CN104447528B - 吡啶-2,3-二羧酸二乙酯的制备方法 - Google Patents
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- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
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Abstract
本发明公开了一种吡啶‑2,3‑二羧酸二乙酯的制备方法：以丙炔胺、丁炔二酸二乙酯为原料，在有机溶剂中，以双氧水为氧化剂进行反应，最终得吡啶‑2,3‑二羧酸二乙酯；反应温度为60～70℃，反应时间为11～13小时，丙炔胺、丁炔二酸二甲酯、双氧水的摩尔比为1：1：1.4～1.6，所述有机溶剂为乙醇。采用本发明的方法制备吡啶‑2,3‑二羧酸二乙酯，具有产率高、生产成本低、环境污染小等技术优势。
Description
技术领域
本发明属医药中间体的合成方法，具体涉及吡啶-2,3-二羧酸二乙酯的制备方法。
背景技术
吡啶-2,3-二羧酸二乙酯是一种重要的医药中间体，在药物合成具有广泛的应用，例如，它是一种新型抗生素氟喹诺酮药物的中间体吡咯并吡啶环类化合物的起始合成原料(欧文华等，精细化工，2008,25,1029)。它也被用于合成一些先导化合物，如人肝素结合性表皮生长因子抑制剂(Yoshiizumi,K.等，Bioorg.Med.Chem.(生物有机和药物化学)，2003,11,433)。
吡啶-2,3-二羧酸二乙酯的水解产物喹啉酸，即吡啶-2,3-二羧酸，也是一类重要的医药、农药及压敏色素中间体。同时，喹啉酸是人体内一种神经传递素，并且杂志《神经精神药理学》(Neuropsychopharmacology)报道喹啉酸与数种脑部疾病的发生有关，如阿兹海默症、自闭症与精神分裂症。
目前，吡啶-2,3-二羧酸二乙酯主要有以下两种合成方法：
1、以喹啉酸为起始原料，经浓硫酸催化与乙醇进行酯化反应或用二氯亚砜酰化后再与乙醇反应得到目标产物(欧文华等，精细化工，2008,25,1029；Barczynski,P等Journal of MolecularStructure,2012，21-27，1018)。这些方法存在反应时间长、后处理时需要对废酸进行再处理、对环境产生较大污染等问题；而且，起始原料喹啉酸也不易得到，其常常通过环境污染严重的喹啉氧化法制得。
2、以2-氨基丁烯二酸二乙酯为原料与丙烯醛在回流(正丁醇为溶剂)条件下环加成反应15小时得到吡啶-2,3-二羧酸二乙酯(Keishiro,N.等，美国专利号4948896)。
此方法存在反应原料2-氨基丁烯二酸二乙酯市场上难以购买、价格昂贵，反应效率不高(收率为72.3％)，反应时间长，反应温度高等弊端。
发明内容
本发明要解决的技术问题是提供一种产率高、生产成本低、环境污染小的吡啶-2,3-二羧酸二乙酯的制备方法。
为了解决上述技术问题，本发明提供一种方便高效的吡啶-2,3-二羧酸二乙酯的制备方法：以丙炔胺、丁炔二酸二乙酯为原料，在有机溶剂中，以双氧水为氧化剂进行反应，最终得吡啶-2,3-二羧酸二乙酯；
反应温度为60～70℃(较佳为65℃)，反应时间为11～13小时(较佳为12小时)；丙炔胺、丁炔二酸二甲酯、双氧水的摩尔比为1：1：1.4～1.6(较佳为1：1：1.5)；所述有机溶剂为乙醇。
作为本发明的吡啶-2,3-二羧酸二乙酯的制备方法的改进：
反应所得的反应液常压蒸馏回收乙醇后，加水和乙酸乙酯萃取，所得的有机层(位于上层)依次经水、饱和食盐水洗涤后，常压蒸馏回收乙酸乙酯；所得浓缩物进行减压(6mmHg)蒸馏(备注说明：收集165～170/6mmHg馏分)，得吡啶-2,3-二羧酸二乙酯。
在本发明中，一般而言：每0.2mmol的丁炔二酸二乙酯配用100～150毫升作为有机溶剂的乙醇。
本发明以市场上容易购买的原料丙炔胺和丁炔二酸二乙酯为原料，反应高产率得到目标化合物。
本发明以35％双氧水(即，H2O2的质量浓度为35％)为绿色氧化剂，合成了吡啶-2,3-二羧酸二乙酯(式3)，本合成方法原料易得，反应条件温和，绿色环保，后处理简单，为高效合成2,3-吡啶二羧酸二乙酯提供了一种简单易行的方法。本发明的合成方法未见文献报道。
具体而言，本发明为吡啶-2,3-二羧酸二乙酯的合成提供一种新方法，以双氧水为氧化剂，乙醇为溶剂，丙炔胺(I)、丁炔二酸二乙酯(II)为反应原料一锅法环合反应，高产率得到目标化合物(III)。
本发明提供的2,3-吡啶二羧酸二乙酯合成方法具有以下特点：
1、本方法所用原料易得，后处理简单，对环境污染较小；
2、反应温度温和，安全方便；
3、产率高，可达80％以上。
4、此合成方法未见文献报道。
具体实施方式
下面将通过实施例对本发明作进一步的说明。
实施例1、吡啶-2,3-二羧酸二乙酯制备方法：
