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Synfacts 2017; 13(06): 0563
DOI: 10.1055/s-0036-1590388
Synthesis of Natural Products and Potential Drugs
© Georg Thieme Verlag Stuttgart · New York

Synthesis of MK-8248

Contributor(s):
Philip Kocienski
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
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Further Information

Publication History

Publication Date:
16 May 2017 (online)

 
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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.


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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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