Direct Phosphorylation of Psilocin Enables Optimized cGMP Kilogram-Scale Manufacture of Psilocybin
Jessica Sable, Tura Patterson, Gary Tarpley, Poncho Meisenheimer, Robert B. Kargbo, Alexander M. Sherwood, Andrew J. Walker, Nicholas V. Cozzi, Raymond E. Dagger, Kelsey O’hern, Kristi W. Kaylo
ACS Omega July 1, 2020 DOI: 10.1021/acsomega.0c02387 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Methodological report Peer reviewed |
|---|---|
| Topics | Psilocybin |
| Keywords | Phosphorylation |
| Citations | 41 |
| Key points | A second-generation kilogram-scale synthesis of psilocybin was developed that features an optimized Speeter-Anthony tryptamine synthesis and direct phosphorylation of psilocin with phosphorous oxychloride, producing over one kilogram of high-purity psilocybin under cGMP. |
Abstract
A second-generation kilogram-scale synthesis of the psychedelic tryptamine psilocybin has been developed. The synthesis was designed to address several challenges first encountered with the scale-up of previously described literature procedures, which were not optimized for providing consistent yield and purity of products, atom economy, or being run in pilot plant-scale reactors. These challenges were addressed and circumvented with the design of the second-generation route, which featured an optimized cGMP large-scale Speeter-Anthony tryptamine synthesis to the intermediate psilocin with improved in-process control and impurity removal over the three steps. Psilocin was subsequently phosphorylated directly with phosphorous oxychloride for the first time, avoiding a tedious and poor atom economy benzyl-protecting group strategy common to all previously described methods for producing psilocybin. In this report, the challenges encountered in a 100 g scale first-generation literature-based synthesis are highlighted, followed by a detailed description of the newly developed second-generation synthesis to provide over one kilogram of high-purity psilocybin under cGMP.