CN1070843C - (s)-n,n'-二[2-羟基-1-(羟甲基)乙基)-5-[(2-羟基-1-氧代丙基)氨基]-2,4,6-三碘-1,3-苯二羧酰胺从水中结晶的方法 - Google Patents

(s)-n,n'-二[2-羟基-1-(羟甲基)乙基)-5-[(2-羟基-1-氧代丙基)氨基]-2,4,6-三碘-1,3-苯二羧酰胺从水中结晶的方法 Download PDF

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CN1070843C
CN1070843C CN96191028A CN96191028A CN1070843C CN 1070843 C CN1070843 C CN 1070843C CN 96191028 A CN96191028 A CN 96191028A CN 96191028 A CN96191028 A CN 96191028A CN 1070843 C CN1070843 C CN 1070843C
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iopamidol
crystallization
hydroxy
water
solution
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CN1164853A (zh
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M·莫罗
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Bracco International BV
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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07CACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00Preparation of carboxylic acid amides
    • C07C231/22Separation; Purification; Stabilisation; Use of additives
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00Preparations for testing in vivo
    • A61K49/04X-ray contrast preparations

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Abstract

本发明涉及称作碘帕醇的S-N,N′-二〔2-羟基-1-(羟甲基)乙基〕-5-〔(2-羟基-1-氧代丙基)氨基〕-2,4,6-三碘-1,3-苯二羧酰胺从水中结晶的一种方法,根据本发明,可获得符合药典标准的结晶无水碘帕醇。

