Kilo-Scale Synthesis of the Dinucleotide DNA Methyltransferase Inhibitor Guadecitabine

IF 3.5 3区化学 Q2 CHEMISTRY, APPLIED

Organic Process Research & Development Pub Date : 2024-05-10 DOI:10.1021/acs.oprd.4c00072

Matthew Johnson*, Ramakrishnan Chidambaram, Nipun Davar, Christian Madsen, Yogesh S. Sanghvi and Robert Short,

引用次数: 0

Abstract

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千吨级合成

本研究介绍了针对新型二核苷酸 DNA 甲基转移酶抑制剂瓜地他滨的可扩展溶液相合成的工艺研发。高选择性酶介导的 5′-OH 乙酰化地西他滨 N,N-二甲基甲脒衍生物，并分离出作为叔丁胺盐的倒数第二中间体，是该开发计划的关键成果。通过这一途径，临床级吉他他滨（SGI-110）的 GMP 生产达到了公斤级规模。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Organic Process Research & Development 化学-应用化学

CiteScore

6.90

自引率

14.70%

发文量

251

审稿时长

2 months

期刊介绍： The journal Organic Process Research & Development serves as a communication tool between industrial chemists and chemists working in universities and research institutes. As such, it reports original work from the broad field of industrial process chemistry but also presents academic results that are relevant, or potentially relevant, to industrial applications. Process chemistry is the science that enables the safe, environmentally benign and ultimately economical manufacturing of organic compounds that are required in larger amounts to help address the needs of society. Consequently, the Journal encompasses every aspect of organic chemistry, including all aspects of catalysis, synthetic methodology development and synthetic strategy exploration, but also includes aspects from analytical and solid-state chemistry and chemical engineering, such as work-up tools，process safety, or flow-chemistry. The goal of development and optimization of chemical reactions and processes is their transfer to a larger scale; original work describing such studies and the actual implementation on scale is highly relevant to the journal. However, studies on new developments from either industry, research institutes or academia that have not yet been demonstrated on scale, but where an industrial utility can be expected and where the study has addressed important prerequisites for a scale-up and has given confidence into the reliability and practicality of the chemistry, also serve the mission of OPR&D as a communication tool between the different contributors to the field.