Synthesis and determination of absolute configuration of a non-peptidic αβ integrin antagonist for the treatment of idiopathic pulmonary fibrosis

A diastereoselective synthesis of ( S )-3-(3-(3,5-dimethyl-1 H -pyrazol-1-yl)phenyl)-4-(( R )-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoic acid ( 1 ), a potential therapeutic agent for the treatment of Idiopathic Pulmonary Fibrosis, which is currently undergoing Phase I clinical trials is reported. The key steps in the synthesis involved alkylation of 2-methylnaphthyridine with ( R )- N -Boc-3-(iodomethyl)-pyrrolidine, and an asymmetric Rh-catalysed addition of an arylboronic acid to a 4-( N -pyrrolidinyl)crotonate ester. The overall yield of the seven linear step synthesis was 8% and the product was obtained in >99.5% ee proceeding with 80% de. The absolute configuration of 1 was established by an alternative asymmetric synthesis involving alkylation of an arylacetic acid using Evans oxazolidinone chemistry, acylation using the resulting 2-arylsuccinic acid, and reduction. The absolute configuration of the benzylic asymmetric centre was established as ( S ). Integrin inhibitor (cell adhesion assays) pIC 50 α v β 6 = 8.4, α v β 3 = 6.0, α v β 5 = 5.9 and α v β 8 = 7.7.