title: Facile synthesis of 4-substituted-4-aminopiperidine derivatives, the key building block of piperazine-based CCR5 antagonists.
abstract: 4-Substituted-4-aminopiperidine is an interesting structural motif found in a number of bioactive compounds. An efficient and convenient method for the synthesis of 4-differently substituted-4-aminopiperidine derivatives was described, employing isonipecotate as a starting material and Curtius rearrangement as a key step. The alkylation of isonipecotate could introduce various substituents at the 4-position of the piperidine ring. With this key building block, we are able to efficiently synthesize piperazino-piperidine based CCR5 antagonist in a highly convergent manner free of using toxic reagents such as diethylaluminum cyanide. The concise synthesis of a potent bioavailable CCR5 antagonist as HIV-1 entry inhibitor, Sch-350634 (1) was accomplished in excellent yield using N'-Boc-4-methyl-4-aminopiperidine 5a as a smart building block. The new methodology provides a facile and practical access to the piperazino-piperidine amide analogs as HIV-1 entry inhibitors.
authors.affiliation: State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Shanghai Institutes for Biological Sciences, CAS, 555 Zuchongzhi Road, Shanghai 201203, China.
authors.forename: Xiao-Hua
authors.initials: XH
authors.lastname: Jiang
authors.forename: Yan-Li
authors.initials: YL
authors.lastname: Song
authors.forename: Ya-Qiu
authors.initials: YQ
authors.lastname: Long
mesh_terms: D000478:Alkylation; D019380:Anti-HIV Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D065100:CCR5 Receptor Antagonists; D002460:Cell Line; D015497:HIV-1 / Q000187:drug effects*; D007540:Isonipecotic Acids / Q000737:chemistry; D009942:Organometallic Compounds / Q000494:pharmacology / Q000633:toxicity; D010880:Piperidines / Q000138:chemical synthesis* / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: C481395:4-aminopiperidine; D019380:Anti-HIV Agents; D065100:CCR5 Receptor Antagonists; D007540:Isonipecotic Acids; D009942:Organometallic Compounds; D010880:Piperidines; C488013:diethylaluminum cyanide