Process research and development of a dihydropyrimidine dehydrogenase inactivator: Large-scale preparation of eniluracil using a Sonogashira coupling
Process research and development of a dihydropyrimidine dehydrogenase inactivator: Large-scale preparation of eniluracil using a Sonogashira coupling
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DOI：
10.1021/op0100100
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发表时间：
2001-07-01
影响因子：
3.4
通讯作者：
Jenkins, KP
中科院分区：
文献类型：
--
作者：
Cooke, JWB;Bright, R;Jenkins, KP
Eniluracil（5-乙炔基尿嘧啶）是二氢嘧啶脱氢酶的强效灭活剂，二氢嘧啶脱氢酶是广泛使用的抗癌药物5-氟尿嘧啶代谢的限速酶。介绍了三步法合成恩尿嘧啶的工艺研究与开发。使用5-碘尿嘧啶和三甲基甲硅烷基乙炔之间的Sonogashira偶联以>60 kg规模合成5-（2-三甲基甲硅烷基乙炔基）尿嘧啶。采用氢氧化钠脱保护、乙酸酸化的方法，以高产率、高质量地完成了恩尿嘧啶的合成。描述了该方法的优化，特别注意使钯和铜催化剂的输入最小化，并确保铜催化剂良好地悬浮在反应混合物中。
Eniluracil (5-ethynyluracil) is a potent inactivator of the enzyme dihydropyrimidine dehydrogenase, which is the rate-limiting enzyme in the metabolism of 5-fluorouracil, a widely used anticancer drug. The process research and development of a three-stage route to eniluracil is described. A Sonogashira coupling between 5-iodouracil and trimethylsilylacetylene was used to synthesise 5-(2-trimethylsilylethynyl)uracil on a >60 kg scale. Sodium hydroxide deprotection and acidification with acetic acid completed the synthesis of eniluracil in high yield and quality. The optimisation of this process is described with particular attention paid to minimising the input of palladium and copper catalysts and ensuring that the copper catalyst is well suspended in the reaction mixture.