Short and Straightforward Enantioselective Synthesis of Both Enantiomers of Mequitazine through Iridium-Catalyzed Asymmetric Hydrogenation of a Nonfunctionalized Cyclic Enamine

Abstract

A short and straightforward asymmetric synthesis of both enantiomers of the antihistaminic drug mequitazine is reported. This atom-economical and attractive method features an iridium-catalyzed asymmetric hydrogenation of a nonfunctionalized cyclic enamine as a key step to install the C ₃-stereogenic center. After a full investigation of the effects of catalyst precursors, ligands, solvents, temperature, and hydrogen pressure, mequitazine (1) is obtained in good yield (up to 80%) and with acceptable enantiomeric excesses up to 47%.

Key words

mequitazine - iridium - asymmetric catalysis - hydrogenation - enamine

• References and Notes


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• 11 Typical Procedure for the Asymmetric Hydrogenation of Enamine Salts 2 A glass tube was charged with Ir(COD)₂]SbF₆ (1 mol%) and ligand (S,S)-L10 (2.2 mol%) in anhydrous THF (c 0.05 M). After stirring 30 min at r.t., the endo-dehydromequitazine HCl salt (2a, 1 mmol) was added following by I₂ (5 mol%, 0.05 mmol). The tube was placed in a stainless-steel autoclave, which was subjected to three vacuum/argon cycles. The hydrogenation was performed at 50 °C under 90 bar of hydrogen pressure for 48 h. After careful releasing of the hydrogen gas and treatment with 5 mL of aq NaOH (0.5 M), the reaction mixture was extracted with CH₂Cl₂ (3 × 5mL) and the organic phases were combined, dried over Na₂SO₄, and concentrated under reduced pressure. The crude product was then purified by column chromatography using neutral alumina (Al₂O₃) eluted with a mixture of CH₂Cl₂–MeOH (9:1) to give (–)-(S)-mequitazine 1 (85% yield, 47% ee) as a white solid. Spectral data are in agreement with those of authentic sample of (–)-(S)-1. ¹H NMR (300 MHz, CDCl₃): δ = 1.64–1.32 (m, 4 H), 1.92–1.84 (m, 1 H), 2.26 (m, 1 H), 2.45 (dd, J = 13.5, 5.8 Hz, 1 H), 2.85–2.69 (m, 4 H), 3.12 (dd, J = 13.5, 11.8 Hz, 1 H), 3.88 (m, 2 H), 6,95–6,89 (m, 4 H), 7.20–7.14 (m, 4 H). ¹³C NMR (75 MHz, CDCl₃): δ = 21.0, 22.6, 27.3, 32.3, 47.3, 47.5, 49.8, 52.5, 116.1, 122.9, 126.2, 127.5, 127.9, 145.6. The ee of (–)-(S)-1 was determined by HPLC analysis of the crude product using a chiral Chiralcel OJ column. Eluent: hexane–i-PrOH (85:15), detector: 254 nm, flow rate: 1 mL/min, (+)-(R)-1: t _R = 12.2 min; (–)-(S)-1: t _R = 40.5 min