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Synthesis of Pyridopyrazine-1,6-dione γ-Secretase Modulators via Selective 4-Methylimidazole N1-Buchwald Arylation. 2019
Longfei Xie, and
Christopher W Am Ende, and
Martin Pettersson, and
Danica A Rankic, and
Neal W Sach, and
Subbas Sakya, and
John M Humphrey
Pfizer Worldwide Research and Development , Eastern Point Road , Groton , Connecticut 06340 , United States.
An efficient synthesis of pyridopyrazine-1,6-dione γ-secretase modulators (GSMs) is described. Our route features the construction of a crystalline lactone intermediate via a selective palladium-catalyzed 4-methylimidazole N1-arylation using the Buchwald Xantphos Pd G4 precatalyst, which does not require a preactivation step. The weak inorganic base KHCO3 was employed to minimize saponification of a particularly sensitive lactone substrate. Additional key transformations include DABAL-Me3-mediated lactone aminolysis and a mild TBD/ethyl trifluoroacetate mediated lactam ring closure to afford a representative GSM in high yield.
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