稳定同位素标记1,4-二氢吡啶类药剂的5,6-位及其取代基碳的合成

doi:10.6023/cjoc202006078

有机化学 ›› 2021, Vol. 41 ›› Issue (2): 788-794.DOI: 10.6023/cjoc202006078 上一篇下一篇

研究论文

稳定同位素标记1,4-二氢吡啶类药剂的5,6-位及其取代基碳的合成

胡宇钊^a, 全海源^a^,^b, 王留洋^a, 王智楠^a, 梅向东^a, 宁君, 折冬梅^a^,^*()

a 中国农业科学院植物保护研究所北京 100193
b 中国化工集团曙光橡胶工业研究设计院有限公司广西桂林 541000

收稿日期:2020-06-30 修回日期:2020-08-15 发布日期:2020-10-12
通讯作者: 折冬梅
作者简介:
* Corresponding author. E-mail: dongmeishe@163.com
† 共同第一作者(These authors contributed equally to this work).
基金资助:
国家重点研究发展计划(2016YFD0200201); 国家自然科学基金(31772175); 国家自然科学基金(31621064)

Synthesis of Stable Isotope Labeled ¹³C₄-1,4-Dihydropyridines on 5,6-Position and Its Substituent Carbon

Yuzhao Hu^a, Haiyuan Quan^a^,^b, Liuyang Wang^a, Zhinan Wang^a, Xiangdong Mei^a, Jun Nin, Dongmei She^a^,^*()

a Institute of Plant Protection, Chinese Academy of Agricultural Sciences, Beijing 100193
b Shuguang Rubber Industry Research & Design Institute, Guilin, Guangxi 541000

Received:2020-06-30 Revised:2020-08-15 Published:2020-10-12
Contact: Dongmei She
Supported by:
the National Key Research and Development Program of China(2016YFD0200201); the National Natural Science Foundation of China(31772175); the National Natural Science Foundation of China(31621064)

文章分享

1. cjoc202006078辅助材料.pdf(823KB)

摘要/Abstract

1,4-二氢吡啶结构是许多生物活性物以及药物分子的重要骨架,同时也是非常重要的有机合成中间体。当前并没有一种适用的方法用于¹³C标记1,4-二氢吡啶的合成. 提供了一种¹³C标记1,4-二氢吡啶的合成方法以¹³C₂-乙酸钠为标记原料, 经磷酸酸化得到¹³C₂-乙酸, 羰基二咪唑酰化¹³C₂-乙酸得到¹³C₂-N-乙酰咪唑, 随后在咪唑钠的作用下进行克莱森缩合反应获得1,2,3,4-¹³C₄-乙酰乙酰咪唑的钠盐, 经乙酸酸化得到1,2,3,4-¹³C₄-乙酰乙酰咪唑, 再通过与醇进行酯化得到1,2,3,4-¹³C₄-乙酰乙酸酯, 1,2,3,4-¹³C₄-乙酰乙酸酯经氨基甲酸铵氨化得到1,2,3,4-¹³C₄-3-氨基丁烯酸酯。随后采用Hantzsch改进法合成了5,6-位及其取代基碳标记的¹³C₄-尼群地平、¹³C₄-苯磺酸氨氯地平和¹³C₄-马来酸氨氯地平. 该方法操作简单, 反应条件温和且产率高, 为1,4-二氢吡啶的5,6-位及其取代基引入¹³C同位素标记合成提供了新的思路,满足中国仿制药物一致性评价的稳定同位素内标自主合成需求。

