Engineering Hydroxylase and Ketoreductase Activity, Selectivity, and Stability for a Scalable Concise Synthesis of Belzutifan

Please click Additional Files below to see the full abstrac

Driving Aspirational Process Mass Intensity Using SMART-PMI and Innovative Chemistry

An important metric for gauging the impact a synthetic route has on chemical resources, cost, and sustainability is process mass intensity (PMI). Calculating the overall PMI or step PMI for a given synthesis from a process description is more and more common across the pharmaceutical industry, especially in process chemistry departments. Our company has established a strong track record of delivering on our Corporate Sustainability goals, being recognized with eight EPA Green Chemistry Challenge Awards in the last 15 years and we show how these routes help define aspirational PMI tar-gets. While green chemistry principles help in optimizing PMI and developing more sustainable processes, a key challenge for the field is defining what a ‘good’ PMI for a molecule looks like given its structure alone. An existing tool chemists have at their disposal to predict PMI requires the synthetic route be provided or proposed (e.g., via retrosynthetic analysis) which then enables practitioners to compare predicted PMIs between routes. We have developed SMART-PMI (in-Silico MSD Aspirational Research Tool) to fill the gap in predicting PMI from molecular structure alone. Using only a 2D chemical structure, we can generate a predicted SMART-PMI from a measure of molecular complexity. We show how these predictions correlate with historical PMI data from our company’s clinical and commercial portfolio of processes. From this SMART-PMI prediction, we have established target ranges which we termed “Successful”, “World Class”, and “Aspirational” PMI. The goal of this range is to set the floor for what is a “good” PMI for a given molecule and provide ambitious targets to drive innovative green chemistry. Using this model, chemists can develop synthetic strategies that make the biggest impact on PMI. As innovation in chemistry and processes lead to better and better PMIs , in turn, this data can drive ever more aggressive targets for the model. The potential of SMART-PMI to set industry-wide aspirational PMI tar-gets is discussed

CRTH2 Antagonist MK-7246: A Synthetic Evolution from Discovery through Development

In this paper, we report the development of different synthetic routes to MK-7246 (<b>1</b>) designed by the Process Chemistry group. The syntheses were initially designed as an enabling tool for Medicinal Chemistry colleagues in order to rapidly explore structure–activity relationships (SAR) and to procure the first milligrams of diverse target molecules for in vitro evaluation. The initial aziridine opening/cyclodehydration strategy was also directly amenable to the first GMP deliveries of MK-7246 (<b>1</b>), streamlining the transition from milligram to kilogram-scale production needed to support early preclinical and clinical evaluation of this compound. Subsequently a more scalable and cost-effective manufacturing route to MK-7246 (<b>1</b>) was engineered. Highlights of the manufacturing route include an Ir-catalyzed intramolecular N–H insertion of sulfoxonium ylide <b>41</b> and conversion of ketone <b>32</b> to amine <b>31</b> in a single step with excellent enantioselectivity through a transaminase process. Reactions such as these illustrate the enabling impact and efficiency gains that innovative developments in chemo- and biocatalysis can have on the synthesis of pharmaceutically relevant target molecules

Process Development of C–N Cross-Coupling and Enantioselective Biocatalytic Reactions for the Asymmetric Synthesis of Niraparib

Process development of the synthesis of the orally active poly­(ADP-ribose)­polymerase inhibitor niraparib is described. Two new asymmetric routes are reported, which converge on a high-yielding, regioselective, copper-catalyzed <i>N</i>-arylation of an indazole derivative as the late-stage fragment coupling step. Novel transaminase-mediated dynamic kinetic resolutions of racemic aldehyde surrogates provided enantioselective syntheses of the 3-aryl-piperidine coupling partner. Conversion of the C–N cross-coupling product to the final API was achieved by deprotection and salt metathesis to isolate the desired crystalline salt form

Evolution of a Green and Sustainable Manufacturing Process for Belzutifan: Part 1Process History and Development Strategy

An improved synthesis has been developed for belzutifan, a novel HIF-2α inhibitor for the treatment of Von Hippel–Lindau (VHL) disease-associated renal cell carcinoma (RCC). The efficiency of previous supply and commercial routes was encumbered by a lengthy 5-step sequence, needed to install a chiral benzylic alcohol by traditional methods. Identification and directed evolution of FoPip4H, an iron/α-ketoglutarate dependent hydroxylase, enabled a direct enantioselective C–H hydroxylation of a simple indanone starting material. While this enabling transformation set the stage for a greatly improved synthesis, several other key innovations were made including the development of a base-metal-catalyzed sulfonylation, a KRED-catalyzed dynamic kinetic resolution, and a facile SNAr reaction in water. Together, these improvements resulted in a significantly shorter synthesis (9 steps) versus the supply route (16 steps) and a 75% reduction in process mass intensity (PMI), while also removing the reliance on third-row transition metals and toxic solvents

Synthesis of Bis-Macrocyclic HCV Protease Inhibitor MK-6325 via Intramolecular <i>sp</i>²–<i>sp</i>³ Suzuki–Miyaura Coupling and Ring Closing Metathesis

A practical asymmetric synthesis of the complex fused bis-macrocyclic HCV protease inhibitor MK-6325 (<b>1</b>) is described. Through the combination of a high yielding and low catalyst loading ring-closing metathesis (RCM) to forge the 15-membered macrocycle with an intramolecular <i>sp</i>²–<i>sp</i>³ Suzuki–Miyaura cross-coupling to append the 18-membered macrocycle, multikilogram access to the unique and challenging architecture of MK-6325 (<b>1</b>) has been achieved

Synthesis of the GPR40 Partial Agonist MK-8666 through a Kinetically Controlled Dynamic Enzymatic Ketone Reduction

A scalable and efficient synthesis of the GPR40 agonist MK-8666 was developed from a simple pyridine building block. The key step to set the stereochemistry at two centers relied on an enzymatic dynamic kinetic reduction of an unactivated ketone. Directed evolution was leveraged to generate an optimized ketoreductase that provided the desired <i>trans</i> alcohol in >30:1 dr and >99% ee. Further, it was demonstrated that all four diastereomers of this hydroxy-ester could be prepared in high yield and selectivity. Subsequently, a challenging intramolecular displacement was carried out to form the cyclopropane ring system with perfect control of endo/exo selectivity. The endgame coupling strategy relied on a Pd-catalyzed C–O coupling to join the headpiece chloropyridine with the benzylic alcohol tailpiece

Practical Asymmetric Synthesis of a Calcitonin Gene-Related Peptide (CGRP) Receptor Antagonist Ubrogepant

The development of a scalable asymmetric route to a new calcitonin gene-related peptide (CGRP) receptor antagonist is described. The synthesis of the two key fragments was redefined, and the intermediates were accessed through novel chemistry. Chiral lactam <b>2</b> was prepared by an enzyme mediated dynamic kinetic transamination which simultaneously set two stereocenters. Enzyme evolution resulted in an optimized transaminase providing the desired configuration in >60:1 <i>syn</i>/<i>anti</i>. The final chiral center was set via a crystallization induced diastereomeric transformation. The asymmetric spirocyclization to form the second fragment, chiral spiro acid intermediate <b>3</b>, was catalyzed by a novel doubly quaternized phase transfer catalyst and provided optically pure material on isolation. With the two fragments in hand, development of their final union by amide bond formation and subsequent direct isolation is described. The described chemistry has been used to deliver over 100 kg of our desired target, ubrogepant