A practical and asymmetric synthesis of potent anti-HIV nucleoside MK-8527 is described. The key discoveries are a novel stereoselective dynamic kinetic resolution (DKR) Mitsunobu glycosylation and selective amination of the resulting 2,6-dichloro nucleoside. The new route was successfully demonstrated on the kilogram scale and provided isolated MK-8527 with more than 99% HPLC purity through crystallization.

MK-1084 is a potent KRAS G12 inhibitor characterized by a complex macrocyclic ring system incorporating two atropisomeric axes from a restricted rotation around both C-C and N-C bonds. Herein, we report an efficient synthetic approach to manufacture MK-1084 to enable clinical trials. By leveraging the in-depth understanding of the inherent properties of axial chirality, we discovered and developed a one-pot crystallization-induced diastereomer transformation (CIDT)/carbonylation process to establish the unique and challenging macrocyclic core with double axial chiral centers from a racemic advanced precursor and readily available raw materials.

Pharmaceutical companies are increasingly leveraging the power of biocatalysis to enable the development of concise and robust commercial manufacturing processes for their therapeutics. Yet, implementation of biocatalysis via protein engineering often requires years to generate a production-ready enzyme. To enable rapid clinical supply, we engineered an enoate-reductase (ERED) to catalyze a key asymmetric reduction in a concise 4-step chemoenzymatic route toward the orally bioavailable STING agonist MK-2118. Within 2 months, we evolved a Z-selective ERED with high activity that delivered the desired product in high yield and exquisite enantioselectivity. The 4-step chemoenzymatic process was used to successfully deliver >10 kg of MK-2118 from readily available starting materials at 40% overall yield and >99% ee to accelerate clinical trials.

We report the total synthesis of enlicitide decanoate, an orally bioavailable inhibitor of proprotein convertase subtilisin/kexin type 9 that is being developed for the treatment of atherosclerotic cardiovascular disease. It is a highly complex macrocyclic peptide with a significant number of nonpeptide structural elements that presents a daunting synthetic chemistry challenge. We describe the development of a convergent, efficient, and robust manufacturing process that enables the large-scale production of enlicitide.

Here we report the development of a large-scale manufacturing process for the synthesis of the Northern Fragment of enlicitide decanoate (MK-0616), an orally bioavailable inhibitor of proprotein convertase subtilisin/kexin type 9 (PCSK9). The key topics covered are (1) process development for the selective tryptophan allylation; (2) development of the one-pot process for two consecutive peptide coupling reactions; (3) process development for the one-pot cleavage of two N-tert-butyloxycarbonyl (N-Boc) groups and a tert-butyl ester; and (4) process development of the magnesium chloride (MgCl2)-mediated selective macrolactamization. This optimized process was demonstrated to produce the key fragment at >150 kg scale per batch in the synthesis of enlicitide.

Direct, stereoselective hydroxylation of unactivated C-H bonds has the potential to dramatically streamline organic synthesis, and enzymes are particularly well-suited for facilitating these transformations, enabling clean and efficient processes that are scalable for industrial applications. Here, we report the development of a chemoenzymatic process for producing trans-3-hydroxy-l-proline (1), a key intermediate in synthesizing the proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor enlicitide decanoate (MK-0616). This process proceeds by direct biocatalytic aerobic C(sp3)-H hydroxylation of l-proline, mediated by an engineered Fe(II)- and alpha-ketoglutarate (alpha-KG)-dependent oxygenase. Through integrated enzyme discovery, protein engineering, and process development, we achieved a robust large-scale biocatalytic oxidation using minimal enzyme loading at high substrate concentrations. In combination with a high-yielding in situ protection and an efficient isolation procedure, this methodology has been used to produce high-purity N-Cbz-trans-3-hydroxy-l-proline 5 at >400 kg scale.