关键词: 1,4-二氢吡啶, 乙酰乙酸酯, 同位素, 合成

1,4-Dihydropyridines are important central motifs that are abundant in many biologically active molecules and drug molecules, as well as versatile building blocks for organic synthesis. Currently, there is no suitable method for the synthesis of ¹³C-labeled 1,4-dihydropyridine. A method was described for the synthesis of ¹³C₄-1, 4-dihydropyridines in this article. Using ¹³C₂-sodium acetate as the raw material for labeling, ¹³C₄-acetoacetates were obtained by phosphoric acid acidification, ¹³C₂-Acetic acid was acylated with N,N-carbonyldiimidazole to give ¹³C₂-N-acetylimidazole. Then, the sodium salt of 1,2,3,4-¹³C₄-acetoacetylimidazole was synthesized from ¹³C₂-N-acetylimidazole by Claisen condensation under the catalysis of sodium imidazolate. The sodium salt of 1,2,3,4-¹³C₄-acetoacetylimidazole was acidified with acetic acid to obtain 1,2,3,4-¹³C₄-acetoacetylimidazole, and then esterified with alcohol to obtain 1,2,3,4-¹³C₄-acetylacetic esters. 1,2,3,4-¹³C₄-acety- lacetic esters were aminated by ammonium carbamate to give 1,2,3,4-¹³C₄-3-aminocrotonates. Subsequently, 5,6-position and its substituent carbon-labeled ¹³C₄-nitrandipine, ¹³C₄-amlodipine besylate and ¹³C₄-amlodipine maleate were synthesized using Hantzsch modified method. The method has simple operation, mild reaction conditions, and high yield. This study provides a new idea for the introduction of 1,4-dihydropyridine which 5,6-position and its substituents are labeled with ¹³C isotope. And it meets the independent synthesis requirements of stable isotope internal standards for the consistency evaluation of generic drugs in China.

Key words: 1,4-dihydropyridines, acetylacetic esters, isotope, synthesis

引用此文

胡宇钊, 全海源, 王留洋, 王智楠, 梅向东, 宁君, 折冬梅. 稳定同位素标记1,4-二氢吡啶类药剂的5,6-位及其取代基碳的合成[J]. 有机化学, 2021, 41(2): 788-794.

Yuzhao Hu, Haiyuan Quan, Liuyang Wang, Zhinan Wang, Xiangdong Mei, Jun Nin, Dongmei She. Synthesis of Stable Isotope Labeled ¹³C₄-1,4-Dihydropyridines on 5,6-Position and Its Substituent Carbon[J]. Chinese Journal of Organic Chemistry, 2021, 41(2): 788-794.

导出引用 EndNote|Reference Manager|ProCite|BibTeX|RefWorks

分享此文

图/表 7

图式1. 13C4-1,4-二氢吡啶的合成路线

Scheme 1. Synthetic route of 13C4-1,4-dihydropyridines

图式2. 已报道的13C标记乙酰乙酸酯的合成路线

Scheme 2. Reported synthetic route of 13C-labeled acetylacetic esters

Scheme 3. 13C4-尼群地平的合成路线

. The synthetic route of 13C4-nitrendipine

Figure 1. 13C4-尼群地平的碎片离子

. Fragment ions of 13C4-nitrendipine

图2. 13C4-尼群地平的结构式

Figure 2. Structural formula of 13C4-nitrendipine

Scheme 4. 13C4-苯磺酸氨氯地平和13C4-马来酸氨氯地平的合成路线

. Synthetic route of 13C4-amlodipine besylate and 13C4-amlodipine maleate

图3. 13C4-氨氯地平(1)、13C4-苯磺酸氨氯地平(2)和13C4-马来酸氨氯地平(3)的结构式

Figure 3. Structural formula (1) of 13C4-amlodipine besylate (2) and 13C4-amlodipine maleate (3)

