Miller SP.
*
Morris WJ.
*
Orr RK.
Eckert J.
Milan J.
Maust M.
Cowden C.
Cui J.
Merck & Co., Rahway, USA
Synthesis of the γ-Secretase Modulator MK-8428.
J. Org. Chem. 2017;
82: 2957-2964
Key words
MK-8248 - γ-secretase modulator - amino acid dehydrogenase - 1,2,4-oxadiazine ring
formation - reductive amination
Significance
MK-8428 is a γ-secretase modulator that is of interest for the treatment of Alzheimer’s
disease. Key steps in the synthesis depicted are (1) an amino acid dehydrogenase mediated
conversion of α-keto carboxylic acid A into 3,4,5-trifluoro-(S)-phenylglycine (B) and (2) a four-step sequence including a dehydrative intramolecular cyclization
to form the oxadiazine ring.
Comment
On treating a solution of I with hexamethyldisilazane (HMDS) and catalytic amounts of trimethylsilyl trifluormethanesulfonate
(TMSOTf), the desired intramolecular cyclization took place in high yield. This silyl-mediated
dehydration provided a milder alternative to Brønsted acids. The target molecule MK-8428
was isolated as its crystalline hemi-fumarate salt.
