SYNTHESIS OF PROTECTED 5-FORMYLPYRIDO[2,3-D]PYRIMIDINE VIA A 2,3,4-TRISUBSTITUTED PYRIDINE USING AN ORTHO-LITHIATION STRATEGY - APPLICATIONTO THE SYNTHESIS OF A FOLATE DERIVATIVE

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 pyridine 4-carboxaldehyde is chlorinated at the 2-position and then treated with LDA and methyl chl oroformate to give a 2,3,4-trisubstituted pyridine (12). Treatment of 12 with guanidine hydrochloride gives the pyrido[2,3-d]pyrimidine in g ood yield. A 4-aminobenzoylglutamic acid side chain is installed by me ans of a reductive amination step to provide a 5-substituted derivativ e that is, after deprotection, a conformationally unrestricted analog of 5,10-methylenetetrahydrofolate (1), the natural co-factor for thymi dylate synthase, an important chemotherapeutic target in the treatment of cancer.