Direct Phosphorylation of Psilocin Enables Optimized cGMP Kilogram-Scale Manufacture of Psilocybin

Introduction

Kargbo and colleagues place this work in the context of a resurgence of clinical research into psychedelic compounds, where psilocybin has emerged as a particularly suitable candidate because of its historical human use, tolerability across a range of doses, and prior pharmaceutical production. As demand for kilogram-scale active pharmaceutical ingredient (API) has risen to support modern clinical trials and potential commercial manufacture, the authors identified a need for a reliable, reproducible cGMP-compliant synthetic route that performs well at pilot-plant scale and meets quality-by-design (QbD) criteria including yield, purity, atom economy, and process control. This paper reports a second-generation, kilogram-scale synthesis of psilocybin that reworks the early literature-based multistep route. The new route features an optimised Speeter–Anthony tryptamine sequence to produce psilocin, followed by a novel direct phosphorylation of psilocin using phosphorus oxychloride (POCl3), thereby avoiding the benzyl-protecting group strategy used in prior syntheses. The study aims to document the challenges encountered during scale-up of a first-generation, literature-adapted process and to describe the design, in-process controls, and outcomes of the improved cGMP-capable synthesis capable of delivering over one kilogram of high-purity psilocybin.