2,4-DIAMINO-5-BENZYLPYRIMIDINES AS ANTI-BACTERIAL AGENTS .4. 6-SUBSTITUTED TRIMETHOPRIM DERIVATIVES FROM PHENOLIC MANNICH INTERMEDIATES - APPLICATION TO THE SYNTHESIS OF TRIMETHOPRIM AND 3,5-DIALKYLBENZYL ANALOGS
2,4-DIAMINO-5-BENZYLPYRIMIDINES AS ANTI-BACTERIAL AGENTS .4. 6-SUBSTITUTED TRIMETHOPRIM DERIVATIVES FROM PHENOLIC MANNICH INTERMEDIATES - APPLICATION TO THE SYNTHESIS OF TRIMETHOPRIM AND 3,5-DIALKYLBENZYL ANALOGS
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DOI：
10.1021/jm00179a012
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发表时间：
1980-01-01
影响因子：
7.3
通讯作者：
RAUCKMAN, BS
中科院分区：
文献类型：
--
作者：
ROTH, B;AIG, E;RAUCKMAN, BS
通过使2，4-二氨基-6-取代的嘧啶与2，6-二甲氧基-4-[（N，N-二甲基氨基）甲基]苯酚在120 - 160 ℃下反应，可以容易地制备多种6-取代的甲氧苄啶类似物。C.反应活性较低的2，6-二烷基-4-[（N，N-二甲氨基）甲基]苯酚与2，4-二氨基-6-（烷硫基）嘧啶成功反应，得到5-（取代苄基）嘧啶。当嘧啶环上存在非反应性的6-取代基时，产物的酚基以高产率烷基化。用Raney N.以6-甲硫基为原料，高收率地合成了甲氧苄啶。6-取代甲氧苄啶类似物作为大肠杆菌二氢叶酸还原酶抑制剂和抗菌剂的活性都很低。
The preparation of a wide variety of 6-substituted trimethoprim analogues was readily accomplished by the reaction of 2,4-diamino-6-substituted-pyrimidines with 2,6-dimethoxy-4-[(N,N-dimethylamino)methyl]phenol at 120-160.degree. C. The less reactive 2,6-dialkyl-4-[(N,N-dimethylamino)methyl]phenols reacted successfully with 2,4-diamino-6-(alkylthio)pyrimidines to give 5-(substituted benzyl)pyrimidines. The phenolic groups of the products were alkylated in high yield when a nonreactive 6-substituent was present in the pyrimidine ring. 6-(Alkylthio) groups were easily removed with Raney N. Trimethoprim was obtained in high yield from its 6-(methylthio) counterpart. The 6-substituted trimethoprim analogues all had low activity as inhibitors of Escherichia coli dihydrofolate reductase and as antibacterial agents.