A microplate-based assay to rapidly identify adsorbents suitable for removing process impurities is described. A solution containing both product and impurity is added to a number of wells, each containing a small amount of a candidate adsorbent. After equilibration, analysis of the supernatant solution allows one to determine the extent of adsorption of both product and impurity. Fast analysis techniques such as flow injection analysis LC-MS or the use of colorimetric indicators allows rapid identification of the most selective adsorbents for a given separation problem.

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A facile preparation of enantiopure ethyl (1S,5S,6S)-6-fluoro-2-oxobicyclo[3.1.0]hexane-6-carboxylate is described. The key feature of the synthesis involves copper-catalyzed enantioselective intramolecular cyclopropanation of a diazoketone to form endo-fluorocyclopropane in a single operation. Removal of a problematic chloroketone impurity using a reactive resin treatment enabled a high throughput enantiopurity upgrade by chiral HPLC. The development of a scalable synthesis of is presented, including details of the selection of catalyst and ligand optimization, incorporation of a reactive resin treatment and selection of chiral HPLC media and conditions.

The development of potent gamma-secretase inhibitors having substituted heterocycles attached to a benzobicyclo[4.2.1]nonane core is described. This work led to the identification of [6S,9R,11R]-2',3',4',5,5',6,7,8,9,10-decahydro-2-(5-(4-fluorophenyl)-1-methylpyrazol-3-yl)-5'-(2,2,2-trifluoroethyl)spiro[6,9-methanobenzocyclooctene-11,3'-[1,2,5]thiadiazole] 1',1'-dioxide (16), which has excellent in vitro potency (0.06 nM) and which reduced amyloid-beta in APP-YAC mice with an ED(50) of 1 mg/kg (po). 16 had a good pharmacokinetic profile in three preclinical species.

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