Herein
is described the development of a large-scale manufacturing
process for molnupiravir, an orally dosed antiviral that was recently
demonstrated to be efficacious for the treatment of patients with
COVID-19. The yield, robustness, and efficiency of each of the five
steps were improved, ultimately culminating in a 1.6-fold improvement
in overall yield and a dramatic increase in the overall throughput
compared to the baseline process.
Azidoethyl phenyl sulfide, a readily accessible and reasonably stable synthon for ethyl azide with acceptable thermal safety properties, was investigated in a preliminary design space evaluation of a [3 + 2]-cycloaddition with cyanoacetamide under continuous-flow conditions in the Syrris AFRICA flow reactor.
1,1'-Carbonyldiimidazole was found to induce the formation of a variety of 3,4-disubstituted 1,2,5-oxadiazoles (furazans) from the corresponding bisoximes at ambient temperature. This method enables these inherently energetic compounds to be prepared at temperatures well below their decomposition points and with improved functional group compatibility relative to prior methods. Conditions were developed that allowed for the first high-yielding synthesis of chlorofurazans from their amino counterparts, enabling the mild synthetic manipulation of these heterocycles.
The
manufacturing route toward gefapixant citrate generates a trace
amount of cyanide as a byproduct of a reaction employing the reagent
chloroacetonitrile. In the development of a cyanide control strategy,
conventional process and analytical approaches fell short because
of challenges and incompatibilities with the matrices of the process
and waste streams. To overcome these, we identified and adapted specific
procedures for cyanide control. Our strategy ensured safety for patients,
operators, and waste management.
The unnatural, alkyne-containing nucleoside analog islatravir
(MK-8591) is synthetically accessed through a biocatalytic cascade starting from
2-ethynylglycerol as a building block. Herein, we describe the development of an
efficient synthesis of this building block including the initial route, route
scouting and final process development. Key challenges that have been overcome are
the development of an efficient and safe acetylenic nucleophile addition to an appropriate
ketone, and the identification of a 2-ethynylpropane-1,2,3-triol derivative
with favorable physical properties. An acid-catalyzed cracking of commercially
available 1,3-dihydroxyacetone dimer and subsequent 1,2-addition of an
acetylenic nucleophile has been discovered and optimized into the manufacturing
process
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