述了用于通过经由PVP树脂洗脱溶解在水中的粗产物来除去无机盐的程序。
Inorg.Chem.1980,19,1319描述了使用Dowex50W-X4树脂纯化DOTA的程序。
Inorg.Chem.1997,36,6086描述了用IR120H+树脂纯化DO3A-butrol以除去盐的程序。
同样地，若干其他树脂被报告用于纯化螯合物以除去无机盐。所涉及的树脂方法是高成本的且螯合物中的一些键合至树脂，该树脂然后需要用氨溶液或甲酸溶液洗涤。铵离子的除去变得特别困难，因为配体形成铵盐。
当在商业规模制造中需要大的离子交换柱时，螯合物的制造变得困难。因为大部分螯合物具有高的水溶解度，所以水的蒸馏变得费时且还导致潜在的降解产物。
发明概述
本发明的目的之一是提供用于制备不存在杂质的纯形式的螯合物的工艺，所述杂质例如无机盐和其他离子例如氯化物、溴化物、硫酸盐或类似物。
本发明的又一个目的是开发具有低的循环时间的工艺，该工艺是商业上可行的、低成本的且不利用树脂或利用最少量的树脂。
发明详述
不使用离子交换柱纯化的螯合物的纯化程序是特别有利的，因为它们是较不费时的且是相当低成本的。
现在，已经惊讶地发现，聚氨基羧酸酯化合物当在优选地0.75以下的高度酸性的条件下被分离时作为它们的酸式盐被分离，且通过重结晶从水或水溶剂混合物纯化这些盐之后，导致具有200ppm以下的含量的任何无机盐或离子例如钠、钾或类似物的聚氨基羧酸酯。用于盐形成的酸可以是盐酸、氢溴酸、硫酸和类似物。酸优选地是盐酸，且被分离的盐是作为盐酸盐。
采用的水溶剂混合物是水/丙酮、水/乙醇、水/甲醇或类似物以获得不含不期望的氯化物或溴化物离子的产物，这具有非常严格的规定。
将由此获得的盐溶解在水中且然后用碱性水溶液或可选择的树脂调节至所需的pH。这里值得注意地提及的是，采用的树脂的量是最少的且用于将溶液的pH调节为约1.5-3.0，由此消除任何另外的无机盐形成的机会。当采用的树脂是最少量时，工艺不会遭受现有技术的缺点。pH优选地用碱性阴离子树脂来调节。
在本工艺中被采用的树脂是以氢氧化物形式的树脂，例如AmberlystA26OH树脂和类似物。可以被用于pH调节的碱是氢氧化钾、氢氧化钠、氢氧化铵、三乙胺或类似物。
下面示出了用于DOTA的工艺示意图的实例。针对DOTA描述的实例不是限制性的，且相似的纯化工艺可以应用于任何聚氨基羧酸酯。
以下实施例更详细地描述工艺。
实施例1:DOTA的合成
将100ml水和100g cyclen HCl装载到烧瓶中。将反应物质冷却至0-10℃并用氢氧化钠将溶液的pH调节到10-10.5。将氯乙酸装载到反应中，同时用氢氧化钠溶液连续调节pH至10-10.5。将反应缓慢地升高至70-75℃且维持，直到反应完成。冷却反应物质并用浓HCl将反应的pH调节至0.75以下，且过滤分离的固体，该固体为DOTA盐酸盐。使固体从水中重结晶并检查硫酸盐灰分含量为0.10％以下。然后将固体溶解在800ml水中并用amberlyst A26OH树脂将溶液的pH调节至约2.5至3.0，以获得不含盐酸盐的螯合物。然后将物质过滤，且将获得的滤液蒸馏至200-300ml水，并通过加入丙酮使固体沉淀。将固体过滤并干燥以产生具有0.1％以下的硫酸盐灰分含量和200ppm以下的钠和氯化物含量、具有所需纯度的标题产物。
实施例2:BOPTA的合成
向烧瓶装载100ml水和50g N-[2-[(2-氨基乙基)氨基]乙基]-O-(苯基甲基)丝氨酸。将反应物质冷却至0-10℃并用氢氧化钠将溶液的pH调节到10.5-11.5。将氯乙酸装载到反应中，同时用氢氧化钠溶液连续调节pH至10.5-11.5。将反应温度缓慢地升高至70-75℃且维持，直到反应完成。冷却反应物质并用浓HCl将反应的pH调节至0.75以下，且装载丙酮。过滤分离的固体，该固体为BOPTA盐酸盐。使固体从水中重结晶并检查硫酸盐灰分含量为0.10％以下。然后将固体溶解在800ml水中并用amberlyst A26OH树脂将溶液的pH调节至约2.0。然后将物质过滤，且将滤液蒸馏至200-300ml水，并通过加入丙酮使固体沉淀。将由此获得的固体过滤并干燥以产生具有0.1％以下的硫酸盐灰分含量、具有所需纯度的产物。

Claims (7)

1.一种用于纯化聚氨基羧酸酯的工艺，所述聚氨基羧酸酯比如DOTA、DTPA、DO3A-butrol、BOPTA，所述工艺包括：
a)用无机酸处理聚氨基羧酸酯水溶液，其中所述溶液的pH为0.75以下；
b)使沉淀的聚氨基羧酸酯酸式盐在水或水溶剂混合物中重结晶；
c)用树脂或碱性溶液处理所述聚氨基羧酸酯酸式盐的水溶液以将pH维持在1.5至3.0；
d)分离纯的聚氨基羧酸酯螯合物。
2.根据权利要求1所述的工艺，其中采用的所述无机酸选自盐酸、氢溴酸、硫酸。
3.根据权利要求1所述的工艺，其中纯化的所述聚羧酸酯是DOTA，且采用的所述无机酸是盐酸。
4.根据权利要求1所述的工艺，其中纯化的所述聚羧酸酯是BOPTA，且采用的所述无机酸是盐酸。
5.根据权利要求1所述的工艺，其中采用的所述树脂是碱性阴离子树脂，例如amberlyst A26OH树脂。
6.根据权利要求1所述的工艺，其中被分离的所述聚氨基羧酸酯包含200ppm以下的钠、钾、硫酸盐、氯化物、溴化物、铵盐杂质。
7.通过权利要求1所述的工艺获得的基本上纯的聚氨基羧酸酯，其中所述硫酸盐灰分在0.1％以下，且离子杂质在200ppm以下。
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