新型Venetoclax四氢吡喃衍生物的合成
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摘要
以1-Boc-3-氮杂环丁酮和甲基三苯基溴化磷为起始原料,经Wittig反应、加成环化、脱卤、羰基还原、成醚、哌嗪取代、苯甲酸甲酯衍生物取代、水解、磺胺缩合、脱Boc和四氢吡喃取代反应,合成了一个新型的含四元螺环胺四氢吡喃结构的磺胺类Venetoclax衍生物,总产率22%,其结构经~1H NMR和HR-MS(ESI)表征。
A novel sulfanilamide Venetoclax derivative containing a four-membered spirocycle amine tetrahydropyran moiety, with total yield of 22%, was synthesized by an eleven-step route of wittig reaction, addition cyclization, dehalogenation, carbonyl reduction, etherification, piperazine substitution, methyl benzoate derivative substitution, hydrolysis reaction, sulfanilamide condensation, deprotection of Boc group and tetrahydropyran substitution using 1-N-Boc-3-azetidinone and methyltriphenylphosphonium bromide as starting materials. The structure was characterized by ~1H NMR and HR-MS(ESI).
A novel sulfanilamide Venetoclax derivative containing a four-membered spirocycle amine tetrahydropyran moiety, with total yield of 22%, was synthesized by an eleven-step route of wittig reaction, addition cyclization, dehalogenation, carbonyl reduction, etherification, piperazine substitution, methyl benzoate derivative substitution, hydrolysis reaction, sulfanilamide condensation, deprotection of Boc group and tetrahydropyran substitution using 1-N-Boc-3-azetidinone and methyltriphenylphosphonium bromide as starting materials. The structure was characterized by ~1H NMR and HR-MS(ESI).
引文
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[3] KVANSAKUL M,HINDS M.The bcl-2family:structures,Interactions and targets for drug discovery[J].Apoptosis,2015,20(2):136-150.
[4] 尹智勇,杨俊元,祁宏.Bcl-2蛋白质家族调控细胞凋亡机制的研究进展[J].信阳师范学院学报(自然科学版),2017,30(2):340-344.
[5] ROBERTS A,DAVIDS M,PAGEL J,et al.Targeting bcl2 with Venetoclax in relapsed chronic lymphocytic leukemia[J].N Engl J Med,2016,374(4):311-322.
[6] STILGENBAUER S,EICHHORST B,SCHETELIG J,et al.Venetoclax in relapsed or refractory chronic lymphocytic leukaemia with 17p deletion:A multicentre,open-label,phase 2 study[J].Lancet Oncol,2016,17(6):768-778.
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[9] AHMED S,AYSCOUGH A,BARKER G R,et al.1,2,4-Triazolo-[1,5-a]pyridine HIF prolyl hydroxylase domain-1(PHD-1) inhibitors with a novel monodentate binding interaction[J].J Med Chem,2017,60(13):5663-5672.
[10] GIEDT R J,SPRACHMAN M M,YANG K S,et al.Imaging cellular distribution of bcl inhibitors using small molecule drug conjugates[J].Bio conjugate Chem,2014,25(11):2081-2085.
[11] CAI W S,WANG S,JALANI H B,et al.Oxidative cascade reaction of N-aryl-3-alkylideneazetidines and carboxylic acids:Access to fused pyridines[J].Org Lett,2018,20(13):3833-3837.
[12] SKERRATT S E,MILLS J E,MISTRY J.Identification of false positives in “HTS hits to lead”:The application of bayesian models in HTS triage to rapidly deliver a series of selective TRPV4 antagonists[J].Med Chem Commun,2013,4(1):244-251.
[13] BRYAN M C,CHAN B,DIEDERICH F,et al.Preparation of azaindazole compounds as inhibitors of T790M containing EGFR mutants:WO 2014210354[P].2014.
[14] RICE K D,AAY N,ANAND N K,et al.Novel carboxamide-based allosteric MEK inhibitors:Discovery and optimization efforts toward XL518(GDC-0973)[J].ACS Med Chem Lett,2012,3(5):416-421.
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[16] ANDERSON D R,VOLKMANN R A,MENNITI F.Selective octahydrocyclopenta[c]pyrroles as negative modulators of NR2B and their preparation:WO 2015048507[P].2015.
[17] ABOUABDELLAH A,CHEREZE N,FAYOL A,et al.(5-Membered heterocyclyl)alkyl 7-azaspiro [3,5]nonane-7-carboxylate derivatives,their preparation and use as fatty acid amido hydrolase (FAAH) inhibitors for treating FAAH-related pathologies:WO 2010130945[P].2010.
[18] WADSWORTH H,JONES P A,CHAU W F,et al.Exploration of the structure-activity relationship of the diaryl anilide class of ligands for translocator proteinpotential novel positron emitting tomography imaging agents[J].Bioorg Med Chem Lett,2012,22(18):5795-5800.
[19] BRUNCKO M,DING H,DOHERTY G A,et al.Preparation of N-(phenylsulfonyl)benzamides and N-(3-pyridylsulfonyl)benzamides as apoptosis-inducing agents for the treatment of cancer and immune diseases and autoimmune diseases:US 20110124628[P].2011.
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