Coupling to the pyrimido[4,5-b][1,4]oxazine ring system: Synthesis of potential antifolates

The ability of 2-amino-4-hydroxy-7H-pyrimido4,5-b]1,4]oxazine derivatives to inhibit dihydrofolate reductase led to a search for means of synthesizing new side chain substituted analogs of this marginally stable pyrimidooxazine system. A study of the synthesis and use of 6-functionalized pyrimido4,5-b]1,4]oxazines for coupling side chains was begun and has now revealed methods for coupling p-aminobenzoic acid with 2-amino-4-hydroxy-6-carboxy-7H-pyrimido4,5-b]1,4]oxazine and hydrolyzed 2-amino-4-hydroxy-6-carbe-thoxymethylene-6,7-dihdyro-5H-pyrimido4,5-b]1,4]oxazine. The products are of interest for evaluation as potential antifolates.