The first GMP synthesis of MK-2118, a small molecule agonist of the stimulator of interferon genes (STING) is described. The small molecule represents a dramatic change in the chemical matter from the more complex cyclic dinucleotides previously disclosed. In this article, we detail the route-scouting, decision-making, and development details of a first GMP campaign typical for a first delivery on an accelerated timeline. The route chosen involves a key copper-mediated Negishi coupling using a chiral organozinc reagent and subsequent direct isolation. Several unexpected challenges are outlined, which highlight the difficulty in developing a first scale-up process.

中文翻译：

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首次 GMP 合成干扰素基因刺激剂小分子激动剂 MK-2118


描述了 MK-2118 的首次 GMP 合成，MK-2118 是干扰素基因刺激剂 (STING) 的小分子激动剂。小分子代表了化学物质与之前公开的更复杂的环状二核苷酸的巨大变化。在本文中，我们详细介绍了第一个 GMP 活动的路线探索、决策和开发细节，该活动通常用于加速时间表上的首次交付。所选择的路线涉及使用手性有机锌试剂进行关键的铜介导的根岸偶联以及随后的直接分离。概述了一些意想不到的挑战，凸显了开发第一个放大工艺的难度。