Synthesis Development of the Selective Estrogen Receptor Degrader (SERD) LSZ102 from a Suzuki Coupling to a C-H Activation Strategy

被引：11

作者：

Baenziger, Markus ^{[1
]}

Baierl, Marcel ^{[1
]}

Devanathan, Krishnaswamy ^{[2
]}

Eswaran, Sumesh ^{[2
]}

Fu, Peng ^{[3
]}

Gschwend, Bjoern ^{[1
]}

Haller, Michael ^{[1
]}

Kasinathan, Gopu ^{[2
]}

Kovacic, Nikola ^{[1
]}

Langlois, Audrey ^{[1
]}

Li, Yongfeng ^{[4
]}

Schuerch, Friedrich ^{[1
]}

Shen, Xiaodong ^{[3
]}

Wan, Yinbo ^{[3
]}

Wickendick, Regina ^{[1
]}

Xie, Siwei ^{[4
]}

Zhang, Kai ^{[4
]}

机构：

[1] Novartis Pharma AG, Chem & Analyt Dev, CH-4056 Basel, Switzerland

[2] Anthem Biosci Private Ltd, Bommasandra 560099, Karnataka, India

[3] Suzhou Novartis Tech Dev Co Ltd, Chem & Analyt Dev, Changshu 215537, Jiangsu, Peoples R China

[4] Lianhe Chem Technol Co Ltd, Taizhou 318020, Zhejiang, Peoples R China

来源：

ORGANIC PROCESS RESEARCH & DEVELOPMENT | 2020年 / 24卷 / 08期

关键词：

Pd-catalyzed reactions; Pd-catalyzed C-H activation; Higa cyclization; SNAr reaction; Pd removal; LSZ102; CATALYZED DIRECT C2-ARYLATION; DIRECT ARYLATION; PALLADIUM ACETATE; THIONYL CHLORIDE; ARYL HALIDES; DERIVATIVES; OXIDATIONS; INHIBITORS; DIOXINS;

D O I：

10.1021/acs.oprd.0c00076

中图分类号：

O69 [应用化学];

学科分类号：

081704 ;

摘要：

The development of the synthetic process to the selective estrogen receptor degrader (SERD) drug candidate LSZ102 from the medicinal chemistry synthesis to the streamlined large-scale manufacturing route is described. The synthesis of LSZ102 could be significantly improved in regard to overall yield, removal of all chromatographic purifications, and reduction in the number of steps by revisiting the original disconnection strategy. Key features of the final process include construction of the benzothiophene core via Higa cyclization, late-stage phenolation using a Pd-catalyzed hydroxylation of an aryl bromide, and end-game assembly through a Pd-catalyzed C-H activation step. The overall yield could be significantly improved, and the costs could be reduced.

引用

页码：1405 / 1419

页数：15

共 31 条

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