By condensation of 3-[2(E)-(4-(2,2,3,3-tetrafluoropropoxy)phenyl)vinyl]-1H-1,2,4-triazole (I) with (+)-(R)-2-(2,4-difluorophenyl)-3-(1H-1,2,4-triazol-1-yl)-1,2-epoxypropane (II) by means of anhydrous K2CO3 in hot DMF. The starting products (I) and (II) are obtained as follows: a) The condensation of 4-chlorobenzonitrile (III) with 2,2,3,3-tetrafluoropanol (IV) by means of NaH in DMF gives 4-(2,2,3,3-tetrafluoropropoxy)benzonitrile (V), which is reduced to the corresponding benzaldehyde (VI) with diisobutylaluminum hydride in toluene. The condensation of diethoxyphosphorylacetic acid ethyl ester (VII) with aldehyde (VI) by means of KOH in THF yields (E)-4-(2,2,3,3-tetrafluoropropoxy)cinnamic acid ethyl ester (VIII), which is saponified to the corresponding acid (IX) with NaOH in ethanol-water. The reaction of (IX) first with refluxing SOCl2 and then with aqueous ammonia in toluene affords the corresponding amide (X), which is finally condensed with formyl hydrazide (XI) by means of trimethyloxonium tetrafluoroborate in CH2Cl2 to give (I). b) The reaction of 1,3-dichloroacetone (XII) with 2,4-difluorobromobenzene (XIII) by means of butyllithium in ether gives 1,3-dichloro-2-(2,4-difluorophenyl)-2-propanol (XIV), which is converted into 3-chloro-2-(2,4-difluorophenyl)-1,2-epoxypropane (XV) by treatment with NaH in DMF. The reaction of (XV) with tellurium and sodium hydroxymethylsulfinate in water yields 2-(2,4-difluorophenyl)allyl alcohol (XVI), which by stereoselective epoxidation with titanium tetraisopropoxide and diethyl (+)-tartrate in methylene chloride is converted into (R)-(-)-2-(2,4-difluorophenyl)-2,3-epoxypropanol (XVII). The reaction of (XVII) with 1,2,4-triazole (XVIII) by means of K2CO3 in THF affords (S)-(-)-2-(2,4-difluorophenyl)-3-(1H-1,2,4-triazole-1-yl)-propane-1,2-diol (XIX), which is finally treated with methanesulfonyl chloride and triethylamine in ether to give (II).
The intermediate (XIX) can be obtained by two related ways: 1. The condensation of 1,3-dichloroacetone (XIII) with 2,4-difluorobromobenzene (XII) by means of n-BuLi gives 1,3-dichloro-2-(2,4-difluorophenyl)-2-propanol (XIV), which is converted into the epoxide (XV) by reaction with KOH in toluene. The reaction of (XV) with isobutyric anhydride (XXII) yields the diester (XX), which is stereoselectively hydrolyzed with Lipase D in an acetate buffer to afford the (R)-monoester (XXIV). The reaction of (XXIV) with Ms-Cl and pyridine provides the monomesylate (XXV), which is treated with KOH in toluene to give the hydroxymethyl epoxide (XVII). Finally, this compound is treated with 1,2,4-triazole (XVIII) and K2CO3 in refluxing THF to afford the target intermediate. Alternatively, the mesylate (XXV) can be treated with 1,2,4-triazole (XVIII) and Na2CO3 in refluxing methanol to yield directly the target intermediate (XIX). 2. The acylation of 1,3-dihydroxypropanone (XXI) with butyric anhydride (XXII), pyridine and DMAP gives the diester (XXIII), which is submitted to a Grignard condensation with 2,4-difluorobromobenzene (XIII) by means of Mg to afford the already described intermediate, the diester (XIX).