SYNTHESES OF 5-TRIFLUOROMETHYLURACIL + 5-TRIFLUOROMETHYL-2-DEOXYURIDINE
SYNTHESES OF 5-TRIFLUOROMETHYLURACIL + 5-TRIFLUOROMETHYL-2-DEOXYURIDINE
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DOI：
10.1021/jm00331a001
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发表时间：
1964-01-01
影响因子：
7.3
通讯作者：
REMY, DC
中科院分区：
文献类型：
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作者：
HEIDELBERGER, C;PARSONS, DG;REMY, DC
从三氟丙酮开始合成5-三氟甲基尿嘧啶，将其转化为氰醇，然后转化为乙酸氰醇，后者热解为三氟丙烯腈。向后者加入溴化氢的甲醇溶液，得到β-溴-α-三氟-甲基丙酰胺，将其与脲或N-乙酰脲缩合，得到α-三氟甲基-β-脲基丙酰胺或其乙酰基衍生物。通过在盐酸中回流将脲基酰胺环化为5-三氟-甲基-5,6-二氢尿嘧啶。二氢嘧啶的溴化和脱卤化氢作用得到5-三氟-甲基尿嘧啶，将其酶促转化为5-三氟甲基-2[镜像]-脱氧尿苷。后一种化合物掺入 DNA，对噬菌体具有诱变作用，抑制（以核苷酸形式）胸苷酸合成酶，并且是小鼠腺癌 755 生长的有效抑制剂。 5-三氟甲基尿嘧啶在弱碱性条件下定量转化为5-羧基尿嘧啶，并与甘氨酸和甘氨酰甘氨酸缩合，得到5-尿酰基甘氨酸和5-尿酰基甘氨酰甘氨酸。
5-Trifluoromethyluracil has been synthesized starting with trifluoroacetone, which was converted into the cyanohydrin and then into the cyanohydrin acetate, which was pyrolyzed to trifluoroacrylonitrile. To the latter was added hydrogen bromide in methanol, and [beta]-bromo-[alpha]-trifluoro-methylpropionamide was obtained, which was condensed with urea or N-acetylurea to give [alpha]-trifluoromethyl-[beta]-ureido propionamide or its acetyl derivative. The ureidoamides were cyclized to 5-trifluoro-methyl-5,6-dihydrouracil by refluxing in hydrochloric acid. Bromina-tion and dehydrohalogenation of the dihydropyrimidine gave 5-trifluoro-methyluracil, which was converted enzymatically into 5-trifluoromethyl-2[image]-deoxyuridine. The latter compound is incorporated into DNA, is mutagenic to bacteriophage, inhibits (in the nucleotide form) the enzyme, thymidylate synthetase, and is a potent inhibitor of the growth of Adenocarcinoma 755 in mice. 5-Trifluoromethyluracil under mild alkaline conditions is quantitatively converted into 5-carboxyuracil and was condensed with glycine and glycylglycine to give 5-uracoylglycine and 5-uracoylglycylglycine.