Synthesis of LY2886721
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;
17. November 2015 (online)
Key wordsLY2886721 - BACE inhibitor - dipolar cycloaddition - nitrone - aminothiazines - ring formation - continuous flow - hydrogenolysis
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 (H → 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.