A platform for automated nanomole-scale reaction screening and micromole-scale synthesis in flow

被引：331

作者：

Perera, Damith ^{[1
]}

Tucker, Joseph W. ^{[2
]}

Brahmbhatt, Shalini ^{[1
]}

Helal, Christopher J. ^{[2
]}

Chong, Ashley ^{[1
]}

Farrell, William ^{[1
]}

Richardson, Paul ^{[1
]}

Sach, Neal W. ^{[1
]}

机构：

[1] La Jolla Labs, Pfizer Worldwide Res & Dev, 10770 Sci Ctr Dr, San Diego, CA 92121 USA

[2] Pfizer Worldwide Res & Dev, Eastern Point Rd, Groton, CT 06340 USA

来源：

SCIENCE | 2018年 / 359卷 / 6374期

关键词：

LIGAND KNOWLEDGE-BASE; REACTION OPTIMIZATION; REACTORS; INHIBITORS; COUPLINGS; EXPANSION; SELECTION; DESIGN;

D O I：

10.1126/science.aap9112

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

The scarcity of complex intermediates in pharmaceutical research motivates the pursuit of reaction optimization protocols on submilligram scales. We report here the development of an automated flow-based synthesis platform, designed from commercially available components, that integrates both rapid nanomole-scale reaction screening and micromole-scale synthesis into a single modular unit. This system was validated by exploring a diverse range of reaction variables in a Suzuki-Miyaura coupling on nanomole scale at elevated temperatures, generating liquid chromatography-mass spectrometry data points for 5760 reactions at a rate of >1500 reactions per 24 hours. Through multiple injections of the same segment, the system directly produced micromole quantities of desired material. The optimal conditions were also replicated in traditional flow and batch mode at 50- to 200-milligram scale to provide good to excellent yields.

引用

页码：429 / 434

页数：6

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