Discovery and Development of an Efficient Process to Atovaquone

• Published in: Organic process research & development 2012-10, Vol.16 (10), p.1607-1617
• Main Authors: Britton, Hugh, Catterick, David, Dwyer, Andrew N, Gordon, Andrew H, Leach, Stuart G, McCormick, Chris, Mountain, Clive E, Simpson, Alec, Stevens, David R, Urquhart, Michael W. J, Wade, Charles E, Warren, John, Wooster, Nick F, Zilliox, Audrey
• Format: Article
• Language: English
• ISSN: 1083-6160; 1520-586X
• DOI: 10.1021/op300165q

The discovery and development of an efficient and more sustainable manufacturing route to the anti-pneumocystic agent atovaquone (2-((1R,4R)-4-(4-chlorophenyl)­cyclohexyl)-3-hydroxynaphthalene-1,4-dione) 1 is described. The existing commercial route to atovaquone delivers a poor yield of product and uses expensive reagents. The new synthesis commences with readily available phthalic anhydride, which is converted to 1,4-isochromandione 5 and then to atovaquone 1 by reaction with 4-(4-chlorophenyl)­cyclohexanecarboxylic acid 3 using key bromination, Rosenmund reduction, and rearrangement chemistries. Downstream processing to atovaquone is both high yielding and robust, and the resulting process has been demonstrated on 200-kg scale. The process is simple, uses cheap raw materials, and is more sustainable in that it avoids low-yielding silver-promoted chemistry and isomerisation procedures. It includes a robust, facile, and highly efficient procedure to 1,4-isochromandione 5, and routes to 4-(4-chlorophenyl)­cyclohexanecarboxaldehyde 9 have also been developed, including a Rosenmund method that was demonstrated on pilot-plant scale. Also discussed are the route-derived impurities and processing amendments to control their formation.