During the development of a drug substance manufacturing process, reduction of a ketone intermediate by Li(t-BuO)3AlH gave varying stereoselectivity between lab experiments and batch processing in the pilot plant. As part of an investigation to understand the variability, an ab initio QM computational study on the reduction of a model system, 4-t-butylcyclohexanone, was initiated to determine the origins of the stereoselectivity. Various microsolvation states for Li ion (tris-solvated, bis-solvated, solvated monosolvate, and mono-solvated) were included in the calculations. After removing the tris-solvated system due to its relatively high energy, the remaining three systems exhibited a 2- or 3-step mechanism to reach the desired alcohol product. Details of the mechanism and its potential impact on the stereoselective reduction will be discussed.

Computational study on the stereoselective reduction of a ketone intermediate with Li(t-BuO)3AlH

253rd National Meeting (2017)

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