From Batch to Continuous Flow Synthesis in Enzymatic Process Towards Molnupiravir

Molnupiravir has been recognized as one of the limited therapeutic options for the treatment of COVID-19 and is known to exhibit pan-antiviral potency. Due to the urgent demand during the COVID-19 pandemic, various methods were developed to provide more efficient synthetic routes. In this report, a facile 2-step and scalable synthesis of molnupiravir for batch processing is presented, and the implementation of continuous flow biocatalysis is demonstrated to improve synthetic efficiency. The key step was carried out using immobilized lipase and isobutyric anhydride to enable regioselective esterification. In the batch process, cytidine (2) was transaminated to afford N4-hydroxycytidine (NHC, 3) in 75 % yield, followed by esterification of NHC to yield molnupiravir with 64 % yield, resulting in an overall yield of 48 % and 99.98 % purity (HPLC).

In comparison to the batch process, the continuous flow esterification step was shown to provide similar product yield and purity, while offering several advantages including a 2.42-fold increase in productivity (mol/day), a 2.47-fold improvement in reaction time, and a 30-fold higher space-time-yield. Through optimization, both the batch and continuous flow biocatalysis processes were enhanced to increase efficiency and reduce environmental impact, thereby offering a more sustainable approach for the industrial production of molnupiravir.

• Hongnak, S
• Vorasin, O
• Aunbamrung, P
• Techapanalai, S
• Tiyasakulchai, T
• Sonwong, W
• Jaito, N
• Thongpanchang, C
• Whungsinsujarit, S
• Srikun, O
• Srimongkolpithak, N

• National Center for Genetic Engineering and Biotechnology (BIOTEC), National Science and Technology Development Agency (NSTDA), Pathum Thani, Thailand

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