Guadecitabine (SGI-110) is a dinucleotide that is a prodrug of decitabine. The dinucleotide contains decitabine (top fragment) and 2′-deoxyguanosine (9; dG; bottom fragment) connected via a 3′ → 5′ phosphodiester bond. The manufacturing process of guadecitabine requires a large quantity of N², 3′-O-(4-tert-butylphenoxyacetyl)-protected dG (2; Bis-Tac-dG) to incorporate the bottom fragment. The protected 2 being a critical starting material of the dinucleotide imposes stringent quality requirements for its synthesis and isolation. Presented herein is the development work leading to a practical and scalable route for compound 2 starting from commercial dG. Salient features of the approach included one-pot protection of 5′-OH group of N²-Tac-dG (3) with 4,4′-dimethoxytrityl (DMT) group followed by 3′-O-Tac protection furnishing fully protected dG 8, thus reducing the cycle time with fewer isolation steps and lowering the solvent usage. Subsequently, cleavage of DMT group from 8 utilizing NaIO₄ enabled a mild, highly selective, and robust route to produce high purity (>99%) Bis-Tac-dG on kilogram-scale. The structure and origin of major impurities were determined by comparison with reference standards and carefully controlled to an acceptable level in compound 2. The improved synthesis was scaled to prepare multiple ∼60 kg batches of 2 to supply all clinical studies up to phase III.

中文翻译：

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Bis-Tac-dG 公斤级生产路线的开发：瓜地他滨的基本组成部分

瓜德西他滨 (SGI-110) 是一种二核苷酸，是地西他滨的前药。该二核苷酸包含地西他滨（顶部片段）和 2'-脱氧鸟苷（9；dG；底部片段）通过 3' → 5' 磷酸二酯键连接。瓜地西他滨的制造过程需要大量的N ² , 3′- O- (4-叔丁基苯氧基乙酰基)-保护的 dG ( 2 ; Bis-Tac-dG) 以掺入底部片段。受保护的2是二核苷酸的关键起始材料，对其合成和分离提出了严格的质量要求。本文介绍的是从商业 dG 开始的化合物2的实用且可扩展的路线的开发工作。该方法的显着特点包括用 4,4'-二甲氧基三苯甲基 (DMT) 基团对N ² -Tac-dG ( 3 )的 5'-OH 基团进行一锅保护，然后进行 3'- O -Tac 保护，提供完全保护的 dG 8，从而通过更少的分离步骤缩短循环时间并降低溶剂的使用量。随后，利用 NaIO _4从8中裂解 DMT 基团，实现了温和、高选择性和稳健的路线，以公斤级生产高纯度 (>99%) Bis-Tac-dG。通过与参考标准比较来确定主要杂质的结构和来源，并小心地将化合物2控制在可接受的水平。改进的合成规模可制备多个 ∼60 kg 批次（每批2 个），以供应至 III 期的所有临床研究。