参考文献 45

[1]	Wan J.; Liu Y. RSC. Adv. 2012, 2, 9763. doi: 10.1039/c2ra21406g
[2]	Eisner U.; Kuthan J. Chem. Rev. 1972, 72, 1. doi: 10.1021/cr60275a001
[3]	Kappe C.-O. ChemInform 2001, 32, 1043.
[4]	Samrat A.-K, Pratibha B.-A. Mini-Rev. Med. Chem. 2014, 14, 282. doi: 10.2174/1389557513666131119204126
[5]	Janis R.-A.; Triggle D.-J. J. Med. Chem. 1983, 26, 775. pmid: 6304312
[6]	Boecker R.-H.; Guengerich F.-P. J. Med. Chem. 1986, 29, 1596. doi: 10.1021/jm00159a007
[7]	Sausins A.; Duburs G. ChemInform 1988, 19, 269.
[8]	Godfraind T.; Miller R.; Wibo M. Pharmacol. Rev. 1986, 38, 321. pmid: 2432624
[9]	Mager P.-P.; Coburn R.-A.; Solo A.-J.; Triggle D.-J.; Rothe H. Drug Des. Discovery 1992, 8, 273.
[10]	Stilo A.-D.; Visentin S.; Cena C.; Gasco A.-M.; Ermondi G.; Gasco A. J. Med. Chem. 1998, 41, 5393. pmid: 9876109
[11]	Bossert F.; Meyer H.; Wehinger E. Angew. Chem., Int. Ed. Engl. 1981, 20, 762. doi: 10.1002/(ISSN)1521-3773
[12]	Sunkel C.-E.; Miguel C.-J.; Santos L.; Garcia A.-G.; Artalejo C.-R.; Villarroya M.; Gonzalez-Morales M.-A.; Lopez M.-G.; Cillero J. J. Med. Chem. 1992, 35, 2407. pmid: 1377748
[13]	Cooper K.; Fray M.-J.; Parry M.-J.; Richardson K.; Steele J. J. Med. Chem. 1992, 35, 3115. pmid: 1507200
[14]	Lavilla R. J. Chem. Soc., Perkin. Trans. 1 2002, 1141.
[15]	Comins D.-L.; O'Connor S. Adv. Heterocycl. Chem. 1988, 44, 199.
[16]	Goldmann S.; Stoltefuss J. Angew. Chem., Int. Ed. Engl. 1991, 30, 1559. doi: 10.1002/(ISSN)1521-3773
[17]	Chandra R. Adv. Heterocycl. Chem. 2001, 78, 269.
[18]	Fischer C.; Heuer B.; Heuck K.; Eichelbaum M. Biomed. Environ. Mass Spectrom. 1986, 13, 645. pmid: 2952187
[19]	Ohtaka K.; Kajiwara M. J. Labelled Compd. Radiopharm. 2003, 46, 1177. doi: 10.1002/(ISSN)1099-1344
[20]	Quan H.-Y.; Wang L.-Y.; Wang Z.-N.; Nin J.; Mei X.-D.; She D.-M. ChemistrySelect 2020, 5, 7222. doi: 10.1002/slct.v5.24
[21]	Yuan S.-S.; Ajami A.-M. J. Labelled Compd. Radiopharm. 1984, 21, 525. doi: 10.1002/jlcr.v21:6
[22]	Reynolds K.-A.; O'Hagan D.; Gani D.; Robinson J.-A. J. Chem. Soc., Perkin. Trans. 1 1988, 3195.
[23]	Huetter P.; Zeller K.-P. Synthesis 1985, 334.
[24]	Townsend C.-A.; Christensen S.-B.; Davis S.-G. J. Chem. Soc., Perkin Trans. 1 1988, 839.
[25]	Pillai A.-D.; Rani S.; Rathod P.-D.; Xavier F.-P.; Vasu K.-K.; Padh H.; Sudarsanam V. Bioorg. Med. Chem. 2005, 13, 1275. doi: 10.1016/j.bmc.2004.11.016
