Process research and development directed toward a scalable, solution-phase synthesis of the novel dinucleotide DNA methyltransferase inhibitor guadecitabine is described. Highly selective enzyme-mediated 5′-OH acetylation of a decitabine N,N-dimethylformamidine derivative and isolation of the penultimate intermediate as the tert-butylamine salt were key achievements of the development program. This route allowed kilo-scale GMP production of clinical-grade guadecitabine (SGI-110).

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二核苷酸 DNA 甲基转移酶抑制剂瓜地他滨的公斤级合成

描述了针对新型二核苷酸 DNA 甲基转移酶抑制剂瓜地西他滨的可扩展溶液相合成的工艺研究和开发。地西他滨N , N-二甲基甲脒衍生物的高选择性酶介导的 5'-OH 乙酰化以及倒数第二个中间体叔丁胺盐的分离是该开发计划的关键成就。该路线允许以公斤级 GMP 生产临床级瓜地西他滨 (SGI-110)。