Grivsky E M, Lee S, Sigel C W, Duch D S, Nichol C A
J Med Chem. 1980 Mar;23(3):327-9. doi: 10.1021/jm00177a025.
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.
描述了通过一种对许多6-(取代苄基)-5-甲基吡啶并[2,3 - d]嘧啶的制备具有普遍适用性的路线合成2,4 - 二氨基 - 6-(2,5 - 二甲氧基苄基)-5 - 甲基吡啶并[2,3 - d]嘧啶(BW301U, 7)的方法。关键中间体2,4 - 二氨基 - 7,8 - 二氢 - 6-(2,5 - 二甲氧基苄基)-5 - 甲基 - 7 - 氧代吡啶并[2,3 - d]嘧啶(4)，通过用N,N - 二甲基甲酰胺 - 亚硫酰氯的1:1络合物处理转化为7 - 氯化合物5，并且5在氢氧化钾存在下用钯 - 炭进行氢解以产生7。BW301U是一种有效的哺乳动物二氢叶酸还原酶的脂溶性抑制剂，并且对大鼠的Walker 256癌肉瘤具有显著活性。
