Article pubs.acs.org/OPRD
Scalable and Practical Synthesis of Halo Quinolin-2(1H)‑ones and Quinolines Cornelia Zaugg,† Gunther Schmidt,*,‡ and Stefan Abele‡ Chemistry Process R&D, Actelion Pharmaceuticals Ltd., Gewerbestrasse 16, CH-4123 Allschwil, Switzerland S Supporting Information *
ABSTRACT: A practical and scalable synthesis of halo quinolin-2(1H)-ones is presented. The heterocycles are easily accessed from inexpensive halo anilines in a two-step sequence. The anilines are acylated with methyl 3,3-dimethoxypropionate under basic conditions in quantitative yields. The crude amides undergo cyclization in sulfuric acid to the desired halo quinolin-2(1H)ones in 28−93% yield (2 steps). The synthetic sequence was successfully applied on 800 g scale. Anilines with strong electron withdrawing or electron donating groups were poor substrates for this procedure. 6-Iodoquinolin-2(1H)-one and 6-bromo-8iodoquinolin-2(1H)-one were further functionalized to obtain quinolines substituted with various functional groups.
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INTRODUCTION Quinolin-2(1H)-one derivatives display a wide range of pharmacological properties. They show antiviral,1 anticancer,2 antibacterial,3 antiinflammatory,4 antipsychotic,5 and cardiac stimulant6 activity and are used for the treatment of respiratory disease.7 For our ongoing anti-infective program, several 100 g quantities of 8-bromo (3b) or 8-iodoquinolin-2(1H)-one 3a were required. The first gram amounts were synthesized following the procedure of Cottet et al.8 by cyclizing 2bromocinnamanilide with aluminum trichloride. This procedure was not suitable for scale-up due to the large amount of the Friedel−Crafts catalyst and the concomitant problematic exothermic aqueous quench. In the literature, several methods are available for the formation of quinolin-2(1H)-ones. A recent publication describes a general palladium catalyzed cyclization of anilines with acryl esters in high yields.9 Unfortunately, the procedure was only demonstrated on a scale
