Development of a Robust Manufacturing Route for Molnupiravir, an Antiviral for the Treatment of COVID-19.

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.

The Emergence of Universal Chromatographic Methods in the Research and Development of New Drug Substances.

Manufacturing process development of new drug substances in the pharmaceutical industry combines numerous chemical challenges beyond the efficient synthesis of complex molecules. Optimization of a synthetic route involves the screening of multiple reaction variables with a desired outcome that not only depends on an increased product yield but is also highly influenced by the removal efficacy of residual chemicals and reaction byproducts during the subsequent synthetic route. Consequently, organic chemists must survey a wide array of synthetic variables to develop a highly productive, green, and cost-effective manufacturing process. The time constraints of developing robust quantitative methods prior to each processing step can easily lead to sample analysis becoming a bottleneck in synthetic route development. In this regard, conventional "on demand" analytical method development and optimization approaches, traditionally used for guiding synthetic chemistry efforts, become unsustainable. This Account introduces recent efforts to address the aforementioned challenges through the development and implementation of generic or more universal chromatographic methods that can cover a broad spectrum of targeted compound classes. Such generic methods require significant resolving power to enable baseline resolution of multicomponent mixtures in a single experimental run without additional method customization but must be simple enough to allow for routine use by chemists, chemical engineers and other researchers with little experience in chromatographic method development. These powerful analytical methodologies are often employed to minimize the time spent developing new analytical assays, while also facilitating method transfer to manufacturing facilities and application in regulatory settings. Diverse examples of universal and fit-for-purpose analytical procedures are presented herein, illustrating the power of modern readily available analytical technology for streamlining the development of new drug substances in organic chemistry laboratories across both academic and industrial sectors. With recent advances in analytical instrumentation and column technologies, universal chromatographic methods are quickly becoming a proactive and effective strategy to accelerate the discovery and implementation of new synthetic methodologies, especially but not limited to laboratories where the synthetic process route is undergoing rapid change and optimization. Targets of these generic methods include analysis of organic solvents, acid and basic additives, nucleotide species, palladium scavengers, impurity mapping, enantiopurity, synthetic intermediates, active pharmaceutical ingredients and their counterions, dehalogenation byproducts, and mixtures of organohalogenated pharmaceuticals, among other chemicals used or formed in process chemistry reactions.

Scalable Synthesis of Diazeniumdiolates: Application to the Preparation of MK-8150.

Synthetic diazeniumdiolate (DAZD)-based nitric oxide is utilized to modulate the nitric oxide (NO) concentration in cellular environments and to control physiological processes, yet chemists are still struggling to find efficient and scalable methodologies that will enable them to access sufficient quantities of the high-energy diazeniumdiolate intermediates for biological studies. Now, a general, scalable, safer, and high-yielding new methodology adaptable to the large-scale synthesis of DAZDs has been developed.

Combining traditional 2D and modern physical organic-derived descriptors to predict enhanced enantioselectivity for the key aza-Michael conjugate addition in the synthesis of Prevymis™ (letermovir).

Quantitative structure-activity relationships have an extensive history for optimizing drug candidates, yet they have only recently been applied in reaction development. In this report, the predictive power of multivariate parameterization has been explored toward the optimization of a catalyst promoting an aza-Michael conjugate addition for the asymmetric synthesis of letermovir. A hybrid approach combining 2D QSAR and modern 3D physical organic parameters performed better than either approach in isolation. Using these predictive models, a series of new catalysts were identified, which catalyzed the reaction to provide the desired product in improved enantioselectivity relative to the parent catalyst.

Asymmetric Synthesis of Functionalized trans-Cyclopropoxy Building Block for Grazoprevir.

A practical and asymmetric synthesis of a functionalized trans-cyclopropoxy building block for the preparation of the HCV NS3/4a protease inhibitor grazoprevir is reported. Intramolecular SN2 displacement-ring closure, followed by a Baeyer-Villiger oxidation, yields the desired trans-cyclopropanol with full control of diastereoselectivity. A terminal alkyne is then effectively installed using LiNH(CH2)2NEt2. Starting from (S)-epichlorohydrin, the cyclopropoxy building block is prepared in 51% overall yield with >99.8% optical purity without isolation of any intermediates.

Asymmetric Hydrogen Bonding Catalysis for the Synthesis of Dihydroquinazoline-Containing Antiviral, Letermovir.

A weak Brønsted acid-catalyzed asymmetric guanidine aza-conjugate addition reaction has been developed. C2-symmetric, dual hydrogen-bond donating bistriflamides are shown to be highly effective in activating α,ß-unsaturated esters toward the intramolecular addition of a pendant guanidinyl nucleophile. Preliminary mechanistic investigation, including density functional theory calculations and kinetics studies, support a conjugate addition pathway as more favorable energetically than an alternative electrocyclization pathway. This methodology has been successfully applied to the synthesis of the 3,4-dihydroquinazoline-containing antiviral, Letermovir, and a series of analogues.

Asymmetric Synthesis of a Potent HIV-1 Integrase Inhibitor.

