1014679-82-3Relevant articles and documents
Suzuki-Miyaura approach to JNJ-26076713, an orally active tetrahydroquinoline-containing αvβ3/ αvβ5 integrin antagonist. Enantioselective synthesis and stereochemical studies
Kinney, William A.,Teleha, Christopher A.,Thompson, Andrew S.,Newport, Maria,Hansen, Ryan,Ballentine, Scott,Ghosh, Shyamali,Mahan, Andrew,Grasa, Gabriela,Zanotti-Gerosa, Antonio,Dingenen, Jules,Schubert, Carsten,Zhou, Yong,Leo, Gregory C.,McComsey, David F.,Santulli, Rosemary J.,Maryanoff, Bruce E.
, p. 2302 - 2310 (2008)
(Chemical Equation Presented) An improved scale-up synthesis was required for the αvβ3/αvβ 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.