Description

(S)-N,N′-二〔2-羟基-1-(羟甲基)乙基〕-5 -〔(2-羟基-1-氧代丙基)氨基〕-2,4,6 -三碘-1,3-苯二羧酰胺从水中结晶的方法
本发明涉及S-N,N′-二〔2-羟基-1-(羟甲基)乙基〕-5-〔(2-羟基-1-氧代丙基)氨基〕-2,4,6-三碘-1,3-苯二羧酰胺从水中结晶的一种方法,该化合物以碘帕醇的名称为人们所熟知,是非离子型X射线造影剂领域中的一种世界顶尖的化合物。
在文献中已知碘帕醇的合成,例如在GB 1472050中描述过,预知在方法的最后通过应用离子交换树脂和随后从乙醇中再结晶进行最终净化,生成可溶于水的产物(在一个4℃下的冷藏室中,历时数天,2.3克产物从10克碘帕醇在10毫升水中形成的溶液中结晶出来)。这种良好的溶解性和它在甲醇中极小的溶解性以及在环氧乙烷、苯、氯仿和乙醇中的不溶性在连续发表的论文中报道过,例如Felder E.等,Boll.Chim.Farm.,1981,120,639或Felder E.,Invest.Radiol.,1984,19,S164和Analytical Profiles ofDrug Substances(药物分析模型),17卷,第115页中关于碘帕醇的专题。
所述论文描述了碘帕醇的不同晶形,即:无水的、一水合物的和五水合物的形式,每种形式有不同的红外光谱、X射线粉末衍射图和独特的焓测定和重量测定的差示热分析图。所述晶体以极慢的动力从水溶液中获得。
近来,专利申请WO-A-9504031提及了碘帕醇从中结晶的不同溶剂(正丁醇、异丁醇和/或叔丁醇)。此外,该申请还描述了从水中结晶碘帕醇以获得一种符合药典标准(例如美国药典标准(US Pharmacopeia美国药典ⅩⅫ712))的产物的尝试,但结果很差,因为产率低和必须通过在高于100℃的温度下持续加热以去除结晶水。
我们现在已惊喜地发现,这也是本发明的一个目的,碘帕醇可以以工业上可接受的产率轻易地从水中结晶,从而生成一种满足药典标准的产物。
实际上,按照本发明的方法,可以获得一种符合药典标准的结晶无水碘帕醇。
此外,按照本发明的方法,用水作为碘帕醇的结晶溶剂,在负有责任的和现代的环境政策中尤其重要,因为它避免了有机溶剂的应用。
本发明的方法包括以下步骤:--通过加热将碘帕醇溶于去离子水中;--用活性碳进行溶液的脱色;--在60℃下水溶液的真空浓缩;--添加无水碘帕醇的结晶胚,以便为结晶提供晶种;--在60℃下结晶;--所生成沉淀物的过滤;--湿产物的真空干燥。
尤其优选的是在有不同数量的合适的结晶胚(1%-5%-10%)存在的情况下溶液呈饱和的结晶条件,其中碘帕醇在水中的浓度大于78.6%(克/毫升溶液)。
按照本发明的方法获得的无水碘帕醇不吸收湿度,而从碘帕醇水溶液的简单浓缩到干燥生成的非晶形产物立即通过在水中的增溶而吸收水分。
已令人惊喜地发现,这也是本发明的另一个目的,当按照本发明获得的产物含有来自前面的合成步骤的残余溶剂时,用合适数量的直链或支链(C1-C4)醇进行结晶固体的简单冲洗,可将所述残余溶剂的含量降至10ppm以下。
冲洗对于去除例如二甲基乙酰胺,专利GB1472050中公开的在碘帕醇合成方法中应用的一种溶剂,特别有用。
尤其优选的是绝对乙醇的应用,因为它容易获得、其毒理模型已知且它容易进行工业处理。
以下实施例意在举例说明实施本发明的方法的最佳实验条件。
实施例1碘帕醇从水中的结晶
500千克碘帕醇在600千克去离子水中形成的溶液用5千克CarbopuronR进行脱色。悬浮物被过滤并经100千克水冲洗。溶液在约60℃和150毫米汞柱压力下被浓缩至370升(625千克)的体积,并用1千克无水结晶胚接种。当温度小心地保持在60℃时,溶液结晶,历时8小时。然后在60℃下它被过滤而不冲洗,水溶液被收集(210千克)。在60℃下,浓缩至干(5~30毫米汞柱)后,得到350千克所希望的产物。
产率:69.9%
产物的生化性质符合药典标准。
实施例2碘帕醇从按照实施例1获得的母液中的回收
从三批结晶,每批500千克碘帕醇中获得的母液收集在一起,用285升去离子水稀释。在80℃下,溶液用5千克CarbopuronR脱色并过滤。过滤器用100千克水冲洗。在60℃和150毫米汞柱下,溶液被浓缩,生成333升残液,然后残液被1千克前面制备的产物接种。在60℃下产物结晶,历时8小时。然后过滤而不冲洗,355千克湿产物在60℃和真空下被浓缩,从而生成316千克碘帕醇。
产率(干燥物):63%
从实施例1开始的结晶产率:90.9%
产物的生化性质符合药典标准。
实施例3按照实施例1获得的晶体的净化,当存在二甲基乙酰胺残余物时。
按照实施例1的步骤过滤后获得的结晶固体,其中二甲基乙酰胺含量为50ppm,用绝对乙醇冲洗5次(比率等于12.5%乙醇重量/碘帕醇重量),生成的固体在50℃和真空下被干燥。
所生成产物的分析表明二甲基乙酰胺的含量等于16ppm。

Claims (5)

1一种碘帕醇从水中结晶的方法,以生成结晶无水形式的所述化合物,包括以下步骤:--通过加热将碘帕醇溶于去离子水中;--用活性碳进行溶液的脱色;--在60℃下水溶液的真空浓缩;--添加无水碘帕醇的结晶胚,以便为结晶提供晶种;--在60℃下结晶;--所生成沉淀物的过滤;--湿产物的真空干燥。
2根据权利要求1的方法,其中碘帕醇在水溶液中的浓度大于78.6%(克/毫升溶液)。
3根据权利要求1的方法,其中碘帕醇无水形式的结晶胚以1~10%的起始碘帕醇的量被加入。
4根据权利要求1的方法,其中过滤后的结晶固体进一步被直链的或支链的(C1-C4)醇冲洗。
5根据权利要求4的方法,其中所述醇是乙醇。
CN96191028A 1995-09-08 1996-08-02 (s)-n,n'-二[2-羟基-1-(羟甲基)乙基)-5-[(2-羟基-1-氧代丙基)氨基]-2,4,6-三碘-1,3-苯二羧酰胺从水中结晶的方法 Expired - Lifetime CN1070843C (zh)

