合成路线1

Falecalcitriol can be obtained by several different ways: 1) The reaction of 24-(tosyloxy)chol-5-en-3beta-ol tetrahydropyranyl ether (I) with LiBr gives the corresponding 24-bromo derivative (II), which is treated with activated Mg (to yield the Grignard reagent) and hexafluoroacetone affording 26,26,26,27,27,27-hexafluoro-3beta-(tetrahydropyranyloxy)cholest-5-en-25-ol (III). The hydrolysis of (III) with p-toluenesulfonic acid gives the diol (V), which is oxidized with dichlorodicyanobenzoquinone (DDQ) in hot dioxane yielding the hexafluoro-25-hydroxycholest-1,4,6-trien-3-one (VI). The epoxidation of (VI) with H2O2 and NaOH in methanol/THF affords the 1alpha,2alpha-epoxide (VII), which is reduced with Li in liquid ammonia to give the hexafluorocholest-5-en-1alpha,3beta,25-triol (VIII). The acetylation of (VIII) with acetic anhydride and dimethylaminopyridine (DMAP) yields the corresponding triacetate (IX), which is treated with N-bromosuccinimide (NBS) and collidine (2,4,6-trimethylpyridine) to afford the hexafluoro-1alpha,3beta,25-triacetoxycholest-5,7-diene (X). The U.V. irradiation of (X) with a medium pressure mercury lamp in benzene/ethanol gives the triacetylated vitamin D3 derivative (XI), which is finally deacetylated with KOH in methanol/THF. 2) An alternative synthesis of the intermediate 26,26,26,27,27,27-hexafluoro-3beta-(tetrahydropyranyloxy)cholest-5-en-25-ol (III) is the reaction of the previously obtained bromo derivative (II) with sodium benzenesulfinate in DMF yielding the sulfone (IV), which is then condensed with hexafluoroacetone by means of lithium diisopropylamide (LDA) in THF.