Subscribe to RSS
DOI: 10.1055/s-0039-1691565
An Improved, Practical, and Scalable Five-Step Synthesis of Psilocybin
Abstract
Described herein is an improved synthesis of 3-[2-(dimethylamino)ethyl]-1H-indol-4-yl dihydrogen phosphate (psilocybin). The protocol outlines: synthesis of multigram quantities of psilocybin, identification of critical in-process parameters, and isolation of psilocybin without the use of chromatography, TLC, or aqueous workup. The synthesis furnishes psilocybin in five steps in 23% overall yield from an inexpensive acetoxyindole starting material. With specific focus on process control and impurity fate and removal, the improved procedure is amenable to providing high-quality psilocybin.
Key words
psilocybin - psilocin - phosphorylation - hydrogenolysis - reduction - quenching method - major depressive disorderSupporting Information
- Supporting information for this article is available online at https://doi.org/10.1055/s-0039-1691565.
- Supporting Information
Publication History
Received: 02 November 2019
Accepted after revision: 12 December 2019
Publication Date:
08 January 2020 (online)
© 2020. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial-License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/)
© Georg Thieme Verlag
Stuttgart · New York
-
References
- 1a Rucker JJ. H, Iliff J, Nutt DJ. Neuropharmacology 2018; 142: 200
- 1b Kyzar EJ, Nichols CD, Gainetdinov RR, Nichols DE, Kalueff AV. Trends Pharmacol. Sci. 2017; 38: 992
- 1c Matsushima Y, Eguchi F, Kikukawa T, Matsuda T. Inflamm. and Regen. 2009; 29: 47
- 2a Dinis-Oliveira RJ. Drug Metab. Rev. 2017; 49: 84
- 2b The LD50/ED50 ratio for aspirin is 199 and 641 for psilocin, which compares favorably to presently approved drugs, see: Palenicek T, Horacek J. Eur. Neuropsychopharm. 2014; 24: 342
- 3 Halberstadt AL, Vollenweider FX, Nichols DE. Behavioral Neurobiology of Psychedelic Drugs, 1st ed. Springer; Berlin: 2018
- 4a Thomas K, Malcolm B, Lastra D. J. Psychoactive Drugs 2017; 49: 446
- 4b Hasler F, Bourquin D, Brenneisen R, Bär T, Vollenweider FX. Pharmaceut. Acta Helv. 1997; 72: 175
- 5 Trulson ME, Heym J, Jacobs BL. Brain Res. 1981; 215: 275
- 6 Roiser JP, Rees G. Curr. Biol. 2012; 22: 231
- 7 Brown RT, Nicholas CR, Cozzi NV, Gassman MC, Cooper KM, Muller D, Thomas CD, Hetzel SJ, Henriquez KM, Ribaudo AS. Clin. Pharmacokinet. 2017; 56: 1543
- 8a Grob CS, Danforth AL, Chopra GS, Hagerty M, McKay CR, Halberstadt AL, Greer GR. Arch. Gen. Psychiatry 2011; 68: 71
- 8b Griffiths RR, Johnson MW, Carducci MA, Umbricht A, Richards WA, Richards BD, Cosimano MP, Klinedinst MA. J. Psychopharmacol. 2016; 30: 1181
- 8c Ross S, Bossis A, Guss J, Agin-Liebes G, Malone T, Cohen B, Mennenga SE, Belser A, Kalliontzi K, Babb J, Su Z, Corby P, Schmidt BL. J. Psychopharmacol. 2016; 30: 1165
- 8d Carhart-Harris RL, Bolstridge M, Rucker J, Day CM. J, Erritzoe D, Kaelen M, Bloomfield M, Rickard JA, Forbes B, Feilding A, Taylor D, Pilling S, Curran VH, Nutt DJ. Lancet Psychiatry 2016; 3: 619
- 8e Carhart-Harris RL, Goodwin GM. Neuropsychopharmacology 2017; 42: 2105
- 8f Idell RD, Florova G, Komissarov AA, Shetty S, Girard RB. S, Idell S. Med. Hypotheses 2017; 100: 46
- 9 Weissman MM, Wickramaratne P, Greenwald S, Hsu H, Ouellette R, Robins LN, Hallmayer J. JAMA 1992; 268: 3098
-
10a World Health Organization; Depression and Other Common Mental Disorders (2017, February); WHO: Genf, 2017; http://www.who.int/mediacentre/factsheets/fs369/en/.
- 10b Kessler RC, Berglund P, Demler O, Jin R, Koretz D, Merikangas KR, Water EE, Wang PS. JAMA 2003; 289: 3095
- 11 Sudak HS. Suicide . In Kaplan & Sadock’s Comprehensive Textbook of Psychiatry, 8th ed., Vol II. Sadock BJ, Sadock VA. Lippincott, Williams & Wilkins; New York: 2005: 2442-2453
- 12 Akiskal HS. Mood Disorders: Historical Introduction and Conceptual Overview . In Kaplan & Sadock’s Comprehensive Textbook of Psychiatry, 8th ed., Vol. I. Sadock BJ, Sadock VA. Lippincott, Williams & Wilkins; New York: 2005: 1559-1575
- 13 Nichols DE, Johnson MW, Nichols CD. Clin. Pharmacol. Ther. 2017; 101: 209
- 14a Hofmann A, Heim R, Brack A, Kobel H, Frey A, Ott H, Petrzilka T, Troxler F. Helv. Chim. Acta 1959; 42: 1557
- 14b Speeter ME, Anthony WC. J. Am. Chem. Soc. 1954; 76: 6208
- 14c Hofmann A, Frey A, Ott H, Petrzilka T, Troxler F. Experientia 1958; 15: 397
- 14d Ono M, Shimamine M, Takahashi K. Bull. Nat. Inst. Hygienic Sci. 1973; 91: 39
- 15a Bartolucci S, Mari M, Di Gregorio G, Piersanti G. Tetrahedron 2016; 72: 2233
- 15b Gathergood N, Scammells PJ. Org. Lett. 2003; 5: 921
- 15c Sakagami H, Ogasawara K. Heterocycles 1999; 51: 1131
- 15d Furman S, Nissim-Bardugo E, Zeeli S, Weitman M, Nudelman A, Finkin-Groner E, Moradov D, Shifrin H, Schorer-Apelbaum D, Weinstock M. Bioorg. Med. Chem. Lett. 2014; 24: 2283
- 15e Hu C, Qin H, Cui Y, Jia Y. Tetrahedron 2009; 65: 9075
- 15f Troxler F, Seemann F, Hofmann A. Helv. Chim. Acta 1959; 42: 2073
- 15g Hofmann A, Frey A, Ott H, Petrzilka T, Troxler F. Experientia 1958; 14: 397
-
16 Reaction monitoring by TLC for this reaction was ambiguous. Even though it showed apparent completion, as it was difficult to distinguish mixtures of O,O-dibenzylpsilocybin and O-monobenzylpsilocybin, see:
Nichols DE,
Frescas S.
Synthesis 1999; 935
- 17 Shirota O, Hakamata W, Goda Y. J. Nat. Prod. 2003; 66: 885
- 18 Fieser LF, Fieser M. Reagents for Organic Synthesis, Vol. 1. Wiley; New York: 1967: 581-595