What Does It Take to Develop Structurally Complex Molecules by Total Synthesis? Rapid Process Development and GMP Manufacturing of E7130 Drug Substance for First-in-Human Clinical Study

IF 3.1 3区化学 Q2 CHEMISTRY, APPLIED

Organic Process Research & Development Pub Date : 2024-04-15 DOI:10.1021/acs.oprd.4c00016

Takeo Sasaki*, Kenzo Yahata, Minetaka Isomura*, Isao Ohashi, Takashi Fukuyama, Yusuke Miyashita, Yuzo Watanabe, Norio Murai, Masaaki Matsuda, Atsushi Kamada, Yosuke Kaburagi, Kazunobu Kira, Kentaro Iso, Yuki Sato, Fumiyoshi Matsuura, Yasunobu Matsumoto, Hiroshi Azuma, Daisuke Iida, Tasuku Ishida, Wataru Itano, Satoshi Nagao, Masashi Seki, Akihiko Yamamoto, Yuji Yamamoto, Naoki Yoneda, Masayuki Matsukura, Osamu Asano, Akio Kayano*, Katsuya Tagami, Takashi Owa and Yoshito Kishi,

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Abstract

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.

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如何通过全合成技术开发结构复杂的分子？用于首次人体临床研究的 E7130 药物的快速工艺开发和 GMP 生产

本文介绍了新型抗癌候选药物 E7130 药物的工艺开发过程。为了快速将这种结构复杂的大型药物用于首次人体临床试验（FIH），需要药物化学、工艺化学和学术团队之间的密切合作。本文介绍了如何在短时间内成功建立合适的合成路线，同时应对具有挑战性的化学反应（如不对称催化 Nozaki-Hiyama-Kishi（NHK）反应和 Zr/Ni- 介导的酮偶联反应）。开发甲磺酸艾瑞布林的经验有助于预测和克服 E7130 项目中遇到的化学和后勤挑战。基于这一背景，在药物化学团队成功完成首次全合成后的 1.5 年内，已在药品生产质量管理规范（GMP）控制下成功生产出 10 多克 E7130 药物物质。

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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.