A ligand-solvent-base screen was performed on a Suzuki-Miyaura coupling reaction, and the screening data, followed by a set of focused experiments, helped to optimize reaction conditions. Further work was carried out that centered on reducing the level of residual palladium in the isolated product. Treatment of the reaction mixture with toluene and 20% aqueous NaHSO 3 at elevated temperature lowered the palladium content from ∼8000 ppm to 100 ppm or less. The Suzuki-Miyaura coupling and palladium removal process were demonstrated on 20-L scale, are highly efficient and cost-effective, and require short cycle times.

HCV NS5B polymerase inhibitor GSK852A (1) was synthesized in only five steps from ethyl 4-fluorobenzoylacetate (3) in 46% overall yield. Key to the efficient route was the synthesis of the highly functionalized benzofuran core 15 from the β-keto ester in one pot and the efficient conversion of ester 6 to amide 19 via enamine lactone 22. Serendipitous events led to identification of the isolable enamine lactone intermediate 22. Single crystal X-ray diffraction and NMR studies supported the intramolecular hydrogen bond shown in enamine lactone 22. The hydrogen bond was considered an enabler in the proposed pathway from ester 6 to enamine lactone 22 and its rearrangement to amide 19. GSK852A (1) was obtained after reductive amination and mesylation with conditions amenable to the presence of the boronic acid moiety which was considered important for the desirable pharmacokinetics of 1. The overall yield of 46% in five steps was a significant improvement to the previous synthesis from the same β-keto ester in 5% yield over 13 steps.

Two short, high-yielding routes to the selective PPARγ agonist GSK376501A were developed and carried out on scale. The key bond -forming reaction in each synthesis was the substitution of a 3,5-difluoro or 3,5-dibromo aryl intermediate with 2-methoxyethanol. A nucleophilic aromatic (S N Ar) substitution reaction under basic conditions was developed for the aryl fluoride substrate. The 3,5-dibromo aryl halide intermediate required copper-catalyzed conditions to achieve substitution of the second bromide. In addition, a 2-methoxyethanol decomposition pathway to generate methanol and ethylene oxide under basic reaction conditions as well as its effect on impurity formation, was elucidated. Both the difluoro and dibromo intermediates were considered as the basis for the final route of manufacture. The difluoro substrates were chosen due to straightforward chemistry, controllable impurity profile, and ease of fluoride removal.