Lithiation of 1,3-bis(O-methoxymethyl)resorcinol (I) by means of n-butyllithium, followed by acylation with acetyl chloride, gave the protected acetophenone (II). Subsequent acid hydrolysis of the methoxymethyl protecting groups furnished diol (III). The 4-hydroxybenzofuran derivative (VI) was prepared by monoalkylation of (III) with ethyl bromoacetate (IV), followed by base-catalyzed cyclization of the resulting keto ester (V). Alkylation of the hydroxybenzofuran (VI) with 1,3-dibromopropane (VII) gave the bromopropyl ether (VIII). This was finally condensed with 3-picolylamine (IX) to produce the title compound.
Alkylation of ethyl 4-hydroxy-3-methylbenzofuran-2-carboxylate (I) with 1,3-dibromopropane (II) in the presence of K2CO3 produced the bromopropyl ether (III). Subsequent displacement of the remaining bromine of (III) with 3-picolylamine (IV) furnished the secondary amine (V). The ester group of (V) was then reduced to alcohol (VI) with LiAlH4. Finally, Mitsunobu coupling of alcohol (VI) with 2,4-difluorophenol (VII) in the presence of 1,1'-(azodicarbonyl)dipiperidine and tributylphosphine gave rise to the target difluorophenyl ether.
Condensation of ethyl 4-hydroxy-3-methylbenzofuran-2-carboxylate (I) with 1,3-dibromopropane (II) affords the benzofuran bromopropyl ether (III). Subsequent displacement of bromide (III) with 3-picolylamine (IV) yields amine (V). The ester group of (V) is then reduced with LiAlH4 to furnish alcohol (VI). Finally, Mitsunobu coupling between alcohol (VI) and 2,3,4-trifluorophenol (VII) in the presence of 1,1'-(azodicarbonyl)dipiperidine (ADDP) and tributylphosphine provides the title compound