CC BY-NC-ND 4.0 · SynOpen 2021; 05(02): 158-160
DOI: 10.1055/a-1524-4439
letter

An Improved, Scalable Synthesis of the Selective Serotonin 2A Receptor Agonist 25CN-NBOH

,
Jitka Nykodemová
,
The Lundbeck foundation (R208-2015-3140) is gratefully acknowledged for financial support.


Abstract

4-{2-[(2-hydroxybenzyl)amino]ethyl}-2,5-dimethoxybenzo­nitrile (25CN-NBOH) was first reported as a potent and highly selective serotonin 2A receptor (5-HT2AR) agonist in 2014. The compound has since found extensive use as a pharmacological tool in a variety of in vivo and in vitro studies. In the present study, we present an improved and scalable synthesis of 25CN-NBOH making this compound readily available to the scientific community.

Supporting Information



Publication History

Received: 08 April 2021

Accepted after revision: 26 April 2021

Publication Date:
08 June 2021 (online)

© 2021. 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/)

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  • 18 Synthesis of 4-{2-[(2-Hydroxybenzyl)amino]ethyl}-2,5-di­meth­oxy­benzonitrile Hydrochloride (1)A flame-dried round-bottom flask equipped with a stirrer bar and flushed with argon was charged with 2 (300 mg, 1.24 mmol), salicylaldehyde (0.144 mL, 1.36 mmol), trimethylamine (0.172 mL, 1.24 mmol), and anhydrous EtOH (32 mL). The reaction mixture was stirred at ambient temperature until the formation of imine was complete as indicated by TLC and UPLCMS. After 3 h the reaction mixture was cooled to 0 °C, then NaBH4 (93.5 mg, 2.47 mmol) was added in small portions. The reaction mixture was stirred for 30 min at ambient temperature before being evaporated in vacuo. The resulting residue was dissolved in DCM (25 mL) then diluted with water (25 mL). The phases were separated, and the aqueous phase further extracted with DCM (2 × 25 mL). The combined organic layers were dried over MgSO4, filtered, and evaporated in vacuo. The crude amine was purified by column chromatography (DCM, MeOH, NH4 [98:2 + 0.25]) giving the desired amine as a clear oil. The purified free base was transformed into the hydrochloride salt by dissolving it in MeOH (5 mL) and passing HCl gas, generated by the addition of 35% aq. hydrochloric acid to CaCl2. The resulting suspension was cooled to 4 °C and left to crystalize over 24 h. The solid formed was filtered, re-suspended in boiling 2-propanol, and diethyl ether was added dropwise until turbidity was observed. The flask was cooled to 4 °C overnight giving the crystalline product. The crystals were isolated by filtration and washed with cold diethyl ether before being dried under high vacuum to yield the desired amine hydrochloride 1 as a white solid (285 mg, 65%). Analytical data were consistent with previously published literature data.Mp 220.5–222.0 °C; Rf = 0.53 (silica gel, 95:5:0.2, DCM/MeOH/NH3). 1H NMR (600 MHz, MeOD): δ = 7.30 (ddd, J = 15.0, 7.6, 1.8 Hz, 2 H), 7.22 (s, 1 H), 7.09 (s, 1 H), 6.93–6.88 (m, 2 H), 4.25 (s, 2 H), 3.91 (s, 3 H), 3.83 (s, 3 H), 3.26 (dd, J = 8.9, 6.5 Hz, 2 H), 3.10 (dd, J = 8.9, 6.5 Hz, 2 H). 13C NMR (151 MHz, MeOD): δ = 157.48, 157.37, 152.73, 133.67, 132.59, 132.42, 121.06, 118.65, 117.12, 116.29, 115.95, 115.75, 101.24, 57.15, 56.71, 48.30, 47.45, 28.82. HRMS-ESI: m/z calcd for C18H21N2O3 [M + H]+: 313.1546; found: 313.1546; HPLC: t R = 17.51 (96.5%).