Concise two-step chemical synthesis of molnupiravir

Pereira, Vinícius R. D.; Bezerra, Marco A. M.; Gomez, Mauro; Martins, Guilherme Machado; Silva, Adilson David da; Oliveira, Kléber T. de; Souza, Rodrigo O. M. A. de; Amarante, Giovanni W.

doi:10.1039/d2ra05064a

Cited by 7 publications

(1 citation statement)

References 11 publications

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“…13 Subsequently, other approaches have been reported starting from uridine and proceeding via its 2′,3′-acetonide-protected 5′-isobutyrate ester (as in the original patent). These involve (a) reordering the synthetic steps, 14 (b) use of HMDS/imidazole instead of triazolization for C4 carbonyl group activation, followed by reaction with hydroxylammonium sulfate, 15 and (c) conversion of the uridine derivative to a 4-thio derivative followed by reaction with NH 2 OH. 16 A manufacture method for molnupiravir retains the original steps.…”

Section: Introductionmentioning

confidence: 99%

Two short approaches to the COVID-19 drug β-d-N⁴-hydroxycytidine and its prodrug molnupiravir

Persaud,

Sahu,

Neary

et al. 2024

Org. Biomol. Chem.

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Section: Introductionmentioning

confidence: 99%

Two short approaches to the COVID-19 drug β-d-N⁴-hydroxycytidine and its prodrug molnupiravir

Persaud,

Sahu,

Neary

et al. 2024

Org. Biomol. Chem.

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From Batch to Continuous Flow Synthesis in Enzymatic Process Towards Molnupiravir

Hongnak,

Vorasin,

Aunbamrung

et al. 2024

Chemistry An Asian Journal

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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 N4‐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.

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Continuous Flow Synthesis of the Nerve Agent Antidote Pralidoxime (2‐PAM) Iodide

Gomez,

da Rocha,

Chaves

et al. 2024

ChemistrySelect

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Pralidoxime salts are important medical countermeasures towards different organophosphorus compounds, either nerve agents or pesticides, as they act as acetylcholinesterase reactivators, avoiding health issues and even death that can result from intoxication with such chemicals. In this work, we present an expeditious study focuses on the optimization of a two‐step continuous‐flow synthesis of 2‐PAM. Initial attempts to replace the solvent composition in the oxime formation reaction with acetonitrile resulted in lower yields, highlighting the significance of a polar protic solvent. Subsequent optimization under continuous‐flow conditions revealed the successful execution of oxime formation at room temperature with a residence time of 20 minutes, achieving an impressive 96 % conversion, surpassing literature‐reported conditions. The methylation step required a high residence time of 60 minutes at 120 °C for a substantial conversion of 78 %. The two‐step continuous‐flow process demonstrated robustness, yielding 75 %, with space‐time yields of 0.32 g/h and 0.18 g/h. Further concentration adjustments increased space‐time yields to 3.2 g/h and 2.2 g/h. Despite solvent incompatibility, a strategic alteration of the reaction sequence allowed for a successful cascade process, integrating the methylation step in acetonitrile and the oxime formation in water. The continuous‐flow system, incorporating a heat exchanger, exhibited stability, maintaining full conversion and a space‐time yield of 0.3 g/h over extended periods. This systematic optimization not only enhances the efficiency of 2‐PAM synthesis but also provides insights into a scalable and practical continuous‐flow cascade process.

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Concise two-step chemical synthesis of molnupiravir

Abstract: Fast, effective and chromatography column-free chemical synthesis of molnupiravir.

Cited by 7 publications

References 11 publications

Two short approaches to the COVID-19 drug β-d-N⁴-hydroxycytidine and its prodrug molnupiravir

Two short approaches to the COVID-19 drug β-d-N⁴-hydroxycytidine and its prodrug molnupiravir

From Batch to Continuous Flow Synthesis in Enzymatic Process Towards Molnupiravir

Continuous Flow Synthesis of the Nerve Agent Antidote Pralidoxime (2‐PAM) Iodide

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Concise two-step chemical synthesis of molnupiravir

Abstract: Fast, effective and chromatography column-free chemical synthesis of molnupiravir.

Cited by 7 publications

References 11 publications

Two short approaches to the COVID-19 drug β-d-N4-hydroxycytidine and its prodrug molnupiravir

Two short approaches to the COVID-19 drug β-d-N4-hydroxycytidine and its prodrug molnupiravir

From Batch to Continuous Flow Synthesis in Enzymatic Process Towards Molnupiravir

Continuous Flow Synthesis of the Nerve Agent Antidote Pralidoxime (2‐PAM) Iodide

Contact Info

Product

Resources

About

Two short approaches to the COVID-19 drug β-d-N⁴-hydroxycytidine and its prodrug molnupiravir

Two short approaches to the COVID-19 drug β-d-N⁴-hydroxycytidine and its prodrug molnupiravir