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RECRYSTALLIZATION METHOD FOR PURIFICATION OF VORICONAZOL

IP.com Disclosure Number: IPCOM000125375D
Publication Date: 2005-May-31
Document File: 4 page(s) / 111K

Publishing Venue

The IP.com Prior Art Database

This text was extracted from a PDF file.
This is the abbreviated version, containing approximately 31% of the total text.

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    RECRYSTALLIZATION METHOD FOR PURIFICATION OF 2R, 3S-2-(2,4- DIFLUOROPHENYL)-3-(5-FLUOROPYRIMIDIN-4-YL)-1-(1H-1,2,4-TRIAZOL-1-YL)-2- BUTANOL

BACKGROUND

VRC is an antifungal drug with a broad spectrum of bioactivity. VRC can be prepared as

5 described, for example, in the following patents: EP 440372 B1, examples 7 and 8, and U.S. Patent No. 6,586,594, preparations 2, 4 and 8, and their equivalents, in which the final compound is isolated as a crystalline solid and not further purified. The only analytical data reported is melting point (127°C, EP '372; 133°C, US '594) and specific optical rotation (-62°, EP '372).

     As used herein and unless otherwise required by the context, VRC refers to VRC free base, i.e., 2R, 3S-2-(2,4-difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-1-(1H-1,2,4-triazol-1-yl)-2-butanol.

     All experimental measurements are subject to experimental error. As used herein in connection with a measured quantity, the term "about" refers to the variation in the measured quantity that would be expected by one skilled in the art exercising a level of care commensurate with the purpose of the

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DETAILED DESCRIPTION

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measurement and the equipment being used.

As used herein, room temperature refers to a temperature of about 20°C to about 27°C.

         One recrystallization method to obtain purified VRC provides purified VRC, that has no endothermic peak between about 121°C and about 124°C when the differential scanning calorimetry (DSC) thermogram thereof is recorded as described herein below. Preferably, the DSC thermogram of 20 purified VRC exhibits a single endotherm having a peak temperature (temperature of maximum excursion or deviation from the baseline) at about 130°C to about 135°C, and no other endotherms outside this range. The enthalpy associated with this single endotherm in the DSC thermogram of purified VRC obtained by the described method is about 86 to about 100, preferably about 90 to about 100 calories per gram.

The VRC useful as starting material in the practice can be from any source. It can be made by,

25 and preferably isolated from, any method for making VRC free base.

         The recrystallization method for purifying VRC (i.e., a method for obtaining purified VRC) includes the steps of: providing a solution of VRC in a solvent selected from lower aliphatic alcohols, alkyl ethers, and cyclic saturated hydrocarbons; refluxing the solution; cooling the solution to room temperature or below to obtain a suspension; and isolating purified VRC from the suspension. 30

     The lower aliphatic alcohols useful can be linear or branched and have the general formula CnH2n+1OH, where n is 2 to 5. Ethanol and 2-propanol (iso-propanol) are preferred lower aliphatic alcohols.

         The alkyl ethers useful can be branched or, preferably, linear and have the general formula CnH2n+1-O-CmH2m+1, where n and m are, independently, 3 to about 6. Di-n-butyl ether is a preferred alkyl 35 ether.

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     The cyclic saturated hydrocarbons useful have the...