Suzuki-Miyaura approach to JNJ-26076713, an orally active tetrahydroquinoline-containing alphaVbeta3/alphaVbeta5 integrin antagonist. enantioselective synthesis and stereochemical studies.
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.
Kinney
William A
WA
Johnson & Johnson Pharmaceutical Research & Development, Welsh & McKean Roads, Spring House, Pennsylvania 19477-0776, USA. wak@pei3.com
Teleha
Christopher A
CA
Thompson
Andrew S
AS
Newport
Maria
M
Hansen
Ryan
R
Ballentine
Scott
S
Ghosh
Shyamali
S
Mahan
Andrew
A
Grasa
Gabriela
G
Zanotti-Gerosa
Antonio
A
Dingenen
Jules
J
Schubert
Carsten
C
Zhou
Yong
Y
Leo
Gregory C
GC
McComsey
David F
DF
Santulli
Rosemary J
RJ
Maryanoff
Bruce E
BE
D039302:Integrin alphaVbeta3 / Q000037:antagonists & inhibitors*; D016023:Integrins / Q000037:antagonists & inhibitors*; D009287:Naphthyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011804:Quinolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D019030:Receptors, Vitronectin / Q000037:antagonists & inhibitors*; D013237:Stereoisomerism; D014961:X-Ray Diffraction
D039302:Integrin alphaVbeta3; D016023:Integrins; C527479:JNJ-26076713; D009287:Naphthyridines; D011804:Quinolines; D019030:Receptors, Vitronectin; C064660:integrin alphaVbeta5