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

The ability of 2‐amino‐4‐hydroxy‐7 H ‐pyrimido[4,5‐ 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 pyrimido[4,5‐ 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‐7 H ‐pyrimido[4,5‐ b ][1,4]oxazine and hydrolyzed 2‐amino‐4‐hydroxy‐6‐carbe‐thoxymethylene‐6,7‐dihdyro‐5 H ‐pyrimido[4,5‐ b ][1,4]oxazine. The products are of interest for evaluation as potential antifolates.