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The complete synthesis of favipiravir from 2-aminopyrazine

Qi Guo, Mingshuo Xu, Shuang Guo, Fuqiang Zhu, Yuanchao Xie, and Jingshan Shen

Chinese Academy of Sciences (CAS), Shanghai, People’s Republic of China

 

E-mail: xieyuanchao@simm.ac.cn

Abstract: Favipiravir was first synthesized from an inexpensive and commercially available starting material, 2-aminopyrazine. The preferred route embedded within Scheme 4 consisted of seven steps, and was highlighted by the novel and efficient synthesis of 3,6-dichloropyrazine-2-carbonitrile 8. This intermediate was prepared in four successive steps which were regioselective chlorination of the pyrazine ring, bromination, Pd-catalyzed cyanation, and Sandmeyer diazotization/chlorination. This protocol eliminated the hazardous POCl3 of previous synthetic methods and offered a better yield (48%) which was 1.3-fold higher than a recently published procedure. From intermediate 8, the subsequent nucleophilic fluorination, nitrile hydration and hydroxyl substitution efficiently afforded the target product. Another synthetic approach with the same starting material was also investigated to bypass the allergy-causing dichloro intermediate 8. However, the key step of monofluorination at the pyrazine C6 position of intermediate 19 or 22 was not achieved.

Keywords: Favipiravir ; 2-Aminopyrazine ; Fluorination ; Sandmeyer reaction 

Full paper is available at www.springerlink.com.

DOI: 10.1007/s11696-018-0654-9

 

Chemical Papers 73 (5) 1043–1051 (2019)

Thursday, September 23, 2021

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