Process Development of Verubecestat

◆Verubecestat is an inhibitor of β-secretase being evaluated for the treatment of Alzheimer’s disease.

◆The first generation route relies on anamide coupling with a functionalized aniline, the preparation of which introduces synthetic inefficiencies.

◆At least three reasonable synthetic intermediates at which C−N coupling could be performed, and so we prepared each and evaluated them by high-throughput screening (HTS) of catalysts and reaction conditions

◆The key breakthrough which enabledisolation of 22 was the use of a 20 mol% aqueous solution of potassium glycolate.

◆This salt solution efficientlychelates titanium alkoxides and oxides without any concomitant precipitation, allowing the various inorganic reaction byproducts to be simply washed away from the organics.

Question: Only a few palladium based methodsshowed promise from guanidine 17 to 1, try to explain it.