An Efficient Synthesis of an α_vβ₃ Antagonist

Abstract

A practical preparation of an alpha(v)beta(3) antagonist is reported. The antagonist consists of three key components, a tetrahydronaphthyridine moiety, a beta-alanine moiety, and a central imidazolidone moiety. The tetrahydronaphthyridine component was prepared using two different methods, both of which relied on variations of the Friedländer reaction to establish the desired regiochemistry. The beta-alanine component was prepared using Davies' asymmetric 1,4-addition methodology as the key stereo-defining step. The central imidazolidone portion was created from these two components using an effective three-step cyclization protocol. Thus, a highly convergent process for the drug candidate was defined.

Thermodynamic Understanding of an Aza-Michael Reaction Enables Five-Step Synthesis of the Potent Integrin Inhibitor MK-0429

“…Strikingly, the disclosed syntheses of 1 , and 2 do not employ direct heterocycle-acrylate couplings, opting instead for stepwise approaches . In contrast, 3 and related compounds are prepared in this way, but the wide range of reported yields (ca.…”

Asymmetric total synthesis of sperabillins B and D via lithium amide conjugate addition

“…Initial studies directed toward the synthesis of an unconjugated heptadienoate focused upon the preparation of either an isopropyl or tert-butyl ester derivative, as it was anticipated that a sterically bulky ester protecting group would discourage 1,2-addition of the lithium amide. 15 Isopropyl (E,E )-2,5-heptadienoate 17 was therefore synthesised in 5 steps, based upon the procedures of Sharma et al 16 and Binet et al 17 The Grignard coupling of THP protected propargyl alcohol 12 with crotyl bromide in the presence of a Cu(I) salt gave the known ether 13 in 73% yield. 16 O-Deprotection using a catalytic amount of PTSA in MeOH afforded alcohol 14 in 90% yield, which was next oxidised to acid 15 with Jones' reagent in 77% yield.…”

Facile synthesis of 7-alkyl-1,2,3,4-tetrahydro-1,8-naphthyridines as arginine mimetics using a Horner–Wadsworth–Emmons-based approach

“…Current routes to install tetrahydronaphthyridines predominantly revolve around late-stage hydrogenation of fully aromatic 1,8-naphthyridine derivatives 3 , usually prepared via an acid or base-catalysed Friedländer reaction between 2-aminonicotinaldehyde ( 1 ) and the corresponding ketone 2 ( Scheme 1 ). Both reactions employ harsh conditions with limited functional group tolerance and limited regiochemical control, which presents considerable purification issues during large-scale synthesis [ 8 – 10 ]. More recently, catalytic methodologies for the asymmetric hydrogenation of 1,8-naphythyridines have been reported [ 11 – 12 ].…”