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

Our company has developed a robust and scalable process to synthesize an amino alcohol tosylate salt, a penultimate intermediate in the synthesis of nemtabrutinib. A key reaction in this synthetic sequence is a reductive acetal ring opening using boron trifluoride diethyl etherate as a Lewis acid and triethylsilane as the reducing agent. Detailed mechanistic inquisition revealed that in the presence of sulfolane, boron trifluoride is reduced by triethylsilane to generate diborane as the active reductant. Diborane poses many process safety hazards; it is highly reactive, flammable, and acutely toxic. The reaction headspace was studied using infrared spectroscopy and gas chromatography, while the reaction stream was studied using heat flow and adiabatic calorimetry to ensure safe scale-up of the process. Process understanding demonstrated that containing diborane within the reactor was essential to control key impurities. Extensive development efforts were directed to design a process that could safely sequester the hazardous gas. Herein, we describe the process safety analysis, the optimization, and the scale-up of the reduction reaction and the isolation, producing two batches of the amino alcohol tosylate salt with high purity at a pilot scale.

The development of a stereospecific synthesis of a IDO1-selective inhibitor is described. The synthetic strategy toward enabling early discovery efforts along with additional findings pertaining to process safety that limited scalability are outlined. A convergent approach that supported the synthesis of material suitable for early preclinical and/or good laboratory practice toxicology studies and avoided the formation of key high-energy intermediates is summarized.

During the process development of a pharmaceutical advanced intermediate, new chemistry using an aqueous workup resulted in the discovery of a new hydrated crystal form of this intermediate. This hydrated crystal form showed thermal instability at a relatively low temperature compared to the original anhydrous form. Thermal stability and associated process safety hazards were investigated in order to ensure process safety and transportation safety of this intermediate.