Historically, biocatalytic ketone reductions involved the use of Bakerʼs yeast. Within the last five years, a significant and growing number of isolated ketoreductases have become available that have ...rendered yeast-based reductions obsolete. The broad substrate range and exquisite selectivities of these enzymes repeatedly outperform other ketone reduction chemistries, making biocatalysis the general method of choice for ketone reductions. Presented here is a summary of our understanding of the capabilities and limitations of these enzymes.
In this paper, we report the development of different synthetic routes to MK-7246 (1) 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 (1), 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 (1) was engineered. Highlights of the manufacturing route include an Ir-catalyzed intramolecular N–H insertion of sulfoxonium ylide 41 and conversion of ketone 32 to amine 31 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.
Sustainable small molecule Active Pharmaceutical Ingredient (API) manufacturing starts at the onset of route development by employing a Green-by-Design strategy. Reliable metrics are imperative for ...setting targets and measuring process improvements throughout the development cycle. This article reviews some of the many tools and methods established to analyze and assess the greenness and sustainability of a process, each of which highlights different aspects of process efficiency, waste formation or overall environmental impact reduction. Most calculations, such as process mass intensity (PMI), are mass-based and do not consider the types of raw materials used. In contrast, a full life cycle assessment (LCA) offers detailed information about the “cradle to grave” environmental impact of a manufacturing route and its specific resources, but the high data requirements and long timelines are not conducive for multiple processes or repeated assessments during process optimization. To address these challenges, we introduce a Streamlined PMI-LCA Tool, developed in collaboration with the ACS Green Chemistry Institute Pharmaceutical Roundtable (ACS GCIPR), that combines PMI with a “cradle to gate” approach to include the environmental footprint of the synthesis’ raw materials. The frequent re-evaluation of a process continuously highlights areas for improvement and guides the prioritization of process development activities to effectively and rapidly achieve a Green-by-Design commercial synthetic route. The utility of this approach to Green-by-Design is demonstrated with the reduction of PMI for MK-7264 from 366 to 88 over the course of process development.
•A Green-by-Design strategy for sustainable manufacturing relies on the consistent application of metrics and targets.•Existing tools set targets and/or score processes using a range of methodologies and structural or manufacturing data.•The Streamlined PMI-LCA Tool facilitates routine process scoring and prioritization of development tasks with minimal data required.•The Green-by-Design development strategy for the MK-7264 active pharmaceutical ingredient is outlined here.
Nonracemic sec-alcohols of opposite absolute configuration were obtained either by asymmetric reduction of the corresponding ketone using 2-propanol as hydrogen donor or by enantioselective oxidation ...through kinetic resolution of the rac-alcohol using acetone as hydrogen acceptor employing whole lyophilized cells of Rhodococcus ruber DSM 44541. The microbial oxidation/reduction system exhibits not only excellent stereo- and enantioselectivity but also a broad substrate spectrum. Due to the exceptional tolerance of the biocatalyst toward elevated concentrations of organic materials (solvents, substrates and cosubstrates), the process is highly efficient. The simple preparation of the biocatalyst and its ease of handling turns this system into a versatile tool for organic synthesis.
Redox enzymes offer many powerful transformations for the efficient industrial-scale synthesis of diverse chemicals desired by society. Here we survey recent preparative applications of redox ...enzymes, highlighting both mature enzyme platforms and promising technologies for future applications. While in some cases commercial enzymes can be employed directly on industrial scales, in other cases protein engineering is necessary to evolve an enzyme fit for non-biological substrates and conditions. Both approaches require the input of process engineering to properly balance the needs of the enzymatic chemistry with the requirements for an industrial process. A convergence of advances in enzyme discovery, protein engineering, and process engineering is expected to fuel a more rapid development of enzymatic synthetic processes and a wider adoption of biocatalysis on industrial scales.
Biocatalytic hydrogen‐transfer reduction of α‐chloro‐ketones furnished non‐racemic chlorohydrins by employing either Rhodococcus ruber as lyophilized cell catalyst or an alcohol dehydrogenase ...preparation from Pseudomonas fluorescens DSM 50106 (PF‐ADH). For all substrates investigated, Rhodococcus ruber gave strictly the “Prelog” product, whereas PF‐ADH showed scattered stereopreference. One possibility for a follow‐up reaction of halohydrins is the ring closure to the corresponding epoxide. A novel “one pot‐one step strategy” was employed to obtain the enantiopure epoxide from the α‐chloro‐ketone in a cascade like fashion at pH>12 involving biocatalytic hydrogen transfer reduction and in situ chemo‐catalyzed ring closure.
A practical procedure for the enzymatic resolution of 2-alkyl-2-aryl-disubstituted epoxides using the Codex HHDH P2E2 enzyme and sodium azide is reported. This method allowed the synthesis of novel ...regio- and enantioselective 1-azido-2-arylpropan-2-ols in excellent yields. Furthermore, these intermediates were used for the preparation of enantiomerically enriched amino alcohols and aziridines containing a tertiary center.
An important metric for gauging the impact that 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. As with other pharmaceutical companies, 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 targets. 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 that 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 complement existing tools by 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 and molecular weight. 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 leads to better and better PMIs, in turn, this data can drive ever more aggressive targets for the model. The potential of SMART-PMI, in combination with other existing PMI tools, to set industry-wide aspirational PMI targets is discussed.
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.
