Process development of E7130 Drug Substance, which is a novel anticancer drug candidate, is described. To accomplish rapid delivery of such a large and structurally complex drug substance for first-in-human (FIH) clinical trial, close collaboration among medicinal chemistry, process chemistry, and academia teams was required. The successful establishment of a suitable synthetic route in a concise time frame while negotiating challenging chemical reactions (e.g., asymmetric catalytic Nozaki–Hiyama–Kishi (NHK) reaction and Zr/Ni-mediated ketone coupling reaction) is described herein. Experience with the development of eribulin mesylate was helpful in anticipating and overcoming the chemical and logistical challenges encountered in the E7130 project. Based on this background, more than 10 g of E7130 Drug Substance has been successfully manufactured under Good Manufacturing Practice (GMP) controls within 1.5 years after the medicinal chemistry team succeeded in the first total synthesis.

中文翻译：

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通过全合成开发结构复杂的分子需要什么？用于首次人体临床研究的 E7130 原料药的快速工艺开发和 GMP 制造

描述了新型抗癌候选药物 E7130 原料药的工艺开发。为了快速交付如此大且结构复杂的药物用于首次人体 (FIH) 临床试验，需要药物化学、过程化学和学术团队之间的密切合作。本文描述了在解决具有挑战性的化学反应（例如，不对称催化野崎-桧山-岸（NHK）反应和Zr/Ni介导的酮偶联反应）的同时，在简洁的时间范围内成功建立合适的合成路线。甲磺酸艾日布林的开发经验有助于预测和克服 E7130 项目中遇到的化学和物流挑战。在此背景下，药物化学团队在首次全合成成功后的1.5年内，在良好生产规范（GMP）控制下成功生产了超过10克的E7130原料药。