Synfacts 2015; 11(12): 1233
DOI: 10.1055/s-0035-1560844
Synthesis of Natural Products and Potential Drugs
© Georg Thieme Verlag Stuttgart · New York

Synthesis of LY2886721

Philip Kocienski
Hansen MM, * Jarmer DJ. * et al. Lilly Research Laboratories, Indianapolis, USA and Dottikon Exclusive Synthesis, Switzerland
Synthesis of BACE Inhibitor LY2886721. Part II. Isoxazolidines as Precursors to Chiral Aminothiazines, Selective Peptide Coupling, and a Controlled Reactive Crystallization.

Org. Process Res. Dev. 2015;
19: 1214-1230
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17. November 2015 (online)



LY2886721 is a BACE inhibitor that is of interest for the treatment of Alzheimer’s disease. In the key intramolecular dipolar cycloaddition, nitrone (Z)-E underwent kinetic selection to afford a mixture of cycloadducts (dr = 6:1) from which the desired isoxazolidine F was isolated in 55% yield by crystallization.



Minimizing formation of a desfluoro impurity during hydrogenolysis of the isoxazolidine ring and removal of the benzyl chiral auxiliary (→ I) was a key challenge. The final acylation occurred without competing acylation of the aminothiazine nitrogen to afford LY2886721 in 17% overall yield on a multi-kilogram scale.