CN102292318A - 制备活化酯的方法 - Google Patents
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Abstract
本发明涉及一种制备式(I)的活化酯的方法，其中R为(C1-C6)烷基、芳基、杂芳基、环烷基或杂环烷基，且Alk为(C1-C6)亚烷基，所述方法包括：将二环己基胺P1盐与碳酸二琥珀酰亚胺基酯(DSC)在溶剂中反应，其中N-羟基琥珀酰亚胺的二环己基胺盐P2沉淀。本发明还涉及式P1的产物。
Description
本发明涉及式(I)的活化酯(activated ester)的制备：
其中R为(C1-C6)烷基、芳基、杂芳基、环烷基或杂环烷基，且Alk为(C1-C6)亚烷基。所述活化酯可用于制备缀合物(conjugate)，即其中抗体与生物活性化合物(例如细胞毒性化合物)经共价键连接。缀合物化学的更详细内容请参考例如，Birch和Lennox，Monoclonal Antibodies：Principles and Applications，Chap.4，Wiley-Liss，New York，N.Y.(1995)。
现有技术
WO 2004/016801公开了包括硝基琥珀酰亚胺单元的活化酯。在图1至图6中公开的这些化合物的制备基于与本发明不同的反应。
J.Med.Chem.2006，49(14)，4392-4408公开了活化酯的制备，特别是方案6的N-琥珀酰亚胺基-[4-甲基-4-(甲基二硫基)]戊酸酯，其通过与本发明不同的反应制备。
Langmuir 2000，16(1)，81-86在方案1中公开了琥珀酰亚胺基-3-(2-吡啶基二硫基)丁酸酯(SPDB)的制备，其通过将相应的酸与N-羟基琥珀酰亚胺偶合。
US 6407263、US 5872261、US 5892057和US 5942628公开了活化酯及其制备方法。
Can.J.Chem.1982，60，976公开了N-羟基琥珀酰亚胺的二环己基胺盐(P2)的制备，其通过二环己基胺与N-羟基琥珀酰亚胺在丙酮中反应。该化合物的CAS号为82911-72-6。
Can.J.Chem.1986，64(11)，2097-2102；J.Chem.Soc.，Perkin Trans.11985，4，765-8；Bull.Soc.Chem.Jpn 1986，59(8)，2505-8；Coll.Czech.Chem.Comm.1985，50(12)，2925-2936公开了由二环己基胺盐制备琥珀酰亚胺酯，但不使用碳酸二琥珀酰亚胺基酯。
Tetrahedron Letters 1979，49，4745-4746公开了DSC及其在合成中的价值(见方案2)。
Biochem.J.1978，173，723-737公开了在N-羟基琥珀酰亚胺和二环己基碳二亚胺的存在下制备活化酯。
JACS 2003，125(30)，8994-8995为技术背景的一部分。
发明概述
本发明涉及制备式(I)的活化酯的方法：
其中R为直链或支链的(C1-C6)烷基、芳基、杂芳基、环烷基或杂环烷基，且Alk为直链或支链的(C1-C6)亚烷基，所述方法包括将二环己基胺盐P1与碳酸二琥珀酰亚胺基酯(disuccinimidyl carbonate，DSC)在溶剂中反应，
其中N-羟基琥珀酰亚胺的二环己基胺盐P2沉淀出来
本发明还涉及式P1的产物：
更具体地，下列产物：
发明详述
定义
·烷基：直链或支链的饱和脂肪族烃基，其通过从烷烃除去一个氢原子得到。可以具体提及以下基团：甲基、乙基、丙基、丁基、戊基、己基、2-甲基丁基、2-甲基戊基和1-甲基戊基；
·亚烷基：二价基团，其通过从烷烃除去两个氢原子得到。可以具体提及以下基团：亚甲基(-CH2-)、亚乙基(-CH2CH2-)、亚正丙基(-CH2CH2CH2-)和亚丁基(-CH2CH2CH2CH2-)；
·环烷基：在环状结构中包含3至10个碳原子的环状烷基。可以具体提及以下基团：环丙基、环戊基和环己基；
·芳基：含有6至10个碳原子的芳香基团。可以具体提及以下基团：苯基、萘基、茚基和芴基；
·杂芳基：5至10个环原子的香基团，其包括一个或多个选自O、S或N的杂原子作为形成环的原子；
·杂环烷基：如上定义的环烷基，其还包括一个或多个选自O、S或N的杂原子作为形成环的原子。
所述制备基于二环己基胺盐P1与碳酸二琥珀酰亚胺基酯(DSC)在溶剂中反应，其中N-羟基琥珀酰亚胺的二环己基胺盐P2沉淀(方案1)。
R为：
·(C1-C6)烷基：例如甲基、乙基、丙基、丁基或戊基，其任选为支链的；
·(C3-C7)环烷基：例如环丙基；
·芳基：例如苯基；
·杂芳基：例如2-吡啶基
·杂环烷基：例如哌啶基。
Alk为(C1-C6)亚烷基，例如亚丙基、亚丁基或亚戊基，其任选为支链的。更具体地为(CH2)n基团，其中n表示1至6的整数。
二环己基胺的作用在于促进反应，并使得N-羟基琥珀酰亚胺不溶，因此得以释出。该反应具有以下优势：
·容易实现：简单接触、不加热、缓慢且可控地放出CO2；
·由于化合物P1呈羧酸盐形式，因此不必加入另外的碱以活化反应；
·释出的化合物P2在所用溶剂中仅具有极低的溶解度，并且其沉淀。因此大部分的P2可容易地通过简单的机械分离(例如过滤)去除；
·该反应使得以良好产率和良好纯度容易地获得活化酯成为可能。
P2通过用二环己基胺中和相应的酸进行制备。DSC为市售产品。
溶剂有利地为酮，其比常用于该类型的反应的溶剂(二氯甲烷或二甲基甲酰胺)显示出较低毒理性问题。所述酮可(例如)为丙酮或甲基异丁基酮(MIBK)。优选MIBK，因为其为水-可混溶的(在20℃，为1.55％ w/w)，其允许水性清洗产物，因此促进除去残留的P2。其还使得通过共沸蒸馏除去残留水成为可能。最后，MIBK为活化酯的良溶剂，但不是化合物P2和P1以及DSC的良溶剂，其允许P1与DSC之间缓慢且可控地反应：因此所述反应物可在最初完全混合，而没有产生安全性问题(快速反应且不可控地释放CO2)。
该反应在环境温度(大约20℃)进行。P2可在一些溶剂中自发地沉淀。为了促进P2的沉淀，在P1和DSC反应之后，可以冷却反应混合物(例如至接近0℃的温度)。