Nemtabrutinib (MK-1026) is a novel oral Bruton’s tyrosine kinase (BTK) inhibitor for treatment of B-cell cancers. An initial synthetic supply route to generate ketone 3 relied on the generation of a highly reactive transient intermediate and the use of n-butyllithium. Cryogenic temperatures (−60 °C) were also required to achieve a modest 61% yield, with one major impurity, resulting from dehalogenation, accounting for the majority of the mass balance. An alternative process was developed to increase the yield and decrease the dependence on cryogenic temperatures, and this advancement was critical to the long-term robustness of the commercial process. Key advancements included performing the requisite deprotonation and metalation steps sequentially and performing the metalation and quench steps in flow. The final flow process was rapidly scaled from grams to tens of kilograms and has been successfully executed in a production facility.

A kilogram-scale synthesis of a key fragment of Ulevostinag (MK-1454), a cyclic dinucleotide agonist of the stimulator of interferon genes (STING), is described. Ulevostinag comprises two non-natural nucleoside derivatives linked together via two P-chiral phosphorothioate groups. The strategy utilized to prepare one of these nucleosides, namely, 3 '-deoxy-3 '-alpha-fluoro-guanosine (3 '-FG), hinges on a diastereoselective alpha-fluorination of a key keto-nucleoside derivative, followed by substrate-directed reduction of the ketone. Herein, we describe the development of a robust and scalable synthesis of this intermediate, a 3 '-deoxy-2 '- keto-guanosine derivative, from guanosine. Salient features of the approach include activation of the 2 ' and 3 '-alcohol groups of guanosine as a bis-tosylate, which enables regioselective E2 elimination to simultaneously deoxygenate the 3 '-position and generate the 2 '-ketone.

Abstract This chapter describes the procedure for preparation of 9‐azabicyclo[3.3.1]nonane‐N‐oxyl (ABNO). ABNO is an effective catalyst for aerobic oxidation of alcohols to ketones and aldehydes. This type of oxidation is particularly attractive for large scale preparations because of the potential to reduce cost and minimize waste. The chapter presents some of the important points to be considered, the conditions that need to be maintained, characterization data, and the reagents required, as well as the techniques used and the equipment setup that are vital to carrying out the process. It also describes the hazards associated with working with chemicals and the ways to deal with these hazards.

Two scalable and efficient synthetic routes for the synthesis of a T-type calcium channel antagonist MK-8998 were developed from a simple pyridine building block. The key step to set the stereochemistry relied on either chiral rhodium catalyst-mediated asymmetric hydrogenation of an enamide or transamination of an arylketone that provided the corresponding product in high enantioselectivity and high yield.

A simple and efficient process to prepare Uprifosbuvir intermediate, 2′-deoxy-α-2′-chloro-β-2′-methyluridine (1), from bis-pivaloyl tertiary alcohol 5a is described. The key discoveries are a novel BSA-promoted anhydrouridine formation catalyzed by HCl as an additive and a milder safe Me2SiCl2-promoted chlorination of anhydrouridine. These discoveries collectively enabled the establishment of a robust process toward compound 1, which was demonstrated successfully at the plant scale.

We report the development and scale-up of a continuous flow photochemical benzylic bromination en route to belzutifan (MK-6482), a small molecule for the treatment of renal cell carcinoma associated with Von Hippel–Lindau syndrome. Compared with the clinical supply route, the photochemical approach circumvents the need for azo radical initiators and proceeds at room temperature. Implementation of continuous flow technology allowed tight control of irradiation and residence time, resulting in a robust process with minimized byproduct formation. This method was selected for the manufacturing process for belzutifan and represents the first commercial continuous flow photochemical process in our company, laying the foundation for the utilization of photochemistry in the pharmaceutical industry.

As practitioners of organic chemistry strive todeliver efficient syntheses of the most complex natural productsand drug candidates, further innovations in synthetic strategies arerequired to facilitate their efficient construction. These aspirationalbreakthroughs often go hand-in-hand with considerable reductionsin cost and environmental impact. Enzyme-catalyzed reactions havebecome an impressive and necessary tool that offers benefits suchas increased selectivity and waste limitation. These benefits areamplified when enzymatic processes are conducted in a cascade incombination with novel bond-forming strategies. In this article, wereport a highly diastereoselective synthesis of MK-1454, a potentagonist of the stimulator of interferon gene (STING) signalingpathway. The synthesis begins with the asymmetric construction oftwofluoride-bearing deoxynucleotides. The routes were designed for maximum convergency and selectivity, relying on the samebenign electrophilicfluorinating reagent. From these complex subunits, four enzymes are used to construct the two bridgingthiophosphates in a highly selective, high yielding cascade process. Critical to the success of this reaction was a thoroughunderstanding of the role transition metals play in bond formation.

