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ENANTIOSELECTIVE PREPARATION OF VORICONAZOLE

IP.com Disclosure Number: IPCOM000205313D
Publication Date: 2011-Mar-25
Document File: 4 page(s) / 51K

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Abstract

The present disclosure relates to an enantioselective process for the preparation of voriconazole using simulated moving bed chromatography.

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ENANTIOSELECTIVE PREPARATION OF VORICONAZOLE

Abstract

The present disclosure relates to an enantioselective process for the preparation of voriconazole using simulated moving bed chromatography. 

Voriconazole, a triazole antifungal agent, chemically is (2R,3S)-2-(2,4-difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-1-(1H-1,2,4-triazol-1-yl)-2-butanol represented by following Formula I.

Formula I

In processes reported heretofore, the racemic (2R,3S/2S,3R)-2-(2,4-difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol compound of Formula V

 

Formula V

is resolved into its enantiomer(s) [i.e., (2R,3S) or (2S,3R)] by making use of chiral acid, for example, R-(-)-10-camphorsulfonic acid.

We have developed an enantioselective process for the preparation of voriconazole of Formula I using simulated moving bed chromatography.  This circumvents the resolution of racemic (2R,3S/2S,3R)-2-(2,4-difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol. The resultant voriconazole is obtained in better yield and has higher purity.  The present process avoids additional steps involved in the separation or purification of voriconazole in the final stage from the undesired optical isomers.

The racemic (2R,3S/2S,3R)-2-(2,4-difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol compound of Formula V may be prepared according to any one of the methods provided in PCT Publication Nos. WO 2007/013096; WO 2006/065726; WO 2007/132354; and U.S. Patent Nos. 6,586,594 and 5,567,817.

The 2-(2,4-difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol compound of Formula V as a racemic mixture (2R,3S/2S,3R) existing in any solid form or as gummy residue or even in-situ as known in the prior art may be used for preparing enantiomerically pure or optically enriched enantiomers, for example, voriconazole of Formula I or compound of Formula VI.  A solution of racemic mixture (2R,3S/2S,3R) of 2-(2,4-difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol compound of Formula V may be prepared prior to subjecting it to the simulated moving bed chromatography.  The solvent for preparing the solution may be a nitrile, for example, acetonitrile or an alkanol, for example, methanol, or a mixture thereof.  The column used in simulated moving bed chromatography may be, for example, Chiralpak OZ (250 x 4.6) mm.  The column temperatures, stationary phase particle size, flow rate, injection volume and mobile phase ratio may be adjusted to optimize output.  The column temperature may be controlled from about 20°C to about 40°C, for example, about 25°C to about 30°C.  The stationary phase particle size may be from about 10 μm to about 30 μm, for example, about 20 μm.  The flow rate may be controlled from about 0.5 ml to about 2 ml per minute, for example, about 1 ml per minute.  The injection volume may be controlled from about 5 μL to about 30 μL, for example, ab...