Weinreb Amide Approach to the Practical Synthesis of a Key Remdesivir Intermediate

Currently, remdesivir is the first and only FDA-approved antiviral drug for COVID-19 treatment. Adequate supplies of remdesivir are highly warranted to cope with this global public health crisis. Herein, we report a Weinreb amide approach for preparing the key intermediate of remdesivir in the glyco...

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Published inJournal of organic chemistry Vol. 86; no. 7; pp. 5065 - 5072
Main Authors Xie, Yuanchao, Hu, Tianwen, Zhang, Yan, Wei, Daibao, Zheng, Wei, Zhu, Fuqiang, Tian, Guanghui, Aisa, Haji A, Shen, Jingshan
Format Journal Article
LanguageEnglish
Published WASHINGTON American Chemical Society 02.04.2021
Amer Chemical Soc
Subjects
Adenosine Monophosphate - analogs & derivatives
Adenosine Monophosphate - chemical synthesis
Alanine - analogs & derivatives
Alanine - chemical synthesis
Amides - chemistry
Antiviral Agents - chemical synthesis
Chemistry
Chemistry, Organic
Physical Sciences
Science & Technology
EBOLA
GS-5734
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Summary:Currently, remdesivir is the first and only FDA-approved antiviral drug for COVID-19 treatment. Adequate supplies of remdesivir are highly warranted to cope with this global public health crisis. Herein, we report a Weinreb amide approach for preparing the key intermediate of remdesivir in the glycosylation step where overaddition side reactions are eliminated. Starting from 2,3,5-tri-O-benzyl-d-ribonolactone, the preferred route consisting of three sequential steps (Weinreb amidation, O-TMS protection, and Grignard addition) enables a high-yield (65%) synthesis of this intermediate at a kilogram scale. In particular, the undesirable PhMgCl used in previous methods was successfully replaced by MeMgBr. This approach proved to be suitable for the scalable production of the key remdesivir intermediate.
ISSN:0022-3263
1520-6904
DOI:10.1021/acs.joc.0c02986