3-Methoxybenzonitrile (I) was converted to the corresponding imidate (II) by treatment with ethanolic HCl. Condensation of (II) with aminoacetaldehyde diethyl acetal (III) gave amidine (IV), which was cyclized with diethyl ethoxymethylenemalonate (V) in refluxing ethanol to yield the pyrimidinone (VI). Hydrolysis of the ethyl ester function of (VI) by treatment with LiI in hot pyridine provided acid (VII). This was subjected to a Curtius rearrangement with diphenylphosphoryl azide, and the intermediate isocyanate was condensed with benzyl alcohol to produce the benzyl carbamate (VIII). Acid hydrolysis of the diethyl acetal group of (VIII), followed by oxidation of the resulting aldehyde with sodium chlorite, furnished the carboxylic acid (IX).
Protection of phenylalaninol (X) as the corresponding benzyl carbamate, followed by Swern oxidation of the alcohol function, furnished N-(benzyloxycarbonyl)phenylalaninal (XI). Aldehyde (XI) was then converted to cyanohydrin (XII) upon treatment with acetone cyanohydrin and Et3N. Reaction of (XII) with an in situ-generated ethanolic solution of HCl gave imidate (XIII). Methyl 4-hydroxy-3-aminobenzoate (XV) was prepared by esterification of 4-hydroxy-3-nitrobenzoic acid (XIV) followed by catalytic hydrogenation of the nitro group. Condensation of imidate (XIII) with the aminophenol (XV) in refluxing EtOH gave rise to the benzoxazole derivative (XVI). After hydrogenolytic cleavage of the carbobenzoxy group of (XVI), the resulting amine (XVII) was coupled with the intermediate pyrimidineacetic acid (IX) in the presence of EDC and HOBt, yielding amide (XVIII). The secondary alcohol of (XVIII) was then oxidized to the corresponding ketone (XIX) using a modified Pfitzner-Moffatt reaction. The carbobenzoxy protecting group of (XIX) was finally removed by treatment with trifluoromethanesulfonic acid in the presence of anisole.