Kilo-Scale Synthesis of the Dinucleotide DNA Methyltransferase Inhibitor Guadecitabine

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).