Process For Preparing Voriconazole

Abstract

Voriconazole is prepared by a process comprising condensing 1-(2,4-difluorophenyl)-2-(1H-1,2,4-triazole-1-yl)ethanone with 4-chloro-6-ethyl-5-fluoropyrimidine, in a ketone, ether, aliphatic hydrocarbon, or aromatic hydrocarbon solvent, to give (2R, 3S/2S,3R)-3-(4-chloro-5-fluoropyrimidin-6-yl)-2-(2,4-diflurophenyl)-1-(1H-1,2,4-triazole-1-yl)butan-2-ol.

1 . A process for preparing voriconazole, comprising the step of condensing 1(2,4-difluorophenyl)-2-(1H-1,2,4-triazole-1-yl) ethanone with 4-chloro-6-ethyl-5-fluoropyrimidine, in a ketone, ether, aliphatic hydrocarbon, or aromatic hydrocarbon solvent, to give (2R,3S/2S,3R)-3-(4-chloro-5-fluoropyrimidin-6-yl)-2-(2,4-diflurophenyl)-1-(1H-1,2,4-triazole-1-yl)butan-2-ol. 
     
     
         2 . The process of  claim 1 , wherein condensing is conducted in the presence of an organolithium derivative. 
     
     
         3 . The process of  claim 1 , wherein condensing is conducted in the presence of a C 1 -C 6  alkyl lithium compound. 
     
     
         4 . The process of  claim 1 , wherein condensing is conducted in the presence of a C 1 -C 6  alkyl lithium compound, optionally condensed with an amine having one or more C 1 -C 6  alkyl group substituents on a nitrogen atom. 
     
     
         5 . The process of  claim 1 , wherein condensing is conducted in an aliphatic hydrocarbon solvent. 
     
     
         6 . A process for preparing voriconazole, comprising the steps of:
 a) condensing 1-(2,4-difluorophenyl)-2-(1H-1,2,4-triazole-1-yl) ethanone with 4-chloro-6-ethyl-5-fluoropyrimidine, in a ketone, ether, aliphatic hydrocarbon, or aromatic hydrocarbon solvent, to give (2R,3S/2S,3R)-3-(4-chloro-5-fluoropyrimidin-6-yl)-2-(2,4-diflurophenyl)-1-(1H-1,2,4-triazole-1-yl)butan-2-ol;   b) hydrogenating (2R,3S/2S,3R)-3-(4-chloro-5-fluropyrimidin-6-yl)-2-(2,4-diflurophenyl)-1-(1H-1,2,4-triazole-1-yl)butan-2-ol to give (2R,3S/2S,3R)-2-(2,4-difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-1-(1H-1,2,4-triazol-1yl)butan-2-ol;   c) resolving (2R,3S/2S,3R)-2-(2,4-difluorophenyl)-3-(5-fluoro pyrimidin-4-yl)-1-(1H-1,2,4-triazol-1yl)butan-2-ol to afford a diastereomeric salt of (2R,3S)-2-(2,4-difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-1-(1H-1,2,4-triazol-1yl)butan-2-ol; and   d) converting a diastereomeric salt to voriconazole.   
     
     
         7 . The process of  claim 6 , wherein condensing is conducted in the presence of an organolithium derivative. 
     
     
         8 . The process of  claim 6 , wherein condensing is conducted in the presence of a C 1 -C 6  alkyl lithium compound. 
     
     
         9 . The process of  claim 6 , wherein condensing is conducted in an aliphatic hydrocarbon solvent. 
     
     
         10 . The process of  claim 6 , wherein resolving comprises reacting (2R,3S/2S,3R)-2-(2,4-difluorophenyl)-3-(5-fluoro pyrimidin-4-yl)-1-(1H-1,2,4-triazol-1yl)butan-2-ol with a chirally active acid to form a diastereomeric salt. 
     
     
         11 . The process of  claim 6 , wherein a product from the condensing is not subjected to a chromatographic separation, prior to step b). 
     
     
         12 . Voriconazole prepared by the process of  claim 6 , having a purity at least about 95 area-percent, by high performance liquid chromatography. 
     
     
         13 . Voriconazole prepared by the process of  claim 6 , having a purity at least about 99 area-percent, by high performance liquid chromatography. 
     
     
         14 . Voriconazole prepared by the process of  claim 6 , having a purity at least about 99.5 area-percent, by high performance liquid chromatography. 
     
     
         15 . The voriconazole of  claim 12 , containing less than about 0.15 area-percent, by high performance liquid chromatography, of each of the impurities:
 2,4-difluro-1H-1-yl-1,2,4-triazolacetophenone;   6-ethyl-5-fluoropyrimidine;   4-chloro-6-ethyl-5-fluropyrimidine;   6-[(1-(5-fluoropyrimidinyl)-6-ethyl]-4-chloro-5-fluoropyrimidine;   (2R,3S/2S,3R)-3-(4-chloro-5-fluoropyrimidin-6-yl)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-butan-2-ol;   (2R,3R/2S,3S)-3-(4-chloro-5-fluoropyrimidin-6-yl)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-butan-2-ol;   (2R,3R/2S,3S)-2-(2,4-difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-1-(1H-1,2,4-triazol-1-yl)-butan-2-ol; and   (2S,3R)-2-(2,4-difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-1-(1H-1,2,4-triazol-1-yl)-butan-2-ol.   
     
     
         16 . The voriconazole of  claim 12 , containing the residual solvents:
 acetone less than about 5000 ppm;   isopropyl alcohol less than about 5000 ppm; and   being substantially free from hexane, heptane, and tetrahydrofuran.   
     
     
         17 . Form A of voriconazole, having an X-ray powder diffraction pattern, using copper K α radiation, substantially according to  FIG. 1 . 
     
     
         18 . The Form A of voriconazole of  claim 17 , having an X-ray powder diffraction pattern, using copper K α radiation, comprising peaks at about 6.9, 9.2, 10.7, 12.7, 13.7, 13.9, 14.4, 14.8, 15.3, 19.8, 20.8, and 27.0, ±0.2 degrees two theta. 
     
     
         19 . The Form A of voriconazole of  claim 17 , prepared by a process comprising:
 dissolving voriconazole in a solvent comprising water at reflux temperatures; and   cooling to obtain separation of solid voriconazole.   
     
     
         20 . The form A of voriconazole of  claim 19 , wherein a solvent comprises water and an organic solvent. 
     
     
         21 . Amorphous voriconazole. 
     
     
         22 . The amorphous voriconazole of  claim 21 , prepared by a process comprising:
 providing a solution of voriconazole and a carrier in an organic solvent; and   removing solvent to obtain a solid residue comprising amorphous voriconazole.   
     
     
         23 . The amorphous voriconazole of  claim 21 , wherein a carrier comprises a polymer of N-vinylpyrrolidone. 
     
     
         24 . A process for preparing crystalline Form B of voriconazole, comprising:
 adding water to a solution of voriconazole in a solvent at an elevated temperature; and   cooling to obtain separation of solid voriconazole.   
     
     
         25 . The process of  claim 24 , wherein a solvent is a ketone.