[26]	Sanchez L.-M.; Sathicq Á.-G.; Romanelli G.-P.; González L.-M.; Villa A.-L. Mol. Catal. 2017, 435, 1.
[27]	Firuzi O, Javidnia K, Mansourabadi E. Arch. Pharm. Res. 2013, 36, 1392. doi: 10.1007/s12272-013-0149-8
[28]	Gaveriya H.; Desai B.; Vora V.; Shah A. Heterocycl. Commun. 2011, 7, 167.
[29]	Jian Z.; Long F.-J. J. Chem. Soc. Pak. 2011, 33, 916.
[30]	Suárez M; Ricard M.-D.-A; Ramírez R.-O.-O; Martin N. New. J. Chem. 2005, 29, 1567. doi: 10.1039/b506018d
[31]	Kumar R.; Andhare N.-H.; Shard A.; Richa; Sinha, A.-K.RSC Adv. 2014, 4, 19111. doi: 10.1039/C4RA02169J
[32]	Sun J.; Zhang-Negrerie A.-D.; Dua Y. Adv. Synth. Catal. 2016, 358, 2035. doi: 10.1002/adsc.v358.13
[33]	Litvi M.; Filipan M.; Pogoreli I.; Cepanec I. Green. Chem. 2005, 7, 771. doi: 10.1039/b510276f
[34]	Zhou K.; Wang X.-M.; Zhao Y.-Z.; Cao Y.-X.; Fu Q.; Zhang S.-Q. Med. Chem. Res. 2011, 20, 1325. doi: 10.1007/s00044-010-9477-0
[35]	Jin L.-Y.; Zhou H. China Prac. Med. 2011, 13, 216. (in Chinese)
	金连玉, 周辉, 中国实用医药, 2011, 13, 216.).
[36]	Furlan B.; Grdadolnik, S0.-G.; Hocevar, S.Croat. Chem. Acta 2009, 82, 299.
[37]	Zhang Y.-L.; Zhang Y.; Chen J.-C.; Chen Z.; Sun T.-M. J. Shenyang Pharm. Univ. 2015, 32 ( 3), 188. (in Chinese)
	张亚鲁, 张毅, 陈建超, 陈钊, 孙铁民, 沈阳药科大学学报, 2015, 32 ( 3), 188.).
[38]	Mueller C.-A.; Ana B.-B.-G.; Weinmann W. J. Mass Spectrom. 2004, 39, 639. doi: 10.1002/(ISSN)1096-9888
[39]	Legeay J.-C.; Daniel C.; Paquin L.; Eynde J.-J.-V.; Bazureau J.-P. Heterocycl. Commun. 2009, 15, 91.
[40]	Yang C.-H.; Li Q.; Liu X.-H.; Zhao X.-K.; Cui Y.-X. J. Chin. Pharm. Sci. 2004, 13, 49.
[41]	Gotrane D.-M.; Deshmukh R.-D.; Ranade P.-V.; Sonawane S.-P.; Bhawal B.-M.; Gharpure M.-M.; Gurjar M.-K. Org. Process Res. Dev. 2010, 14, 640. doi: 10.1021/op900283z
[42]	Xu F.; Hong Q.; Xu Y.; Zhu R.-F.; Shao G.-Q. Anhui Chem. Ind. 2013, 39, 23. (in Chinese)
	许峰, 洪强, 徐勇, 朱仁发, 邵国泉, 安徽化工, 2013, 39, 23.).
[43]	Zhang D.-X.; Li Z.-Q. Guide China Med. 2011, 9, 49. (in Chinese)
	张道旭, 李治乾, 中国医药指南, 2011, 9, 49.).
[44]	G Wang, X.-K.; Ou, W.-H.; Liu, F.; He, X.-M.; Pan, X.-H. Fine Chem. 2009, 26, 1005. (in Chinese)
	王晓科, 欧文华, 刘烽, 何锡敏, 潘仙华, 精细化工, 2009, 26, 1005.).
[45]	Zhang D.-X.; Li Z.-Q. Guide China Med. 2011, 9, 49. (in Chinese)
	张道旭, 李治乾, 中国医药指南, 2011, 9, 49.).

