Short Synthesis of Molnupiravir (EIDD-2801) via a Thionated Uridine Intermediate

Abstract

Molnupiravir (MK-4482, EIDD-2801) is an experimental drug that has been demonstrated to be effective for the treatment of COVID-19 in human clinical trials. Herein, we report a concise synthesis of the drug via a novel thionated derivative that relies on one-pot methodologies, thus decreasing the number of purification steps required. This route provides the drug in an overall 62% yield and >99% purity and uses cheap and readily available bulk chemicals, thereby providing an affordable synthesis of the drug for cheaper and wider global accessibility.

Concise two-step chemical synthesis of molnupiravir

“…It is important to highlight that, an outstanding contribution has been recently reported by Das and Yadav, which consists of previous thiolation reaction, followed by an oxyamination/deprotection process. 8 Despite having one additional operation, this reaction was carried out in a one-pot three-reactions procedure.…”

“…The NMR data matched those previously reported in the literature. 7,8,13 ESI-HRMS calc. for C 13 H 19 N 3 O 7 [M + H] + 330.1296 found 330.1290.…”

“…: 158–160 °C). 8 1 H NMR (500 MHz, CD 3 OD) δ 6.91 (d, J = 8.3 Hz, 1H), 5.82 (d, J = 4.8 Hz, 1H), 5.62 (d, J = 8.2 Hz, 1H), 4.29 (d, J = 3.3 Hz, 2H), 4.16–4.06 (m, 3H), 2.62 (sept, J = 6.9 Hz, 1H), 1.18 (d, J = 6.9 Hz, 6H). 13 C NMR (125 MHz, CD 3 OD) δ 178.3, 151.5, 146.2, 131.8, 99.5, 90.4, 82.52, 74.3, 71.5, 64.9, 35.2, 19.33, 19.3.…”

“…In 2021, Das, Yadav and co-workers reported an outstanding improvement, preparing molnupiravir ( 2 ) in 62% overall yield. 8 However, to this end, a one-pot thionation step was included in the process. A gram-scale experiment was then carried out by taking one equivalent of Lawesson's reagent to produce a thionated intermediate which smoothy gave molnupiravir ( 2 ) after purification by chromatography followed by hydroxyamination/deprotection processes.…”

“One-Pot” Synthesis of Molnupiravir from Cytidine

“…The synthesis of this important antiviral drug has attracted the interest of chemists. − The initially reported synthesis of molnupiravir consisted of five reactions with an overall yield lower than 17% from uridine, which mainly resulted from the introduction of the triazole group with a poor yield , (Scheme ). Later, an optimized synthesis with an overall yield of up to 61% was reported by reordering the reaction sequences and using continuous flow technology .…”