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DOI: 10.1055/s-0036-1590388
Synthesis of MK-8248
Publication History
Publication Date:
16 May 2017 (online)
Key words
MK-8248 - γ-secretase modulator - amino acid dehydrogenase - 1,2,4-oxadiazine ring formation - reductive aminationSignificance
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.
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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.
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