2017年8月27日日曜日

Quinolone Synthesis 2017


Scalable and Practical Synthesis of Halo Quinolin-2(1H)-ones and Quinolines

Chemistry Process R&D, Actelion Pharmaceuticals Ltd., Gewerbestrasse 16, CH-4123 Allschwil, Switzerland
Org. Process Res. Dev., 2017, 21 (7), pp 1003–1011
DOI: 10.1021/acs.oprd.7b00124
Publication Date (Web): June 22, 2017
Copyright © 2017 American Chemical Society
*E-mail: Gunther.Schmidt@idorsia.com. Telephone: +41 61 565 8028.

Abstract

Abstract Image
 
 
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-8-iodoquinolin-2(1H)-one were further functionalized to obtain quinolines substituted with various functional groups.
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.oprd.7b00124.
  • Experimental procedures and analytical data for compounds 2 and 3. (PDF)



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