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Application Number Priority Date Filing Date Title
IT95RM000599 IT1277934B1 (it) 1995-09-08 1995-09-08 Processo per la cristallizzazione da acqua della s-n,n' -bis- ( 2-idrossi -1 -(idrossimetil) etil) -5- ((2 -idrossi -1- ossopropil)
ITRM95A000599 1995-09-08
IT95RM000831 IT1277950B1 (it) 1995-12-19 1995-12-19 Processo per la cristallizzazione da acqua della s-n,n'-bis (2-idrossi -1-(idrossimetil)etil)-5-((2-idrossi-1-ossopropil)ammino).2,4,6-
ITRM95A000831 1995-12-19

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CN100418945C (zh) * 2006-01-13 2008-09-17 江苏省原子医学研究所 一种碘昔兰的纯化方法

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PT101720A (pt) * 1995-06-08 1997-01-31 Hovione Sociedade Quimica S A Processo para a purificacao e cristalizacao de iopamidol
KR20000031642A (ko) * 1998-11-09 2000-06-05 강재헌 이오파미돌의 결정화 방법
CN1608066A (zh) * 2001-11-16 2005-04-20 兰贝克赛实验室有限公司 结晶亚胺培南的制备方法
US20110021834A1 (en) * 2009-07-21 2011-01-27 Ge Healthcare As Continuous process of preparing intermediate for non-ionic x-ray contrast agents
WO2012136813A2 (en) 2011-04-07 2012-10-11 Universitetet I Oslo Agents for medical radar diagnosis
WO2018104228A1 (en) 2016-12-05 2018-06-14 Bracco Imaging Spa Mechanochemical synthesis of radiographic agents intermediates

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WO1995004031A1 (en) * 1993-07-30 1995-02-09 Zambon Group S.P.A. Process for the crystallization of iopamidol

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CH608189A5 (zh) * 1974-12-13 1978-12-29 Savac Ag

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WO1995004031A1 (en) * 1993-07-30 1995-02-09 Zambon Group S.P.A. Process for the crystallization of iopamidol

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN100418945C (zh) * 2006-01-13 2008-09-17 江苏省原子医学研究所 一种碘昔兰的纯化方法

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NO971863L (no) 1997-04-23
WO1997009300A1 (en) 1997-03-13
US5689002A (en) 1997-11-18
CA2204734C (en) 2009-12-29
CZ138597A3 (cs) 1998-02-18
ATE187437T1 (de) 1999-12-15
AU6788896A (en) 1997-03-27
EP0790979B1 (en) 1999-12-08
HK1001861A1 (en) 1998-07-17
DE69605528D1 (de) 2000-01-13
EP0790979A1 (en) 1997-08-27
CA2204734A1 (en) 1997-03-13
CN1164853A (zh) 1997-11-12
PL184937B1 (pl) 2003-01-31
AU708195B2 (en) 1999-07-29
NO308841B1 (no) 2000-11-06
KR100270411B1 (ko) 2000-11-01
JP4070235B2 (ja) 2008-04-02
HU220965B1 (hu) 2002-07-29
HUP9801837A3 (en) 2001-06-28
JPH10508878A (ja) 1998-09-02
PL320027A1 (en) 1997-09-01
HUP9801837A2 (hu) 1998-12-28
KR970707073A (ko) 1997-12-01
NO971863D0 (no) 1997-04-23
BR9606624A (pt) 1997-11-11

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