该反应使得具体制备以下活化酯成为可能：N-琥珀酰亚胺基-3-(2-吡啶基二硫基)丙酸酯(SPDP)、N-琥珀酰亚胺基-3-(2-吡啶基二硫基)丁酸酯(SPDB)或N-琥珀酰亚胺基-[4-甲基-4-(甲基二硫基)]戊酸酯，它们分别由以下的相应的酸的盐制备：
实施例
实施例1：N-琥珀酰亚胺基-[4-甲基-4-(甲基二硫基)]戊酸酯的制备
反应如下：
将4-甲基-4-(甲基二硫基)戊酸的二环己基胺盐(23g)和DSC(18.2g，1.1eq.)在161ml的MIBK中的悬浮液在大约20℃搅拌5小时。然后将悬浮液冷却至大约0℃，再在该温度搅拌1小时，然后过滤。
将固体用2×23ml的MIBK洗涤。合并有机相，用2×58ml的6N HCl水溶液洗涤，然后用92ml去离子水洗涤。然后将有机相在真空下浓缩至干。将所得固体溶于230ml二氯甲烷(DCM)，并将所得溶液用46g二氧化硅处理并搅拌10分钟，然后滤除二氧化硅，并用2×69ml的DCM洗涤。将该操作重复第二次。然后将有机相浓缩至大约一半体积，然后在大约20℃，在大约30分钟加入391ml的正庚烷。将所得白色悬浮液在该温度搅拌大约1小时，经大约1小时冷却至大约-10℃，然后在该温度搅拌大约1小时。然后过滤固体，用2×23ml的正庚烷洗涤，冷却至大约-10℃，然后在真空下在40℃干燥15小时。分离得到4-N-羟基琥珀酰亚胺基-[4-甲基-4-(甲基二硫基)]戊酸酯，产率为70.6％。其通过HPLC测定的纯度为99.65％(除去溶剂)。
实施例2：制备N-琥珀酰亚胺基-3-(2-吡啶基二硫基)丁酸酯(SPDB)反应如下：
将二环己基胺盐(40g，1eq.)和DSC(28.7g，1.1eq.)悬浮于280ml的MIBK中。将混合物在20±3℃搅拌4小时。将悬浮液冷却至0±3℃，在该温度放置30分钟并过滤，将获得的固体用冰冷的MIBK(120ml)洗涤。将母液用水(3×176ml)洗涤，并在旋转蒸发仪(浴温50℃)上在减压下蒸发至干，直至达到MIBK的量≤2.5％。获得的粗品SPDB为黄色油状物的形式。
然后在35±2℃将SPDB(32.5g)溶于乙醇(455ml)。将获得的溶液冷却至18±2℃：纯的SPDB开始结晶。经10分钟加入90ml正庚烷，剧烈结晶。将混合物冷却至0±3℃并经20分钟加入820ml正庚烷。将混合物在0±3℃搅拌1小时。通过过滤分离纯的SPDB，用2×90ml冰冷的正庚烷洗涤，并在烘箱中干燥(30℃，50mbar)。产率：84.8％，HPLC纯度：98.7％。
Claims (11)
1.一种制备式(I)的活化酯的方法：
其中R为直链或支链的(C1-C6)烷基、芳基、杂芳基、环烷基或杂环烷基，且Alk为直链或支链的(C1-C6)亚烷基，
所述方法包括将二环己基胺盐P1与碳酸二琥珀酰亚胺基酯(DSC)在溶剂中反应，
其中N-羟基琥珀酰亚胺的二环己基胺盐P2沉淀
2.权利要求1的方法，其中R为甲基、乙基、丙基、丁基或戊基，其任选为支链的，或为2-吡啶基。
3.权利要求1或2的方法，其中Alk为亚丙基、亚丁基或亚戊基，其任选为支链的。
4.权利要求1或2的方法，其中Alk为(CH2)n基团，n表示1至6的整数。
5.权利要求1至4中任一项的方法，其中所述反应在酮中进行。
6.权利要求5的方法，其中所述酮为MIBK。
7.权利要求1至6中任一项的方法，其中，在P1与DSC反应后，将反应混合物冷却，以促进P2的沉淀。
8.权利要求1至7中任一项的方法，其中P2通过机械分离去除。
9.权利要求8的方法，其中所述机械分离为过滤。
10.式P1的产物：
其中R和Alk如权利要求1至4中任一项所定义。
11.权利要求10的产物，其为下式：
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| FR0807090A FR2939795B1 (fr) | 2008-12-17 | 2008-12-17 | Procede de preparation d'esters actives |
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| PCT/FR2009/052528 WO2010076474A1 (fr) | 2008-12-17 | 2009-12-15 | Procede de preparation d'esters actives |
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| FR2963007B1 (fr) | 2010-07-26 | 2013-04-05 | Sanofi Aventis | Derives anticancereux, leur preparation et leur application therapeutique |
| US10436790B2 (en) | 2011-09-28 | 2019-10-08 | Waters Technologies Corporation | Rapid fluorescence tagging of glycans and other biomolecules with enhanced MS signals |
| US11352325B2 (en) | 2011-09-28 | 2022-06-07 | Waters Technologies Corporation | Rapid fluorescence tagging of glycans and other biomolecules with enhanced MS signals |
| JP7055634B2 (ja) | 2014-10-30 | 2022-04-18 | ウオーターズ・テクノロジーズ・コーポレイシヨン | 標識化グリコシルアミンの迅速調製およびそれを生成するグリコシル化生体分子の分析方法 |
| CN111796039B (zh) | 2014-11-13 | 2023-03-17 | 沃特世科技公司 | 快速标记的n-聚糖的液相色谱校准方法 |