将丙炔胺11g(0.2mmol)、丁炔二酸二乙酯34g(0.2mmol)，100毫升乙醇，约26毫升35％双氧水(为0.30mmol)加至250ml反应瓶中，搅拌下，加热升温至65℃反应12小时，TLC检测反应液(石油醚：乙酸乙酯＝2:1的体积比)，丁炔二酸二乙酯消失。常压蒸馏回收乙醇后，加入100毫升水后用50mL乙酸乙酯萃取，重复三次，合并有机层(位于上层)，后用50ml水以及50ml饱和食盐水洗涤，常压蒸馏回收乙酸乙酯，然后改为减压(6mmHg)蒸馏，收集165～170/6mmHg馏分，得到产品吡啶-2,3-二羧酸二乙酯36.6克，收率：82％。1H NMR(500MHz,CDCl3)δ8.73(d,J＝3.9Hz,1H),8.16(dd,J＝7.9,1.5Hz,1H),7.46(dd,J＝7.9,4.8Hz,1H),4.44(q,J＝7.2Hz,2H),4.36(q,J＝7.2Hz,2H),1.39(t,J＝7.2Hz,3H),1.35(t,J＝7.2Hz,3H)；13C NMR(126MHz,CDCl3)δ165.28,164.24,150.68,150.20,136.65,125.39,123.71,61.24,61.07,13.05,13.02.HRMS(ESI):m/z calcd for C11H13NO4[M+H]+:224.0923,found:224.0921。
以下为不同条件的对照实验：
对比例1-1、将65℃搅拌反应12小时改成25℃搅拌反应12小时，其余同实施例1，未得到反应产物。
对比例1-2、取消双氧水的使用，即，反应中未加入双氧水，65℃搅拌反应12小时，未得到反应产物。
对比例1-3、将65℃搅拌反应12小时改成50℃搅拌反应12小时，其余同实施例1，得到产品吡啶-2,3-二羧酸二乙酯26克，收率：58％。
对比例1-4、取消双氧水的使用，即，反应中未加入双氧水，80℃搅拌反应12小时，得到产品吡啶-2,3-二羧酸二乙酯20克，收率：45％。
最后，还需要注意的是，以上列举的仅是本发明的若干个具体实施例。显然，本发明不限于以上实施例，还可以有许多变形。本领域的普通技术人员能从本发明公开的内容直接导出或联想到的所有变形，均应认为是本发明的保护范围。
Claims (2)
1.吡啶-2,3-二羧酸二乙酯的制备方法，其特征在于：以丙炔胺、丁炔二酸二乙酯为原料，在有机溶剂中，以双氧水为氧化剂进行反应，最终得吡啶-2,3-二羧酸二乙酯；
反应温度为60～70℃，反应时间为11～13小时；丙炔胺、丁炔二酸二甲酯、双氧水的摩尔比为1：1：1.4～1.6；所述有机溶剂为乙醇。
2.根据权利要求1所述的吡啶-2,3-二羧酸二乙酯的制备方法，其特征在于：
反应所得的反应液常压蒸馏回收乙醇后，加水和乙酸乙酯萃取，所得的有机层依次经水、饱和食盐水洗涤后，常压蒸馏回收乙酸乙酯；所得浓缩物进行减压蒸馏，得吡啶-2,3-二羧酸二乙酯。
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| US4948896A (en) * | 1987-07-08 | 1990-08-14 | Daiso Co., Ltd. | Process for preparing pyridine-2,3-dicarboxylic acid compounds |
| CN102276526A (zh) * | 2011-08-08 | 2011-12-14 | 中国科学院长春应用化学研究所 | 一种2-氨基吡啶类化合物合成方法 |
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| US4948896A (en) * | 1987-07-08 | 1990-08-14 | Daiso Co., Ltd. | Process for preparing pyridine-2,3-dicarboxylic acid compounds |
| CN102276526A (zh) * | 2011-08-08 | 2011-12-14 | 中国科学院长春应用化学研究所 | 一种2-氨基吡啶类化合物合成方法 |
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| Title |
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| A new strategy for facile synthesis of tetrasubstituted pyridine derivatives;Jun Chen,等;《Tetrahedron》;20130629;第69卷;第8069-8073页 * |
| N-Propargylic _-Enaminones: Common Intermediates for the Synthesis of Polysubstituted Pyrroles and Pyridines;Sandro Cacchi，等;《ORGANIC LETTERS》;20081231;第10卷;第2629-2632页 * |
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