The intermediate pyrimidineacetic acid (X) was prepared as follows. 4-Fluorobenzonitrile (I) was converted to the corresponding imidate (II) by treatment with ethanolic HCl. Reaction of imidate (II) with aminoacetaldehyde diethyl acetal (III) produced amidine (IV), which was condensed with diethyl ethoxymethylenemalonate (V) in boiling EtOH to furnish pyrimidinone (VI). Hydrolysis of the ethyl ester function of (VI) was carried out by treatment with LiI in hot pyridine. The resulting carboxylic acid (VII) was then subjected to a Curtius rearrangement with diphenylphosphoryl azide, and the intermediate isocyanate was subsequently condensed with benzyl alcohol, producing the benzyl carbamate (VIII). Acid hydrolysis of the diethyl acetal group of (VIII) gave aldehyde (IX), which was then oxidized to carboxylic acid (X) by using sodium chlorite.
Acylation of phenylalanine (XI) with benzoyl chloride (XII) under Schotten-Baumann conditions produced the corresponding benzamide (XIII). The cyclization of benzoylphenylalanine (XIII) in the presence of acetic anhydride afforded oxazolone (XIV), which was then reacted with trifluoroacetic anhydride producing the trifluoromethyl ketone (XV). After ketone (XV) reduction to carbinol (XVI) with NaBH4, the acidic hydrolysis of the benzamido group of (XVI) yielded the amino alcohol (XVII) (1). Condensation of acid (X) with amine (XVII) using EDC and HOBt gave amide (XVIII). The hydroxyl group of (XVIII) was then oxidized to ketone (XIX) employing a modified Pfitzner-Moffatt oxidation. Finally, hydrogenolysis of the benzyloxycarbonyl group of (XIX) furnished the desired aminopyrimidinone.