27443-46-5

A convenient route for the preparation of a protected 5-formylpyrido[2,3-d]pyrimidine from 2,3,4-trisubstituted pyridines has been developed. The readily available diethylacetal of pyridinc 4-carboxaldehyde is chlorinated at the 2-position and then treated with LDA and methyl chloroformate to give a 2,3,4-trisubstituted pyridine (12). Treatment of 12 with guanidine hydrochloride gives the pyrido[23-rf]pyrimidine in good yield. A 4-aminobenzoylglutamic acid side chain is installed by means of a reductive amination step to provide a 5-substituted derivative that is, after deprotection, a confonnationally unrestricted analog of 5,10-methylenetetrahydrofolate(1), the natural co-factor for thymidylate synthase, an important chemotherapeutic target in the treatment of cancer.