| US11035832B2 (en) | 2016-06-21 | 2021-06-15 | Waters Technologies Corporation | Methods of electrospray ionization of glycans modified with amphipathic, strongly basic moieties |
| US11061023B2 (en) | 2016-06-21 | 2021-07-13 | Waters Technologies Corporation | Fluorescence tagging of glycans and other biomolecules through reductive amination for enhanced MS signals |
| CN109690297A (zh) | 2016-07-01 | 2019-04-26 | 沃特世科技公司 | 使用分子量截留过滤和过滤器上去糖基化从复杂基质快速制备标记的葡基胺的方法 |
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| WO2004016801A2 (en) * | 2002-08-16 | 2004-02-26 | Immunogen, Inc. | Cross-linkers with high reactivity and solubility and their use in the preparation of conjugates for targeted delivery of small molecule drugs |
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| US5872261A (en) | 1997-09-18 | 1999-02-16 | Pierce Chemical Company | Preparation of sulfo-N- hydroxy succinimide salts with intermediate formation of diester |
| US5892057A (en) | 1997-09-18 | 1999-04-06 | Pierce Chemical Company | Preparation of sulfo-N-hydroxysuccinimide salts |
| JP2002316987A (ja) * | 2001-04-20 | 2002-10-31 | Sankyo Co Ltd | ２−アルコキシベンゼン誘導体を含有する医薬 |
| WO2006054426A1 (ja) * | 2004-10-29 | 2006-05-26 | National University Corporation Toyama University | 高蛍光量子収率型疎水性蛍光プローブ、それを用いる生体高分子検出法ならびに生体高分子間相互作用検出法 |
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| WO2007008848A2 (en) * | 2005-07-07 | 2007-01-18 | Seattle Genetics, Inc. | Monomethylvaline compounds having phenylalanine carboxy modifications at the c-terminus |
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Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004016801A2 (en) * | 2002-08-16 | 2004-02-26 | Immunogen, Inc. | Cross-linkers with high reactivity and solubility and their use in the preparation of conjugates for targeted delivery of small molecule drugs |
Non-Patent Citations (3)
| Title |
|---|
| HARUO OGURA ET AL: "A NOVEL ACTIVE ESTER SYNTHESIS REAGENT （N，N"-DISUCCINIMIDYL CARBONATE）", 《TETRAHEDRON LETTERS》 * |
| JAN CARLSSON ET AL: "Protein Thiolation and Reversible Protein-Protein Conjugation N-SUCCINIMIDYL 3-(2-PYRIDYLDITHIO)PROPIONATE, A NEW HETEROBIFUNCTIONAL REAGENT", 《BIOCHEM.J.》 * |
| NOBUYA TOKUTAKE ET AL: "Detection of Unusual Lipid Mixing in Cholesterol-Rich Phospholipid Bilayers:The Long and the Short of It", 《J.AM.CHEM.SOC.》 * |
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Effective date of registration: 20161227 Address after: The United States Massachusetts Patentee after: Immunogen Inc. Address before: France Patentee before: Sai Nuofei |