Practical, Highly Convergent, Asymmetric Synthesis of a Selective PPARγ Modulator

A practical, highly convergent, asymmetric synthesis of a selective PPAR gamma modulator 1 is described. The inhibitor contains two key components, a 6-trifluoromethoxy-3-acylindole (6) and (R)-alpha-aryloxybutanoic acid derivative (10). Two methods were developed to overcome the re regioselectivity issues encountered in the preparation of the 6-substituted indole. The first involved an intramolecular Heck reaction of an iodoaryl enamine. The second involved application of a catalytic Meerwein arylation reaction between 2-nitro-4-trifluoromethoxyaniline and isopropenyl acetate and subsequent reductive cyclization. The alpha-aryloxybutanoic acid was prepared via an asymmetric hydrogenation of the corresponding alpha-aryloxy-4-unsaturated acid. Tetrabutylammonium iodide-catalyzed coupling of the two fragments and ester hydrolysis completed the convergent synthesis. The described convergent synthesis was used to prepare > 3 kg of drug substance 1 in 50 % overall yield and with >99.5% ee.