Process for the manufacture of enantiomerically pure antifungal azoles as ravuconazole and isavuconazole

A process for the preparation of enantiomerically pure compounds of general formula I, having the 2R,3R configuration,

• wherein R1, R2 and R3 represent, independently from one another, hydrogen, fluorine, chlorine or CF3-group;
• which comprises
• either
• a) a resolution step of the racemic compound of formula I, having the 2R/S, 3R/S configuration, by adding a chiral acid, crystallizing said mixture, collecting the desired diastereomeric salt of formula I either from the precipitate or from mother liquid and then converting the salt of formula I into an enantiomerically pure form of the compound of formula I by treatment with an appropriate organic or inorganic base or using an ion-exchange resin
• or
• b) a resolution step of the racemic compound of formula II, having the 2R/S, 3R/S configuration,
• wherein R1, R2 and R3 are the same as defined for compound of formula I and wherein R4 and R5 represent, independently from one another, hydrogen, alkyl, aryl, alkylaryl, arylalkyl, alkoxy, aryloxy, arylalkoxy, alkylaryloxy, trialkylsilyl, alkylarylsilyl or with heteroatom(s) substituted alkyl, aryl alkylaryl, arylalkyl, mono-, di- or tri-methoxybenzyl or
• another for nitrogen known protective group, wherein R4 and R5 can also form together aliphatic or aromatic heterocyclic ring system;
• by adding a chiral acid, crystallizing said mixture, collecting the desired diastereomeric salt of formula II, having the 2R,3R configuration, either from the precipitate or from mother liquid and then converting the salt of formula II into an enantiomerically pure form of the compound of formula II by treatment with an organic or inorganic base or an ion-exchange resin, or alternatively using the salt of formula II directly, and after removal of the nitrogen protective groups R4 and R5 in case R4 and R5 are not hydrogens, reacting with 2-chloro-4″-cyanoacetophenone
• or
• c) a resolution step of the racemic compound of formula III, having the 2S/R, 3R/S configuration,
• wherein R1, R2 and R3 are the same as defined for the compound of formula I;
• by adding a chiral acid, crystallizing said mixture, collecting the desired diastereomeric salt of formula III, having the 2S,3R configuration, either from the precipitate or from mother liquid and then converting the salt of formula III into an enantiomerically pure form of the compound III by treatment with an organic or inorganic base or an ion-exchange resin, or using the salt of formula III directly, and reacting with hydrogen sulfide followed by reaction of the resulting compound of formula II with 2-chloro-4′-cyanoacetophenone.