The proposed manufacturing route for BACE inhibitor LY2886721, which had been in clinical development for Alzheimer’s disease, required access to the amino alcohol below. A nitrone cycloaddition with a chiral benzyl hydroxylamine was used to install the chirality, and the amino alcohol was accessed by hydrogenolysis. Pd-catalyzed hydrogenolysis of the N-O bond and the chiral benzyl group gave rise to a desfluoro impurity that was not formed in the earlier synthetic route. The desfluoro analogs of this and the downstream intermediates did not provide sufficient rejection of the desfluoro impurity, so the defluorination needed to be controlled to very low levels in the hydrogenolysis reaction. During the first manufacturing campaign with the new route, we intentionally formed a small amount of this impurity. In subsequent campaigns, the reaction conditions were modified to control the desfluoro impurity to &lt;0.05%. Development efforts yielded both batch and continuous flow packed bed processes for the hydrogenolysis, both of which were capable of controlling the desfluoro impurity within the strict target limits.

Control of a key hydrogenolysis-derived desfluoro impurity in the synthesis of LY2886721

254th National Meeting (2017)

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