The development of a practical asymmetric total synthesis of the potent HIV-1 integrase inhibitor 5 is described. Key transformations include construction of the naphthridine core in a highly efficient manner followed by cyclization of the 8-membered ring. Control of the atropisomers of intermediates and final compound 5 is also described.

A Synthesis of a Spirocyclic Macrocyclic Protease Inhibitor for the Treatment of Hepatitis C.

The development of a convergent and highly stereoselective synthesis of an HCV NS3/4a protease inhibitor possessing a unique spirocyclic and macrocyclic architecture is described. A late-stage spirocyclization strategy both enabled rapid structure-activity relationship studies in the drug discovery phase and simultaneously served as the basis for the large scale drug candidate preparation for clinical use. Also reported is the discovery of a novel InCl3-catalyzed carbonyl reduction with household aluminum foil or zinc powder as the terminal reductant.

Asymmetric synthesis of telcagepant, a CGRP receptor antagonist for the treatment of migraine.

A highly efficient, asymmetric synthesis of telcagepant (1), a CGRP receptor antagonist for the treatment of migraine, is described. This synthesis features the first application of iminium organocatalysis on an industrial scale. The key to the success of this organocatalytic transformation was the identification of a dual acid cocatalyst system, which allowed striking a balance of the reaction efficiency and product stability effectively. As such, via an iminium species, the necessnary C-6 stereogenicity was practically established in one operation in >95% ee. Furthermore, we enlisted an unprecedented Doebner-Knoevenagel coupling, which was also via an iminium species, to efficiently construct the C3-C4 bond with desired functionality. In order to prepare telcagepant (1) in high quality, a practical new protocol was discovered to suppress the formation of desfluoro impurities formed under hydrogenation conditions to <0.2%. An efficient lactamization facilitated by t-BuCOCl followed by a dynamic epimerization-crystallization resulted in the isolation of caprolactam acetamide with the desired C3 (R) and C6 (S) configuration cleanly. Isolating only three intermediates, the overall yield of this cost-effective synthesis was up to 27%. This environmentally responsible synthesis contains all of the elements required for a manufacturing process and prepares telcagepant (1) with the high quality required for pharmaceutical use.

Efficient and practical synthesis of (R)-2-methylpyrrolidine.

An efficient, practical, and high yielding synthesis of (R)-2-methylpyrrolidine is described. The sequence allows for the scalable preparation of the target compound in just four synthetic steps and proceeds in 83% overall yield and >99% optical purity from readily available starting materials.

Asymmetric Diels-Alder reactions of chiral cyclopropylidene imide dienophiles: preparation of gem-dimethyl- and spirocyclopropane norbornyl carboxylic acids.

A highly efficient strategy has been developed for the rapid asymmetric synthesis of gem-dimethyl and spirocyclopropyl norbornyl carboxylic acids. The key transformation involved the unprecedented asymmetric Diels-Alder reaction of highly reactive beta,beta-cyclopropyl-alpha,beta-unstaturated N-acyloxazolidinones with cyclopentadiene affording the adducts in high yield and de.

Development of a novel, highly efficient halide-catalyzed sulfenylation of indoles.

[reaction: see text] The reaction of a variety of indoles with N-thioalkyl- and N-thioarylphthalimides to produce 3-thioindoles is reported. Catalytic quantities of halide-containing salts are crucial to the success of this reaction. This highly efficient reaction provides sulfenylated indoles from bench-stable, readily available starting materials in good to excellent yields.

Enantioselective hydrogenation of alpha-aryloxy alpha,beta-unsaturated acids. Asymmetric synthesis of alpha-aryloxycarboxylic acids.

[reaction: see text] A facile preparation of chiral alpha-aryloxy carboxylic acids via asymmetric hydrogenation of the corresponding unsaturated acids has been discovered. A number of catalysts have been identified that give high product enantioselectivity, and the scope of the reaction has been examined with respect to substitution on the aromatic ring and olefin.

Highly regioselective Friedländer annulations with unmodified ketones employing novel amine catalysts: syntheses of 2-substituted quinolines, 1,8-naphthyridines, and related heterocycles.

Catalysts were evaluated on the preparation of 2-substituted quinolines, 1,8-naphthyridines, and chromone derivatives from unmodified methyl ketones and o-aminoaromatic aldehydes. While oxide catalysts yielded the 2,3-dialkyl substituted products, cyclic secondary amines provided the 2-alkylsubstutited products regioselectively. In particular, pyrrolidine derivatives provided the highest regioselectivity favoring the 2-substituted products. The most reactive and regioselective catalyst was the bicyclic pyrrolidine derivative, TABO (1,3,3-trimethyl-6-azabicyclo[3.2.1]octane), yielding 1,8-naphthyridines with as high as 96:4 regioselectivity. Regioselectivity increased with slow addition of the methyl ketone substrate to the reaction mixture, and was positively related to temperature. Isolated yields of single regioisomers were typically 65-84%, while observed regioselectivities were > or =90:10 for 1,8-naphthyridines and > or =84:16 for quinolines.