Suzuki−Miyaura Approach to JNJ-26076713, an Orally Active Tetrahydroquinoline-Containing α_Vβ₃/α_Vβ₅ Integrin Antagonist. Enantioselective Synthesis and Stereochemical Studies

Abstract

An improved scale-up synthesis was required for the alpha(V)beta(3)/alpha(V)beta(5) integrin antagonist 1, which had demonstrated oral efficacy in eye disease models of angiogenesis and vascular permeability. A stereodefined, quinoline-substituted, unsaturated ester was conveniently prepared by a Suzuki-Miyaura coupling to facilitate exploration of multiple methods of asymmetric reduction. The catalytic chiral hydrogenation of the corresponding unsaturated acid (Z-5b) with a ruthenium-based metal precursor and the (R)-XylPhanePhos ligand proved particularly efficient and economical. The resulting (3S)-quinoline-containing intermediate was reduced to an equal mixture of tetrahydroquinoline diastereomers. The undesired diastereomer could be recycled to the desired one by an oxidation/reduction protocol. The absolute stereochemistry of 1 was established as 3S,3'S by a combination of X-ray diffraction and chemical means.

Advances in the reduction of quinolines to 1,2,3,4‐tetrahydroquinolines

“…Acting as chemotherapeutic targets . Tetrahydroquinoline analogous have been cited as anti‐HIV compound 12 [147–153], antibacterial compounds 13–15 , [154–156], antifungal compound 16 [157–160], antimalarial compounds 17 – 19 [161–168], and antitumor compounds 20–24 [169–179] (Figures 3 and 4).…”

Hydrogen

“…40 The tetrahydroquinoline intermediate to an integrin antagonist could be obtained as a mixture of diastereoisomers via achiral reduction of the heterocyclic ring of the corresponding chiral quinolone (eq 16). 41 Asymmetric reductions of heteroaromatics have been well documented, 42 with examples including preparation a range of tetrahydroquinoline species in high ee (eq 17). 43 Furthermore, phosphine-free asymmetric hydrogenations of quinolines have also been reported.…”

Asymmetric homogeneous hydrogenations at scale

“…There were cost savings for the lower catalyst usage with a cheaper metal that outweighed the need to perform two extra steps. 169,170 Further studies of the reaction parameters showed that when {Ru[(R)-XylPhanePhos]Cl 2 (DMF) n } was used as the catalyst precursor, then triethylamine had to be added to obtain good substrate : catalyst ratios. The maximum was observed around 0.5 equivalents of the base and this was explained by activation of the catalyst; the quinoline moiety within the substrate being basic enough to deprotonate the carboxylic acid.…”