Synlett 2014; 25(11): 1606-1610
DOI: 10.1055/s-0033-1341274
letter
© Georg Thieme Verlag Stuttgart · New York

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

Sébastien Gauthier
a   PSL Research University, Chimie ParisTech - CNRS, Institut de Recherche de Chimie Paris, 75005 Paris, France   Fax: +33(1)44071062   eMail: virginie.vidal@chimie-paristech.fr
,
Laurent Larquetoux
b   Institut de Recherche Pierre Fabre, Centre de Développement et de Chimie Industrielle, 16 Rue Jean Rostand, 81600 Gaillac, France   eMail: philippe.maillos@pierre-fabre.com
,
Marc Nicolas
b   Institut de Recherche Pierre Fabre, Centre de Développement et de Chimie Industrielle, 16 Rue Jean Rostand, 81600 Gaillac, France   eMail: philippe.maillos@pierre-fabre.com
,
Tahar Ayad
a   PSL Research University, Chimie ParisTech - CNRS, Institut de Recherche de Chimie Paris, 75005 Paris, France   Fax: +33(1)44071062   eMail: virginie.vidal@chimie-paristech.fr
,
Philippe Maillos*
b   Institut de Recherche Pierre Fabre, Centre de Développement et de Chimie Industrielle, 16 Rue Jean Rostand, 81600 Gaillac, France   eMail: philippe.maillos@pierre-fabre.com
,
Virginie Ratovelomanana-Vidal*
a   PSL Research University, Chimie ParisTech - CNRS, Institut de Recherche de Chimie Paris, 75005 Paris, France   Fax: +33(1)44071062   eMail: virginie.vidal@chimie-paristech.fr
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Publikationsverlauf

Received: 13. März 2014

Accepted after revision: 31. März 2014

Publikationsdatum:
14. Mai 2014 (online)


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%.

 
  • 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