Discovery and Development of an Efficient Process to Atovaquone

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• 作者：Hugh Britton ; David Catterick ; Andrew N. Dwyer ; Andrew H. Gordon ; Stuart G. Leach ; Chris McCormick ; Clive E. Mountain ; Alec Simpson ; David R. Stevens ; Michael W. J. Urquhart ; Charles E. Wade ; John Warren ; Nick F. Wooster ; Audrey Zilliox
• 刊名：Organic Process Research & Development
• 出版年：2012
• 出版时间：October 19, 2012
• 年：2012
• 卷：16
• 期：10
• 页码：1607-1617
• 全文大小：418K
• 年卷期：v.16,no.10(October 19, 2012)
• ISSN：1520-586X

文摘

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.