N-烯丙基-4-哌啶基苯甲酰胺衍生物的合成及表征
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摘要
以对氯苄氯、5-溴水杨醛为原料,通过消去、还原及溴化合成了4-溴-2-溴甲基-1-((4-溴苄基)氧)苯(Ⅲ),以哌啶-4-酮合成了N-烯丙基-N-(4-哌啶基)-3-氯苯甲酰胺(Ⅳ),通过Ⅲ、Ⅳ合成了一种有望用作CCR5拮抗剂的非肽类小分子化合物N-烯丙基-N-(4-(5-溴-2-(对氯苄基氧基)苄基)哌啶基)-3-氯苯甲酰胺,对该产物进行了1 HNMR、13 CNMR及MS表征.
4-bromo-2-(bromomethyl)-1-((4-chlorobenzyl)oxy)benzene(Ⅲ)was synthesized from1-chloro-4-(chloromethyl)benzene and 5-bromo-2-hydroxybenzaldehyde by elimination reaction,reduction reaction and bromization.N-allyl-3-chloro-N-(piperidin-4-yl)benzamide(Ⅳ)was prepared from piperidin-4-one.Then a novel non-peptide CCR5 antagonist of N-allyl-N-(1-(5-bromo-2-((4-chlorobenzyl)oxy)benzyl)piperidin-4-yl)-3-chlorobenzamide was obtained from Ⅲ and Ⅳ,The structures of the products were characterized by 1 HNMR,13 CNMR and MS.
4-bromo-2-(bromomethyl)-1-((4-chlorobenzyl)oxy)benzene(Ⅲ)was synthesized from1-chloro-4-(chloromethyl)benzene and 5-bromo-2-hydroxybenzaldehyde by elimination reaction,reduction reaction and bromization.N-allyl-3-chloro-N-(piperidin-4-yl)benzamide(Ⅳ)was prepared from piperidin-4-one.Then a novel non-peptide CCR5 antagonist of N-allyl-N-(1-(5-bromo-2-((4-chlorobenzyl)oxy)benzyl)piperidin-4-yl)-3-chlorobenzamide was obtained from Ⅲ and Ⅳ,The structures of the products were characterized by 1 HNMR,13 CNMR and MS.
引文
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[2]Mohsen Shahlaei,Alireza Pourhossein.Modeling of CCR5antagonists as anti HIV agents using combined genetic algorithm and adaptive neuro-fuzzy inference system(GA-ANFIS)[J].Med Chem Res,2013,22:4423-4436.
[3]Mohammed Abdul Rasheed,Nagul Meera Shaik.Concise and aimple synthesis OFM1allosteric agonist TBPB[J].Synthetic Communications,2013,43:1796-1801.
[4]Yongjun Ji,Mao Shu,Yong Lin,et al.Combined 3D-QSAR modeling and molecular docking study on azacycles CCR5antagonists[J].Journal of Molecular Structure,2013,1045:35-41.
[5]Renato Skerlj,Gary Bridger,Yuanxi Zhou,et al.Design and synthesis of pyridin-2-ylmethylaminopiperidin-1-ylbutyl amide CCR5antagonists that are potent inhibitors of M-tropic(R5)HIV-1replication[J].Bioorganic&Medicinal Chemistry Letters,2011,21(23):6950-6954.
[6]Lavina Gharu,Rajesh Ringe,Jayanta Bhattacharya.HIV-1clade C envelopes obtained from late stage symptomatic Indian patients varied in their ability towards relative CD4usages and sensitivity to CCR5antagonist TAK-779[J].Virus Research,2011,158(1):216-224.
[7]Shou-Fu Lu,Binglong Chen,Dave Davey,et al.CCR5receptor antagonists:Discovery and SAR of novel 4-hydroxypiperidine derivatives[J].Bioorganic&Medicinal Chemistry Letters,2007,17(7):1883-1887.
[8]Richard Goehring R,John F W Whitehead,Brown K,et al.1,3-Dihydro-2,1,3-benzothiadiazol-2,2-diones and 3,4-dihydro-1H-2,1,3-benzothidiazin-2,2-diones as ligands for the NOP receptor[J].Bioorganic&Medicinal Chemistry Letters,2004,14(20):5045-5050.
[9]Paul E Finkea,Bryan Oates,Sander G Mills.Antagonists of the Human CCR5Receptor as Anti-HIV-1Agents.Part 4:Synthesis and Structure-Activity Relationships for 1-[N-(Methyl)-N-(phenylsulfonyl)amino]-2-(phenyl)-4-(4-(N-(alkyl)-N-(benzyloxycarbonyl)amino)piperidin-1-yl)butanes[J].Bioorganic&Medicinal Chemistry Letters,2001,11(18):2475-2479.
[10]Christopher K Arnatt,Saheem A Zaidi,Zhu Zhang,et al.Design,syntheses,and characterization of pharmacophore based chemokine receptor CCR5antagonists as anti prostate cancer agents[J].European Journal of Medicinal Chemistry,2013,69:647-658.
[11]Mark A Ashwell,Jean-Marc Lapierre,Alan Kaplan.The design,preparation and SAR of novel small molecule sodium(Na+)channel blockers[J].Bioorganic&Medicinal Chemistry Letters,2004,14(9):2025-2030.
[12]汪淼.CCR5受体拮抗剂的设计——合成与生物活性研究[D].沈阳:沈阳药科大学制药工程学院,2009.