title: Synthesis of trans-3,4-Dimethyl-4-(3-hydroxyphenyl)piperidine Opioid Antagonists: Application of the Cis-Thermal Elimination of Carbonates to Alkaloid Synthesis.
abstract: Improved syntheses of twotrans-3,4-dimethyl-4-(3-hydroxyphenyl)piperidine opioid antagonists from 1,3-dimethyl-4-piperidinone are described. The 1,3-dimethyl-4-arylpiperidinol 23 was selectively dehydrated in a two step process to the 1,3-dimethyl-4-aryl-1,2,3,6-tetrahydropyridine 26 by the cis-thermal elimination of the corresponding alkyl carbonate derivative at 190 degrees C. In the presence of a basic nitrogen, the success of the elimination was found to be critically dependent upon the nature of the carbonate alkyl group, with Et, i-Bu, and i-Pr being preferred (90% yield). Alkylation of the metalloenamine, formed by deprotonation of 26 with n-BuLi, proceeded regio- and stereospecifically to give the trans-3,4-dimethyl-4-aryl-1,2,3,4-tetrahydropyridine 27, which was converted in three steps to the common intermediate, (3R,4R)-3,4-dimethyl-4-(3-hydroxyphenyl)piperidine. LY255582, a centrally-active opioid antagonist, and LY246736-dihydrate, a peripherally-active opioid antagonist, were prepared from 1,3-dimethyl-4-piperidinone in 11.8% yield (8 steps) and 6.2% yield (12 steps), respectively.
authors.affiliation: Chemical Process Research and Development, Lilly Research Laboratories, A Division of Eli Lilly and Company, Indianapolis, Indiana 46285-4813.
authors.forename: John A.
authors.initials: JA
authors.lastname: Werner
authors.forename: Louis R.
authors.initials: LR
authors.lastname: Cerbone
authors.forename: Scott A.
authors.initials: SA
authors.lastname: Frank
authors.forename: Jeffrey A.
authors.initials: JA
authors.lastname: Ward
authors.forename: Parviz
authors.initials: P
authors.lastname: Labib
authors.forename: Roger W.
authors.initials: RW
authors.lastname: Tharp-Taylor
authors.forename: C. W.
authors.initials: CW
authors.lastname: Ryan