- Toward a Practical, Two-Step Process for Molnupiravir: Direct Hydroxamination of Cytidine Followed by Selective Esterification
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A two-step synthesis of molnupiravir (1) is presented. This work focuses on the development of practical reaction and purification conditions toward a manufacturing route. The sequence commences from highly available cytidine (2), and molnupiravir is formed through direct hydroxamination of the cytosine ring and esterification of the sugar's primary alcohol without use of protecting or activating groups. A highly crystalline hydrate of N-hydroxycytidine (3) resulted in an easily purified intermediate, and a practical, off-the-shelf enzyme was selected for the acylation. The yield was increased through a chemically promoted, selective ester cleavage, which converted a byproduct, molnupiravir isobutyryl oxime ester (4), into the final API. Both reactions proceed in >90% assay yield, and crystallization procedures are used to afford intermediates and active pharmaceutical ingredients in purities above 99% with an overall yield of 60%. Excellent throughput and sustainability are achieved by limiting the total concentration to 7 volumes of solvent in the course of the two reactions with an overall PMI of 26 including work-up and isolation. Environmentally friendly solvents, water and 2-methyl tetrahydrofuran, enhance sustainability of the operation.
- Paymode, Dinesh J.,Vasudevan,Ahmad, Saeed,Kadam, Appasaheb L.,Cardoso, Flavio S.P.,Burns, Justina M.,Cook, Daniel W.,Stringham, Rodger W.,Snead, David R.
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- A concise route to MK-4482 (EIDD-2801) from cytidine
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A two-step route to MK-4482 (EIDD-2801, 1) was developed consisting of an esterification and hydroxamination of cytidine. The selective acylation and direct amination eliminate the need for protecting and activating groups and proceed in overall yield of 75%, a significant advancement over the reported yield of 17%. The step count is reduced from five transformations to two, and expensive uridine is replaced with the more available cytidine. This journal is
- Vasudevan,Ahlqvist, Grace P.,McGeough, Catherine P.,Paymode, Dinesh J.,Cardoso, Flavio S. P.,Lucas, Tobias,Dietz, Jule-Phillip,Opatz, Till,Jamison, Timothy F.,Gupton, Frank B.,Snead, David R.
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Various prochirals silapropan-diols were synthetised with good yields. Several enzymatic-catalysed hydrolyses or transesterification have been attempted on this products; when we change the parameters: as the temperature in transesterification reaction, t
- Djerourou, Abdel Hafid,Blanco, Luis
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p. 107 - 136
(2007/10/03)
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