合成路线1

The condensation of 2-fluorobenzylmagnesium bromide (XII) with 2-oxobutyric acid ethyl ester (XIII) in ethyl ether gives 2-(2-fluorobenzyl)-2-hydroxybutyric acid ethyl ester (XIV), which is cyclized by means of NaH in toluene/DMF yielding he ester (VI). The hydrolysis of (VI) with NaOH affords the acid (VII), which is treated with SOCl2 to give the acyl chloride (XV). Then this compound is cyclized with ethylenediamine (XI) by means of AlMe3 in refluxing toluene. The reaction of 2-fluorobenzaldehyde (XVI) with ethyl 2-bromobutyrate (II) by means of potassium tert-butoxide in dioxane gives the epoxide (XVII), which is opened by hydrogenation with H2 over Pd/C in ethanol to afford the previously reported hydroxybutyric ester (XIV). The condensation of 2-fluorophenyllithium (XVIII) or 2-fluorophenylmagnesium bromide (XIX) with 2-(benzyloxymethyl)-2-ethyloxirane (XX) gives 1-(benzyloxy)-2-ethyl-3-(2-fluorophenyl)-2-propanol (XXI), which is cyclized by means of NaH yielding 2-(benzyloxymethyl)-2-ethyl-2,3-dihydrobenzofuran (XXII). Finally, this compound is debenzylated with H2 over Pd/C and oxidized with CrO3 and sulfuric acid to afford the previously reported carboxylic acid (VII). The alkylation of 2,3-dihydrobenzofuran-2-carboxylic acid (XXIII) with ethyl iodide by means of lithium diisopropylamide gives the previously reported carboxylic acid (VII).