Communicationsproposal might invoke a [T2 + r2] intramolecular cyclization to 15 which by suitable hydrogen shift and bond reorganization is transformed into 8.18

The synthesis of 2,4-diamino-6-(2,5-dimethoxybenzyl)-5-methylpyrido[2,3-d]pyrimidine (BW301U, 7) by a route that has general applicability to the preparation of many 6-(substituted benzyl)-5-methylpyrido[2,3-d]pyrimidines is described. The key intermediate, 2,4-diamino-7,8-dihydro-6-(2,5-dimethoxybenzyl)-5-methyl-7-oxopyrido[2,3-d]pyrimidine (4), is converted to the 7-chloro compound 5 by treatment with a 1:1 complex of N,N-dimethylformamide--thionyl chloride, and 5 is hydrogenolyzed with palladium on charcoal in the presence of potassium hydroxide to yield 7. BW301U is a potent lipid-soluble inhibitor of mammalian dihydrofolate reductase and has significant activity against the Walker 256 carcinosarcoma in rats.

Lewis lung carcinoma, and P-388 lymphocytic leukemia in the mouse and the Walker 256 intramuscular carcinosarcoma in the rat. Cytotoxicity and in vivo activity were assayed under the auspices of the Cancer Chemotherapy National Service Center, National Cancer Institute, by the procedures described in Cancer Chemother. Rep., 25, 1 (1962). Cytotoxicity was also assayed by differential agar diffusion by Professor D.

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