Herein, we present a strategy for the preparation of 3'-fluorinated nucleoside analogues via the aminocatalytic, electrophilic fluorination of readily accessible and bench-stable 2'-ketonucleosides. Initially developed to facilitate the manufacture of 3'-fluoroguanosine (3'-FG)─a substructure of anticancer therapeutic MK-1454─this strategy has been extended to the synthesis of a variety of 3'-fluoronucleosides. Finally, we demonstrate the utility of the 2'-ketonucleoside synthon as a platform for further diversification and suggest that this methodology should be broadly applicable to the discovery of novel nucleoside analogues.

A four-step synthesis of the indanone core of belzutifan (MK-6482) is described. This route starts from the commodity raw material dihydrocoumarin and was successfully demonstrated on a large scale to produce indanone 11 in the synthesis of belzutifan, an FDA-approved first-in-class therapy for the treatment of patients with certain types of Von Hippel–Lindau disease-associated tumors.

A synthetic strategy to provide two late-stage intermediates for the synthesis of diverse analogues of ROMK inhibitors for the treatment of hypertension and heart failure is described. Key transformations include carbonylation of a bromoarene, regioselective vinyl ether Heck coupling and bromination, and asymmetric enzyme-mediated ketone reduction and epoxide ring closure. On selection of MK-7145 (1) as clinical candidate, conditions were developed to convert 2 equiv of the epoxide intermediates to the C2-symmetric active pharmaceutical ingredient.

The unnatural, alkyne-containing nucleoside analog islatravir(MK-8591) is synthetically accessed through a biocatalytic cascade starting from2-ethynylglycerol as a building block. Herein, we describe the development of anefficient synthesis of this building block including the initial route, routescouting and final process development. Key challenges that have been overcome arethe development of an efficient and safe acetylenic nucleophile addition to an appropriateketone, and the identification of a 2-ethynylpropane-1,2,3-triol derivativewith favorable physical properties. An acid-catalyzed cracking of commerciallyavailable 1,3-dihydroxyacetone dimer and subsequent 1,2-addition of anacetylenic nucleophile has been discovered and optimized into the manufacturingprocess

An efficient route to the HCV antiviral agent uprifosbuvir was developed in 5 steps from readily available uridine in 50% overall yield. This concise synthesis was achieved by development of several synthetic methods: (1) complexation-driven selective acyl migration/oxidation; (2) BSA-mediated cyclization to anhydrouridine; (3) hydrochlorination using FeCl3/TMDSO; (4) dynamic stereoselective phosphoramidation using a chiral nucleophilic catalyst. The new route improves the yield of uprifosbuvir 50-fold over the previous manufacturing process and expands the tool set available for synthesis of antiviral nucleotides.

Cholesteryl ester transfer protein (CETP) represents one of the key regulators of the homeostasis of lipid particles, including high-density lipoprotein (HDL) and low-density lipoprotein (LDL) particles. Epidemiological evidence correlates increased HDL and decreased LDL to coronary heart disease (CHD) risk reduction. This relationship is consistent with a clinical outcomes trial of a CETP inhibitor (anacetrapib) combined with standard of care (statin), which led to a 9% additional risk reduction compared to standard of care alone. We discuss here the discovery of MK-8262, a CETP inhibitor with the potential for being the best-in-class molecule. Novel in vitro and in vivo paradigms were integrated to drug discovery to guide optimization informed by a critical understanding of key clinical adverse effect profiles. We present preclinical and clinical evidence of MK-8262 safety and efficacy by means of HDL increase and LDL reduction as biomarkers for reduced CHD risk.

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.