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 via OpenAlex
Summary
AI-generated from the abstractA new chemical process produces over one kilogram of high-purity psilocybin, the active compound in psychedelic mushrooms, using a second-generation synthesis designed for large-scale manufacturing. The method improves on earlier procedures by optimizing the Speeter-Anthony tryptamine synthesis to create the intermediate psilocin with better control and impurity removal. It then directly phosphorylates psilocin with phosphorous oxychloride, avoiding a complex benzyl-protecting group strategy used in previous methods. This approach addresses challenges in yield, purity, atom economy, and suitability for pilot plant-scale reactors, providing a more efficient and consistent route for producing psilocybin under current Good Manufacturing Practices.
Study at a glance
| Characteristics | Methodological report Peer reviewed |
|---|---|
| Topics | Psilocybin |
| Keywords | Phosphorylation Chemistry |
| Citations | 41 |
| Key finding | 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.