Hongnak Siriwat, Vorasin Onanong, Aunbamrung Pornthip, Techapanalai Saharat, Tiyasakulchai Thanat, Sonwong Watcharin, Jaito Nongluck, Thongpanchang Chawanee, Whungsinsujarit Saowalak, Srikun Onsiri, Srimongkolpithak Nitipol
National Center for Genetic Engineering and Biotechnology (BIOTEC), National Science and Technology Development Agency (NSTDA), Pathum Thani, Thailand.
Government Pharmaceutical Organization (GPO), Bangkok, Thailand.
Chem Asian J. 2025 Feb 3;20(3):e202401134. doi: 10.1002/asia.202401134. Epub 2024 Dec 6.
Molnupiravir (1) is one among the limited therapeutic options for treating COVID-19 infection and exhibits pan-antiviral potency. Because of urgent demands during the COVID-19 pandemic, a number of methods were developed to offer more efficient routes. In this report, we present a facile 2-step and scalable synthesis of molnupiravir for batch processing and show the implementation of continuous flow biocatalysis to improve the efficiency in synthesis. Our key step entails immobilized lipase and isobutyric anhydride to facilitate regioselective esterification. In batch process, transamination of cytidine (2) provides N-hydroxycytidine (NHC, 3) with 75 % yield followed by esterification of NHC to give molnupiravir with 64 % yield, providing 48 % overall yield and 99.98 % purity (HPLC). Compared to batch approach in the esterification step, the continuous flow process provides similar product yield and purity and highlights the advantages including 2.42-fold better productivity (mol/day), 2.47-fold improved reaction time, and 30-fold higher space-time-yield. The optimized batch and continuous flow biocatalysis enhance synthesis efficiency and reduce environmental impact, offering a sustainable approach for industrial molnupiravir production.
莫努匹拉韦（1）是治疗新冠病毒感染的有限治疗选择之一，具有泛抗病毒效力。由于新冠疫情期间的迫切需求，人们开发了多种方法以提供更高效的路线。在本报告中，我们展示了一种简便的两步法且可扩展的莫努匹拉韦合成方法用于批量处理，并展示了连续流生物催化的实施以提高合成效率。我们的关键步骤包括固定化脂肪酶和异丁酸酐以促进区域选择性酯化。在批量过程中，胞苷（2）的转氨反应以75%的产率提供N-羟基胞苷（NHC，3），随后NHC酯化得到莫努匹拉韦，产率为64%，总产率为48%，纯度为99.98%（高效液相色谱法）。与酯化步骤中的批量方法相比，连续流过程提供了相似的产物产率和纯度，并突出了其优势，包括生产率提高2.42倍（摩尔/天）、反应时间缩短2.47倍以及时空产率提高30倍。优化后的批量和连续流生物催化提高了合成效率并减少了环境影响，为莫努匹拉韦的工业化生产提供了一种可持续的方法。
