Development of a Practical and Scalable Synthetic Route to YM758 Monophosphate, A Novel If Channel Inhibitor

Abstract

A novel, practical, and efficient synthesis of (−)-N-{2-[(R)-3-(6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)piperidino]ethyl}-4-fluorobenzamide monophosphate (YM758 monophosphate, (R)-1·H3PO4 (Figure 1) is described. The target molecule (R)-1 has a potent If current channel inhibitor. Medicinal chemistry synthetic routes were very long and suffered from extensive use of chlorinated solvents and silica-gel column chromatography. A number of steps in the medicinal chemistry route were also unattractive for large-scale synthesis due to some reasons for example the use of unstable intermediates. An important objective of a new synthetic route was avoidance of such a use of unstable intermediate, and it was achieved by the discovery of an important 4,5-dihydrooxazole intermediate 19 and ring-opening N-alkylation of chiral amine with 19 under acidic condition. The new procedure does not require any purification by column chromatography for all steps. The overall yield was significantly improved from 14% or 34% to 49% compared to that of the medicinal synthetic routes. This highly efficient process was successfully demonstrated at a pilot-scale operation, yielding 36.5 kg of (R)-1·H3PO4.