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.

The case-control method, a retrospective design useful in studying the etiology of rare diseases, was utilized to examine the relative risk of posttraumatic stress disorder (PTSD) among individuals with six types of traumatic physical impairments. Odds ratios and associated confidence intervals were calculated for each impairment in a group of 45,320 veterans receiving medical services. Four of the six impairments were found to be risk factors for PTSD. Implications for rehabilitation counseling and research are discussed.

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Pyrrolotriazine 1 is an important precursor to remdesivir. Initial results toward an efficient synthesis are disclosed consisting of sequential cyanation, amination, and triazine formation beginning from pyrrole. This route makes use of highly abundant, commoditized raw material inputs. The yield of triazine was doubled from 31% to 59%, and the synthetic step count was reduced from 4 to 2. These efforts help to secure the remdesivir supply chain.

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