Process Development of Voriconazole:  A Novel Broad-Spectrum Triazole Antifungal Agent

Abstract

In the synthesis of (2R,3S)-2-(2,4-difluorophenyl)-3-(5-fluoro-4-pyrimidinyl)-1-(1H-1,2,4-triazol-1-yl)-2-butanol (voriconazole), the relative stereochemistry is set in the addition of a 4-(1-metalloethyl)-5-fluoropyrimidine derivative to 1-(2,4-difluorophenyl)-2-(1H-1,2,4-triazol-1-yl)-1-ethanone. The diastereocontrol of this reaction has been examined by variation of pyrimidine substitution pattern and by changes in the metalation and reaction conditions. Excellent diastereoselection (12:1) is obtained using an organozinc derivative of 6-(1-bromoethyl)-4-chloro-5-fluoropyrimidine. After removal of the chlorine from the pyrimidine ring, the absolute stereochemistry of voriconazole is established via a diastereomeric salt resolution process using (1R)-10-camphorsulfonic acid. Synthetic routes to the pyrimidine partner have also been evaluated. The initial six-step development route from 5-fluorouracil has been superseded by a four-step synthesis involving fluorination of methyl 3-oxopentanoate and cyclisation with formamidine acetate.

Elemental fluorine in organic chemistry (1997–2006)

“…For example, the Pfizer herbicide, Veroconazole, requires the use of an a fluoro-ketoester building block which is itself synthesised on the manufacturing scale by direct fluorination [42].…”

Temperature Dependence of Mechanical Properties in Molecular Crystals

“…In such a case, increasing the temperature of tableting by a few tens of degrees may yield substantially better products 65. Likewise, some APIs, such as voriconazole, are extremely soft (low H values) and difficult to mill 66,67. In such cases, decreasing the temperature at which milling is performed may yield good results.…”

An Overview of Compartive Study of Pyrazole and Pyrimidine Derivatives

“…Pyrimidines also active antifungal agent which is used for the treatment of serious systemic infections caused by susceptible strains of candida and cryptococcus and hexetidine is mainly used for the treatment of aphthous ulceration [13][14][15][16][17][18][19] …”