Large-Scale Synthesis of the Glucosylceramide Synthase Inhibitor N-[5-(Adamantan-1-yl-methoxy)-pentyl]-1-deoxynojirimycin

A synthetic route for the preparation of glucosylceramide synthase inhibitor N-[5-(adamantan-1-yl-methoxy)-pentyl]-1-deoxynojirimycin methanesulfonic acid salt (AMP-DNM) has been developed. Herein we report the development and optimization of this synthetic route from its initial version in an academic research laboratory at milligram-scale to the final optimized route that was implemented in a cGMP miniplant on kilogram-scale. The definitive route starts with the separate synthesis of building blocks 2,3,4,6-tetra-O-benzyl-1-deoxynojirimycin and 5-(adamantan-1-yl-methoxy)-pentanal. The aldehyde was synthesized from 1,5-pentanediol in five steps and 45% overall yield. Protected 1-deoxynojirimycin was prepared by a successive hemiacetal reduction/Swern oxidation/double reductive amination sequence of 2,3,4,5-tetra-O-benzyl-d-glucopyranose in 52% overall yield. Reductive amination of the two building blocks produced the benzyl-protected penultimate that was isolated as its crystalline (+)DTTA salt in 68% yi...

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