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IMPROVED RESOLUTION OF A 1-(1H-1,2,4-TRIAZOL-1-YL)BUTAN-2-OL DERIVATIVE

IP.com Disclosure Number: IPCOM000218902D
Publication Date: 2012-Jun-08
Document File: 8 page(s) / 69K

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IMPROVED RESOLUTION OF A 1-(1H-1,2,4-triazol-1-yl)butan-2-ol DERIVATIVE

[0001]          Voriconazole is an active pharmaceutical substance with an empirical formula of C16H14F3N5O and a molecular weight of 349.31. Voriconazole is the international commonly accepted non-proprietary name for (2R,3S)-2-(2,4-difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol, which is represented by Formula (I).

(I)

[0002]          Voriconazole is a commercially marketed pharmaceutically active substance known to be useful for the treatment of some fungal infections. In the

United States

, voriconazole is marketed under the trademark VfendTM. The VfendTM products are available as an intravenous solution, a powder for oral suspension (and hence an oral suspension), and film coated tablets for oral administration.

[0003]          U.S. Patent 5,567,817 discloses a process for the enantiomeric resolution of racemic voriconazole. Thus, Example 7 of U.S. Patent 5,567,817 discloses that racemic voriconazole and (1R)-(-)-10-camphorsulfonic acid were dissolved in methanol and then cooled to

0 ºC

to crystallize (2R,3S)-2-(2,4-difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol (1R)-(-)-10-camphorsulfonate 0.5 methanol, which was collected by filtration and subsequently partitioned between dichloromethane and saturated aqueous sodium bicarbonate to give (2R,3S)-2-(2,4-difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol (i.e., voriconazole) after evaporation of the organic layer with an overall yield of 59%. On the other hand, the filtrate of the crystallization, which is enriched in the undesired diastereomeric salt, (2S,3R)-2-(2,4-difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol (1R)-(-)-10-camphorsulfonate, was evaporated in vacuo and partitioned between dichloromethane and saturated aqueous sodium bicarbonate. The organic layer was evaporated and the residue was dissolved in methanol together with (1S)-(+)-10-camphorsulfonic acid, and then cooled to

0 ºC

to crystallize (2S,3R)-2-(2,4-difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol (1S)-(+)-10-camphorsulfonate 0.5 methanol, which was collected by filtration and subsequently partitioned between dichloromethane and saturated aqueous sodium bicarbonate to give (2S,3R)-2-(2,4-difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol (i.e., the undesired enantiomer of voriconazole) after evaporation of the organic layer. The resolution process is summarized in Scheme 1.

Scheme 1

[0004]          PCT Patent application WO 2008/075205 A2 discloses an improved process for the enantiomeric resolution of racemic voriconazole. In Example 1 of WO 2008/075205 A2, racemic voriconazole is treated with (1S)-(+)-10-camphorsulfonic acid in a mixture of ethyl acetate and methanol to obtain (2S,3R)-2-(2,4-difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol (1S)-(+)-10-camphorsulfonate, whi...