目的 改进SKI2496的关键中间体 1-(2-氟-6-(三氟甲基)苄基)-6-甲基-5-(哌嗪-1-基)嘧啶-2,4(1H,3H)-二酮的合成工艺。方法 以2-氟-6-三氟甲基苄胺(1)为原料,先和尿素反应生成1-脲(2),接着与乙酰乙酸叔丁酯胺解、关环得1-(2-氟-6-(三氟甲基)苄基)-6-甲基嘧啶-2,4(1H,3H)-二酮(4),最后经溴代,与无水哌嗪缩合得标题化合物(6)。结果 该工艺共4步反应,总收率44.6%(以1计),其结构经1H-NMR和MS确认。结论 该工艺成本低、操作简单,安全,易工业化生产。
Abstract
OBJECTIVE To establish a preparation process of pivotal intermediate of SKI2496, which is low-cost, environmental-friendly and suitable for industrialization as well. METHODS 1-(2-Fluoro-6-(trifloromethyl)benzyl)urea(2) was synthesized from 2-fluoro-6-(trifluoromethyl)benzylamine(1) with urea,followed by aminolysis with t-butyl acetoacetate and cyclization to give 1--6-methylpyrimidine-2,4(1H,3H)-dione(4).Finally,the title product was obtained via bromation and condensation reaction with piperazine . RESULTS The synthetic process included four steps with an overall yield of 44.6%(based on compound 1) and its structure was confirmed by 1H-NMR and MS. CONCLUSION The process is easy to operate, safe and suitable for industrial production.
关键词
促性腺激素释放激素(GnRH)拮抗剂 /
尿嘧啶 /
药物合成
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Key words
GnRH antagonists /
uracil /
drug synthesis
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中图分类号：
TQ467.2
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参考文献
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