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...
A new strategy for increasing the barrier to rotation in biaryls has been developed that allows for the incorporation of 5-membered aromatic heterocycles into chiral atropisomers. Using this concept, an imidazole-based biaryl P,N-ligand has been designed and prepared as a single enantiomer. This ligand performs exceptionally well in the enantioselective A(3)-coupling, demonstrating the potential of this new design element.
A highly enantioselective copper-catalyzed alkynylation of quinolinium salts is reported. The reaction employs StackPhos, a newly developed imidazole-based chiral biaryl P,N ligand, and copper bromide to effect a three-component reaction between a quinoline, a terminal alkyne, and ethyl chloroformate. Under the reaction conditions, the desired products are delivered in high yields with ee values of up to 98 %. The transformation tolerates a wide range of functional groups with respect to both the alkyne and the quinoline starting materials and the products are easily transformed into useful synthons. Efficient, enantioselective syntheses of the tetrahydroquinoline alkaloids (+)-galipinine, (+)-angustureine, and (-)-cuspareine are reported.
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.
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