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The first total synthesis of Stachybotrys microsporatriprenol phenol (SMTP)-7 is described. Establishment of the two pyran ring stereogenic centers and key reactions featuring a double reductive amination and a double lactam ring formation in flow are described. The (2R,3S)-trans-benzopyran intermediate 7A, isolated by chiral preparative SFC chromatography, was carried forward to afford SMTP-7. Analytical data for synthetic SMTP-7, including 1H and 13C NMR data, HPLC retention time, and UV spectrum, were in excellent agreement with those for natural SMTP-7.

As vixotrigine (1) entered a later clinical phase for trigeminal neuralgia (Zakrzewska, J. M.; et al. Lancet Neurol.2017, 16, 291−300), the development of a sustainable late-stage process was required to meet the supply needs for formulation optimization, phase 3 clinical trials, and registration stability batches (this is the expected commercial formulation). In this article, we describe how the process was streamlined from the early supply route (Giblin, G.; et al. Org. Process Res. Dev.2020, DOI: 10.1021/acs.oprd.0c00382) and a comprehensive control strategy was established. Process improvements included improving safety and scalability for a temperature-sensitive Grignard reaction, simplifying unit operations, removal of heterogenous conditions, and route redesign to afford a high yielding, one-pot sequential alkylation and amidation. Improvement in the salt formation step, combined with wet milling, resulted in improved particle properties with enhanced flow properties of the final active pharmaceutical ingredient. The process mass intensity was improved 65% while maintaining drug substance purity at more than 99.8%. This new process has been scaled up to generate metric ton quantities of drug substance.

Herein are described improvements in a discovery synthesis to enable a rapid scale up of 1to support early phase clinical trials and formulation development studies. Process modifications included route redesign, simplifying a Mitsunobu reaction product’s isolation, improving yields and impurity profiles for isolated intermediates, and removal of a chromatographic purification. Particle engineering studies identified a recrystallization protocol to produce 1with enhanced solid-state properties. This improved process was scaled up to generate multikilogram quantities of drug substance with >99.8% area purity.