合成路线1

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).