稳定同位素标记1,4-二氢吡啶类药剂的5,6-位及其取代基碳的合成

Synthesis of Stable Isotope Labeled ¹³C₄-1,4-Dihydropyridines on 5,6-Position and Its Substituent Carbon

RichHTML

PDF

补充材料

可视化

摘要/Abstract

引用此文

分享此文

图/表 7

参考文献 45

相关文章 15

编辑推荐

相关统计

本文评价

[1]	冯康博, 陈炯, 古双喜, 王海峰, 陈芬儿. 全连续流反应技术在药物合成中的新进展(2019~2022)[J]. 有机化学, 2024, 44(2): 378-397.
[2]	李鹏辉, 谢青洋, 万福贤, 张元红, 姜林. 含环丙基的新型取代嘧啶-5-甲酰胺的合成及杀菌活性研究[J]. 有机化学, 2024, 44(2): 650-656.
[3]	邹发凯, 王能中, 姚辉, 王慧, 刘明国, 黄年玉. 1β-/3R-芳基硫代糖的区域与立体选择性合成[J]. 有机化学, 2024, 44(2): 593-604.
[4]	李路瑶, 贺忠文, 张振国, 贾振华, 罗德平. 三芳基碳正离子在有机合成中的应用[J]. 有机化学, 2024, 44(2): 421-437.
[5]	梅青刚, 李清寒. 可见光促进C(3)(杂)芳硫基吲哚化合物的合成研究进展[J]. 有机化学, 2024, 44(2): 398-408.
[6]	杨维清, 葛宴兵, 陈元元, 刘萍, 付海燕, 马梦林. 1,8-萘酰亚胺衍生物的设计、合成及其对半胱氨酸的识别研究[J]. 有机化学, 2024, 44(1): 180-194.
[7]	于士航, 刘嘉威, 安碧玉, 边庆花, 王敏, 钟江春. 黑腹尼虎天牛接触性信息素的不对称合成[J]. 有机化学, 2024, 44(1): 301-308.
[8]	赵茜帆, 陈永正, 张世明. 碳基非金属催化剂在有机合成领域的应用及机理研究[J]. 有机化学, 2024, 44(1): 137-147.
[9]	陈珊, 陈志林, 胡琼, 蒙艳双, 黄悦, 陶萍芳, 卢丽如, 黄国保. 含双硫脲基团分子钳在非极性溶剂中识别中性分子[J]. 有机化学, 2024, 44(1): 277-281.
[10]	王化坤, 任晓龙, 宣宜宁. 卤盐催化的α,β-环氧羧酸酯与异氰酸酯[3＋2]环加成反应研究[J]. 有机化学, 2024, 44(1): 251-258.
[11]	金玉坤, 任保轶, 梁福顺. 可见光介导的三氟甲基的选择性C－F键断裂及其在偕二氟类化合物合成中的应用[J]. 有机化学, 2024, 44(1): 85-110.
[12]	马翠云, 罗海澜, 张福华, 郭丹, 陈树兴, 王飞. 3-Pyrrolyl BODIPY的绿色生物合成、光物理性质及应用研究[J]. 有机化学, 2024, 44(1): 216-223.
[13]	王博珍, 张婕, 粘春惠, 金茗茗, 孔苗苗, 李物兰, 何文斐, 吴建章. 含有3,4-二氯苯基的酰胺类化合物的合成及抗肿瘤活性研究[J]. 有机化学, 2024, 44(1): 232-241.
[14]	曹瑞霞, 贾玉萍. 含香豆素的吡咯并[2,3-d]嘧啶衍生物的合成及生物活性研究[J]. 有机化学, 2023, 43(9): 3304-3311.
[15]	李焕清, 陈兆华, 陈祖佳, 邱琪雯, 张又才, 陈思鸿, 汪朝阳. 基于有机小分子的汞离子荧光探针研究进展[J]. 有机化学, 2023, 43(9): 3067-3077.

稳定同位素标记1,4-二氢吡啶类药剂的5,6-位及其取代基碳的合成

Synthesis of Stable Isotope Labeled 13C4-1,4-Dihydropyridines on 5,6-Position and Its Substituent Carbon

RichHTML

PDF

补充材料

可视化

摘要/Abstract

引用此文

分享此文

图/表 7

参考文献 45

相关文章 15

编辑推荐

相关统计

本文评价

Synthesis of Stable Isotope Labeled ¹³C₄-1,4-Dihydropyridines on 5,6-Position and Its Substituent Carbon