河北师范大学学报—

期刊信息

刊名：河北师范大学学报（自然科学版）Journal of Hebei Normal University (Natural Science)
主办：河北师范大学
ISSN： 1000-5854
CN： 13-1061/N
中国科技核心期刊
中国期刊方阵入选期刊
中国高校优秀科技期刊
华北优秀期刊
河北省优秀科技期刊

协同采编系统

友情链接

Vonafexor(EYP001)的合成

姜珊¹

刘洪涛²

田文华¹

李文燕¹

(1.河北师范大学化学与材料科学学院，河北省有机功能分子重点实验室, 河北石家庄050024; 2.河北省人民医院药学部，河北石家庄050051）
DOI： 10.13763/j.cnki.jhebnu.nse.202203015

Synthesis of Vonafexor(EYP001)

JIANG Shan¹，LIU Hongtao²，TIAN Wenhua¹，LI Wenyan¹

PDF
下载
HTML

摘要/Abstract

摘要：

以5-溴水杨醛为起始原料，与溴乙酸乙酯通过2步反应环合生成5-溴苯并呋喃-2-甲酸乙酯，再与1-Boc哌嗪反应生成5-(4-叔丁氧羰基哌嗪)苯并呋喃-2-甲酸乙酯；接着经N-氯代丁二酰亚胺（NCS）氯代得到4-氯-5-(4-叔丁氧羰基哌嗪)苯并呋喃-2-甲酸乙酯；最后脱去Boc保护基，与2, 6-二氯苯磺酰氯反应得到4-氯-5-[4-(2, 6-二氯苯磺酰基)-1-哌嗪基]苯并呋喃-2-甲酸乙酯, 水解后得到目标化合物EYP001，总收率为58.3 %.

Abstract：

In this paper，5-bromosalicylic aldehyde was used as the starting material and cyclized with ethyl bromoacetate through a two-step reaction. The ethyl 5-bromobenzofuran-2-carboxylate was achieved，which was then reacted with 1-Boc piperazine to yield tert-butyl 4-(2-(ethoxycarbonyl)benzofuran-5-yl) piperazine-1-carboxylate. A chlorination reaction with N-chlorosuccinimide(NCS) was followed to give tertbutyl 4-(4-chloro-2-(ethoxycarbonyl)benzofuran-5-yl) piperazine-1-carboxylate whose Boc protecting group was removed afterwards.Finally EYP001 was obtained by a sulfonation reaction with 2, 6-dichlorobenzenesulfonyl chloride and then hydrolyzed with a total yield of 58.3 %.

关键词

关键词： Vonafexor ; EYP001 ; 法尼醇X受体激动剂 ; 合成

Key words： vonafexor ; EYP001； farnesol X receptor agonist； synthesis

参考文献 15

[1] MANGELSDORF D J，THUMMEL C，BEATO M，et al.The Nuclear Receptor Superfamily：The Second Decade [J]. Cell Vol，1995，83(6)：835-839. doi: 10.1016/0092-8674(95)90199-x
[2] KOUTSONUNAS I，THEOCHARIS S，DELLADETSIMA I，et al.Fatnesoid X Receptor in Human Metabolism and Disease：The Interplay Between Gene Polymorphisms，Clinical Phenotypes and Disease Susceptibility [J]. Expert Opin Drug Metab Toxicol，2015，11(4)：523-532. doi: 10.1517/17425255.2014.999664
[3] RAMIERE C，SCHOLTES C，DIAZ O，et al.Transactivation of the Hepatitis B Virus Core Promoter by the Nuclear Receptor FXRalpha [J]. J Virol，2008，82(21)：10832-10840. doi: 10.1 1/2- 8/jvi.00883-08
[4] KREMSDORF D，SOUSSAN P，PATERLINI-BRECHOT P，et al.Hepatitis B Virus-related Hepatocellular Carcinoma：Paradigms for Virus-related Human Carinogenesis [J]. Oncogene，2006，25(27)： 3823-3833. doi: 10.1038/sj.onc.1209559
[5] LI Y F，WANG G，PEI L，et al.Synthesis and Anti-hepatitis B Virus Activity of Novel Benzimidazole Derivatives [J]. J Med Chem，2006，49(15)：4790-4794.doi：10.1021/jm060330f
[6] ALEXOPOULOU D，HOLT A C，MEDZHITOV R，et al.Recognition of Double-stranded RNA and Activation of NF-KB by Toll-like Receptor 3 [J]. Nature，2001，413(6857)：732-738. doi: 10.1038/35099560
[7] ARCH R H，GEDRICH R W，THOMPSON C B.Translocation of TRAF Proteins Regulates Apoptotic Threshold of Cells [J]. Biochem Biophys Res Commun，2000，272(3)：936-945. doi: 10.1006/bbrc.2000.2873
[8] PRESCOTT N A，BRAM Y，SCHWARTZ R E, et al.Targeting Hepatitis B Virus Covalently Closed Circular DNA and Hepatitis B Virus X Protein：Recent Advances and New Approaches [J]. Acs Infec Dis ，2019，5(10)：1657-1667.doi：10.1021/acsinfecdis.9b00249
[9] RADREAU P，PORCHEROT M，VONDERSCHER J，et al.Effect of a Novel Synthetic FXR Agonist EYP001 on Hepatitis B Virus Replication in HepaGR Cell Line and Primary Human Hepatocytes [J]. Hepatology，2015, 62(S1)：1014A-1014A.
[10] ANDER P，LOTTEAU V，RADREAU P，et al.Methods and Pharmaceutical Compositions for Thetreatment of Hepatitis B Virus Infection:EPO.WO2015036442A1 [P/OL].2015-03-19 [2021-03-24]. https:∥worldwide.espacenet.com/publicationDetails, description？CC=WO&NR=2015036442A1&KC=A1&FT=D&ND=4&date=20150319&DB=EPODOC&locale=en_EP.
[11] SHAH R A，ALKHOURI N，KOWDLEY K V.Emerging Drugs for the Treatment of Non-alcoholic Steatohepatitis：A Focused Review of Farnesoid X Receptor Agonists [J]. Expert Opin Emerg Drugs， 2020，25(3)：251-260.doi：10.1080/14728214.2020.1796968
[12] LI Y Y，CAO C Y，ZHOU Y L，et al.The Roles and Interaction of FXR and PPARs in the Pathogenesis of Nonalcoholic Fatty Liver Disease [J]. Arab J Gastroenterol，2020，21(3)：162-168.doi： 10.1016/j.ajg.2020.03.018
[13] MIN-DEBARTOLO J，SCHLERMAN F，AKARE S，et al.Thrombospondin-I Is a Critical Modulator in Non-alcoholic Steatohepatitis(NASH) [J]. Plos One，2019，14(12)：e0226854.doi： 10.1371/journal.pone.0226854
[14] WANG B，ZHANG H B，LUAN Z L，et al.Farnesoid X Receptor(FXR) Activation Induces the Antioxidant Protein Metallothionein 1 Expression in Mouse Liver [J]. Exp Cell Res，2020，390(1)： 111949.doi：10.1016/j.yexcr.2020.111949
[15] JOLY S，PORCHEROT M，RADREAU P，et al.The Selective FXR Agonist EYP001 Is Well Tolerated in Healthy Subjects and Has Additive Anti-HBV Effect with Nucleoside Analogues in HepaRG Cells [J]. J Hepatol，2017，66(1)：S690-S690.doi：10.1016/s0168-8278(17)31853-6