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The Discovery and Process Development of a Commercial Route to the Water Soluble Prodrug, Fosfluconazole

2001; American Chemical Society; Volume: 6; Issue: 2 Linguagem: Inglês

10.1021/op010064+

1520-586X

Arthur F. Bentley, Michael Butters, Stuart P. Green, William J. Learmonth, Julie MacRae, Matthew C. Morland, Garry O'Conno, Joanne Skuse,

Synthesis and biological activity

A case history detailing the rationale behind the discovery of 2-(2,4-difluorophenyl)-1,3-bis(1H-1,2,4-triazole-1-yl)-2-propyl dihydrogen phosphate, fosfluconazole (2), a water-soluble prodrug of Diflucan, and the subsequent development of a commercial route is presented. Particular items to note are (i) that this compound was discovered in the Chemical Research and Development Department, hence Chemical Research and Development can play a key role in prodrug discovery, (ii) the strategy behind the selection of phosphate ester promoiety, by phosphorylation of a sterically hindered tertiary alcohol, (iii) the development of the initial route to remove thermally hazardous reagents and to improve processing to allow scale-up, and (iv) the identification and development of the proposed commercial process.