A Scalable, Chromatography-Free Synthesis of the Potent and Highly Selective ERβ Agonist EGX358

Abstract

4-[trans-4-(Hydroxymethyl)cyclohexyl]phenol (EGX358) is a potent and highly selective estrogen receptor beta (ERβ) agonist which has demonstrated efficacy for moderation of a chemically induced hot flash and for memory consolidation in an ovariectomized mouse model for menopause. An improved synthetic route to EGX358 is reported which proceeds in four steps and which is chromatography-free.

Key words

chromatography-free synthesis - Diels–Alder reaction - ionic reduction - estrogen receptor beta agonist - EGX358

Publikationsverlauf

Eingereicht: 11. November 2024

Angenommen nach Revision: 11. Dezember 2024

Artikel online veröffentlicht:
22. Januar 2025

• References

• 1 Present address: S. Chaudhury, Biological and Chemical Sciences, College of Arts & Sciences, New York Institute of Technology, New York, NY 10023, USA.
• 2 Vargas KG, Milic J, Zaciragic A, Wen K, Jaspers L, Nano J, Dhana K, Bramer WM, Kraja B, van Beeck E, Ikram MA, Muka T, Franco OH. Maturitas 2016; 93: 41
• 3 Walf AA, Frye CA. Pharmacol., Biochem. Behav. 2007; 86: 407
• 4 Walf AA, Koonce CJ, Frye CA. Behav. Neurosci. 2008; 122: 974
• 5 Zhao L, Woody SK, Chhibber A. Ageing Res. Rev. 2015; 24: 178
• 6 Jordan VC. Br. J. Pharmacol. 1993; 110: 507
• 7 Hanson AM, Perera KL. I. S, Kim J, Pandey RK, Sweeney N, Lu X, Imhoff A, Mackinnon AC, Wargolet AJ, Van Hart RM, Frick KM, Donaldson WA, Sem DS. J. Med. Chem. 2018; 61: 4720
• 8 Fleischer AW, Schalk JC, Wetzel EA, Hanson AM, Sem DS, Donaldson WA, Frick KM. Horm. Behav. 2021; 130: 104948
• 9 Schwabe MR, Fleischer AW, Kuehn RK, Chaudhury S, York JM, Sem DS, Donaldson WA, LaDu MJ, Frick KM. Front. Aging Neurosci. 2024; 16: 1477045
• 10 Barker G, Webster S, Johnson DG, Curley R, Andrews M, Young PC, Macgregor SA, Lee A.-L. J. Org. Chem. 2015; 80: 9807
• 11 CCDC 2385594 (9) contains the supplementary crystallographic data for this paper. The data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/structures
• 12 Yanagisawa A, Nishimura K, Ando K, Nezu T, Maki A, Kato S, Tamaki W, Imai E, Mohri S.-i. OPR&D 2010; 14: 1182
• 13a Thompson HW. J. Org. Chem. 1971; 36: 2577
• 13b Thompson HW, Naipawer RE. J. Org. Chem. 1972; 37: 1307
• 13c Thompson HW, Rashid SY. J. Org. Chem. 2002; 67: 2813
• 13d Kraft P, Weymuth C, Nussbaumer C. Eur. J. Org. Chem. 2006; 1403
• 14 Lee H.-J, Arumugam N, Almansour A, Kumar RS, Maruoka K. Tetrahedron 2018; 74: 5263
• 15a Crabtree RH, Davis MW. J. Org. Chem. 1986; 51: 2655
• 15b Shultz AG, McCloskey PJ. J. Org. Chem. 1985; 50: 5907