Synthesis of BACE Inhibitor LY2886721. Part II. Isoxazolidines as Precursors to Chiral Aminothiazines, Selective Peptide Coupling, and a Controlled Reactive Crystallization

An efficient synthesis of LY2886721 (1) in five steps and 46% overall yield from the chiral nitrone cycloadduct 2 is presented. Minimizing formation of a des-fluoro impurity during hydrogenolysis to cleave the isoxazolidine ring and remove the benzyl chiral auxiliary was a key challenge. Installation of the aminothiazine moiety required careful stoichiometry control of the reagents BzNCS and CDI, including in situ conversion monitoring, to minimize byproduct formation. A remarkably regioselective peptide coupling afforded 1 without competing acylation at the aminothiazine nitrogen or bis-acylation. Consideration of the combined chemistry and crystallization process identified an optimal solvent system for the peptide coupling and a reactive crystallization that afforded 1 in high purity and with physical property control. A slurry milling operation near the end of the crystallization, followed by “pH cycles” to digest fines formed during milling, significantly reduced the crystal aspect ratio and provided...