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

doi:10.6023/cjoc202006078

Chinese Journal of Organic Chemistry ›› 2021, Vol. 41 ›› Issue (2): 788-794.DOI: 10.6023/cjoc202006078 Previous Articles Next Articles

Article

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)

1. cjoc202006078辅助材料.pdf(823KB)

Abstract

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

Cite this article

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.

Export EndNote|Reference Manager|ProCite|BibTeX|RefWorks

share this article

Fig. & Tab. 7

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

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

. The synthetic route of 13C4-nitrendipine

. Fragment ions of 13C4-nitrendipine

Figure 2. Structural formula of 13C4-nitrendipine

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

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

References 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

Supporting Info.

Knowledge

Abstract

Cite this article

share this article

Fig. & Tab. 7

References 45

Related Articles 15

Recommended Articles

Metrics

Comments

[1]	Penghui Li, Qingyang Xie, Fuxian Wan, Yuanhong Zhang, Lin Jiang. Synthesis and Fungicidal Activity of Novel Substituted Pyrimidine-5-carboxamides Bearing Cyclopropyl Moiety [J]. Chinese Journal of Organic Chemistry, 2024, 44(2): 650-656.
[2]	Fakai Zou, Nengzhong Wang, Hui Yao, Hui Wang, Mingguo Liu, Nianyu Huang. Regio- and Stereo-selective Synthesis of 1β-/3R-Aryl Thiosugar [J]. Chinese Journal of Organic Chemistry, 2024, 44(2): 593-604.
[3]	Luyao Li, Zhongwen He, Zhenguo Zhang, Zhenhua Jia, Teck-Peng Loh. Application of Triaryl Carbenium in Organic Synthesis [J]. Chinese Journal of Organic Chemistry, 2024, 44(2): 421-437.
[4]	Qinggang Mei, Qinghan Li. Recent Progress of Visible Light-Induced the Synthesis of C(3) (Hetero)arylthio Indole Compounds [J]. Chinese Journal of Organic Chemistry, 2024, 44(2): 398-408.
[5]	Weiqing Yang, Yanbing Ge, Yuanyuan Chen, Ping Liu, Haiyan Fu, Menglin Ma. Design and Synthesis of Fluorescent 1,8-Napthalimide Derivatives and Their Identification of Cysteine [J]. Chinese Journal of Organic Chemistry, 2024, 44(1): 180-194.
[6]	Qianfan Zhao, Yongzheng Chen, Shiming Zhang. Application and Mechanism Study of Carbon-Based Metal-Free Catalysts in Organic Synthesis [J]. Chinese Journal of Organic Chemistry, 2024, 44(1): 137-147.
[7]	Shan Chen, Zhilin Chen, Qiong Hu, Yanshuang Meng, Yue Huang, Pingfang Tao, Liru Lu, Guobao Huang. Recognition of Bis-thiourea Tweezers to Neutral Molecules in Non-Polar Solvent [J]. Chinese Journal of Organic Chemistry, 2024, 44(1): 277-281.
[8]	Huakun Wang, Xiaolong Ren, Yining Xuan. Study of the Halide Salt Catalyzed [3＋2] Cycloaddition of α,β-Epoxy Carboxylate with Isocyanate [J]. Chinese Journal of Organic Chemistry, 2024, 44(1): 251-258.
[9]	Yukun Jin, Baoyi Ren, Fushun Liang. Visible Light-Mediated Selective C—F Bond Cleavage of Trifluoromethyl Groups and Its Application in Synthesizing gem-Difluoro-Containing Compounds [J]. Chinese Journal of Organic Chemistry, 2024, 44(1): 85-110.
[10]	Cuiyun Ma, Hailan Luo, Fuhua Zhang, Dan Guo, Shuxing Chen, Fei Wang. Green Biosynthesis, Photophysical Properties and Application of 3-Pyrrolyl BODIPY [J]. Chinese Journal of Organic Chemistry, 2024, 44(1): 216-223.
[11]	Bozhen Wang, Jie Zhang, Chunhui Nian, Mingming Jin, Miaomiao Kong, Wulan Li, Wenfei He, Jianzhang Wu. Synthesis and Antitumor Activity of 3,4-Dichlorophenyl Amides [J]. Chinese Journal of Organic Chemistry, 2024, 44(1): 232-241.
[12]	Shihang Yu, Jiawei Liu, Biyu An, Qinghua Bian, Min Wang, Jiangchun Zhong. Asymmetric Synthesis of the Contact Sex Pheromone of Neoclytus acuminatus acuminatus (Fabricius) [J]. Chinese Journal of Organic Chemistry, 2024, 44(1): 301-308.
[13]	Yang Li, Jinding Yuan, Di Zhao. Deep Eutectic Solvent of 1,3-Dimethylurea/L-(+)-Tartaric Acid for the Green Synthesis of (E)-2-Styrylquinoline-3-carboxylic Acid Derivatives [J]. Chinese Journal of Organic Chemistry, 2023, 43(9): 3268-3276.
[14]	Dandan Sui, Nannan Cen, Ruoqu Gong, Yang Chen, Wenbo Chen. Supporting-Electrolyte-Free Electrochemical Synthesis of Trifluoromethylated Oxindoles in Continuous Flow [J]. Chinese Journal of Organic Chemistry, 2023, 43(9): 3239-3245.
[15]	Ruixia Cao, Yuping Jia. Synthesis and Biological Activity of Novel Pyrrolo[2,3-d]pyrimidine Derivatives Containing Coumarin [J]. Chinese Journal of Organic Chemistry, 2023, 43(9): 3304-3311.