First-Generation Asymmetric Synthesis of the Selective Estrogen Receptor Degrader GDC-9545 (Giredestrant) Featuring a Highly Efficient Pictet–Spengler Reaction and a C–N Coupling Reaction

IF 3.1 3区化学 Q2 CHEMISTRY, APPLIED

Organic Process Research & Development Pub Date : 2021-11-05 DOI:10.1021/acs.oprd.1c00262

Jie Xu*, Kyle Clagg, Ngiap-Kie Lim, Georg Wuitschik, Cheol K. Chung, Haiming Zhang, Francis Gosselin

引用次数: 3

Abstract

An asymmetric synthesis of the selective estrogen receptor degrader GDC-9545 (1) is described. The synthesis features a Friedel–Crafts indole functionalization and a strain-release aminoazetidine formation to construct the two key starting materials 2 and 4, respectively, a diastereoselective Pictet–Spengler reaction (98% yield, 95:5 dr) to assemble the tetrahydrocarboline core, and a highly efficient Pd-catalyzed C–N coupling (90% yield) using [t-BuBrettPhos Pd(allyl)]OTf as the catalyst and DBU as the base to furnish the final C–N bond. This expedient route produces GDC-9545·tartrate active pharmaceutical ingredient in a longest linear sequence of six steps in 37% overall yield with 99.0 area % HPLC purity without chromatographic purification.

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具有高效Pictet-Spengler反应和C-N偶联反应的第一代选择性雌激素受体降解剂GDC-9545 (girestrant)的不对称合成

描述了选择性雌激素受体降解剂GDC-9545的不对称合成(1)。该合成以frietel - crafts吲哚功能化和菌株释放氨基氮杂啶形成为特征，分别构建了两个关键的起始材料2和4，通过非对构选择性Pictet-Spengler反应(98%产率，95:5 dr)组装了四碳氢化合物核心，并以[t-BuBrettPhos Pd(烯丙基)]OTf为催化剂，以DBU为底物进行了高效的Pd催化C-N偶联(90%产率)，形成最终的C-N键。该优化路线生产GDC-9545·酒石酸酯活性药物成分，耗时最长的6步线性序列，总收率为37%，无需色谱纯化，HPLC纯度为99.0 area %。

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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.