Eric M. Simmons

A data-driven strategy for predicting greenness scores, rationally comparing synthetic routes and benchmarking PMI outcomes for the synthesis of molecules in the pharmaceutical industry

Cumulative Process Mass Intensity (PMI) is one of the most popular greenness metrics tracked during the lifecycle of a pharmaceutical compound. Its use is wide-spread, having come to represent the foundation of many assessments of efficiency. These metrics are critical during the development of a compound as analysis of efficiency data (such as PMI outcomes) can help minimize the environmental impact of pharmaceutical manufacturing, highlight areas for potential improvement and thus drive sustainability. However, there are several issues with many of the current metrics, one of the most pressing being the absence of such information when key synthetic strategy decisions are made in early development; many metrics articulate the impact of strategy decisions made in the absence of efficiency data. In this article, we develop a predictive analytics framework, coupled to Monte Carlo simulation, to address this issue and enable a rich understanding of potential PMI outcomes during both the decision making process (prediction) and the outcome review process (comparison). This method leverages real-world data to predict probable PMI ranges for a potential synthesis being considered, utilizing accumulated data which spans a range of molecules and phases of development. The approach can serve two critical functions lacking in current methods: (1) it can act as a decision-aiding tool during the route discovery process, predicting probable PMI outcomes for proposed, potential or unoptimized synthetic routes; (2) it can enable the direct comparison of the PMI outcome of a synthesis to all comparable chemistry, thus providing a benchmarking methodology capable of comparing PMIs across molecules. We envision that this approach will deliver significant impact to the green chemistry community by enabling greener decisions to be made at critical phases of invention, namely the ideation, route selection and development processes (designing green), along with providing a rational method to compare a specific outcome to prior art (benchmarking).

Ni-Catalyzed Carbon–Carbon Bond-Forming Reductive Amination

This report describes a three-component, Ni-catalyzed reductive coupling that enables the convergent synthesis of tertiary benzhydryl amines, which are challenging to access by traditional reductive amination methodologies. The reaction makes use of iminium ions generated in situ from the condensation of secondary N-trimethylsilyl amines with benzaldehydes, and these species undergo reaction with several distinct classes of organic electrophiles. The synthetic value of this process is demonstrated by a single-step synthesis of antimigraine drug flunarizine (Sibelium) and high yielding derivatization of paroxetine (Paxil) and metoprolol (Lopressor). Mechanistic investigations support a sequential oxidative addition mechanism rather than a pathway proceeding via α-amino radical formation. Accordingly, application of catalytic conditions to an intramolecular reductive coupling is demonstrated for the synthesis of endo- and exocyclic benzhydryl amines.

Improving Robustness: In Situ Generation of a Pd(0) Catalyst for the Cyanation of Aryl Bromides

Conditions have been developed for the palladium-catalyzed cyanation of aryl bromides utilizing the air-stable XantPhos-PdCl2 precatalyst. By employing a trialkylamine as a reducing agent, the active Pd(0) species is generated in situ, alleviating the need to employ the air-sensitive Pd2(dba)3. Twenty-two substituted benzonitriles have been synthesized using this method.

High-Throughput Automation in Chemical Process Development

High-throughput (HT) techniques built upon laboratory automation technology and coupled to statistical experimental design and parallel experimentation have enabled the acceleration of chemical process development across multiple industries. HT technologies are often applied to interrogate wide, often multidimensional experimental spaces to inform the design and optimization of any number of unit operations that chemical engineers use in process development. In this review, we outline the evolution of HT technology and provide a comprehensive overview of how HT automation is used throughout different industries, with a particular focus on chemical and pharmaceutical process development. In addition, we highlight the common strategies of how HT automation is incorporated into routine development activities to maximize its impact in various academic and industrial settings.

Adventures in Atropisomerism: Total Synthesis of a Complex Active Pharmaceutical Ingredient with Two Chirality Axes

A strategy to prepare compounds with multiple chirality axes, which has led to a concise total synthesis of compound 1A with complete stereocontrol, is reported.

Enantioselective Synthesis of a γ-Secretase Modulator via Vinylogous Dynamic Kinetic Resolution

Two efficient asymmetric routes to γ-secretase modulator BMS-932481, under investigation for Alzheimers disease, have been developed. The key step for the first route involves a challenging enantioselective hydrogenation of an unfunctionalized trisubstituted alkene to establish the benzylic stereocenter, representing a very rare case of achieving high selectivity on a complex substrate. The second route demonstrates the first example of a vinylogous dynamic kinetic resolution (VDKR) ketone reduction, where the carbonyl and the racemizable stereocenter are not contiguous, but are conjugated through a pyrimidine ring. Not only did this transformation require both catalyst and substrate control to correctly establish the two stereocenters, but it also necessitated that the nonadjacent benzylic center of the ketone substrate be more acidic than that of the alcohol product to make the process dynamic. DFT computations aided the design of this novel VDKR pathway by reliably predicting the relative acidities of the intermediates involved.

An Enantioselective Total Synthesis of (+)-Duocarmycin SA

An efficient, concise enantioselective total synthesis of the potent antitumor antibiotic (+)-duocarmycin SA is described. The invented route is based on a disconnection strategy that was devised to facilitate rapid and efficient synthesis of key core compounds to enable preclinical structure-activity relationship investigations. The key tricycle core was constructed with a highly enantioselective indole hydrogenation to set the stereocenter and a subsequent hitherto unexplored vicarious, nucleophilic-substitution/cyclization sequence to effectively forge a final indole ring. Additionally, the development of a stable sulfonamide protecting group capable of mild chemoselective cleavage greatly enhanced sequence yield and throughput. An understanding of key reaction parameters ensured a robust, reproducible sequence easily executable on decagram scales to this highly promising class of compounds.

Development of Robust, Scaleable Catalytic Processes through Fundamental Understanding of Reaction Mechanisms

Homogenous transition metal-catalyzed reactions have become a mainstay in organic synthesis and are frequently employed in the discovery and manufacture of modern pharmaceutical compounds. Due to the complex, multi-variant nature of these transformations, the pharmaceutical industry primarily relies on parallel experimentation, such as high-throughput (HTP) screening and design of experiments approaches, to identify and optimize conditions for metal-mediated reactions. Although useful for rapid reaction development, these methods have limitations and may fail to provide critical data for the successful scale-up and implementation of these complex multi-step processes. Due to these limitations, it may be necessary to also evaluate a fundamental mechanism-focused approach towards reaction development. In this article, we review several important lessons from our laboratories at Bristol-Myers Squibb where a combination of HTP screening and mechanistic understanding revealed new insights into known catalytic transformations and facilitated the development of robust, reliable catalytic processes to support the bulk production of pharmaceutical targets.

Zinc Acetate-Promoted Buchwald-Hartwig Couplings of Heteroaromatic Amines

Zinc salts have been shown to promote the Buchwald-Hartwig coupling of azaindoles and azaindazoles with heteroaryl chlorides to provide the corresponding 1-aryl-1H-azaindoles and 1-aryl-1H-azaindazoles. The substrate scope and mechanistic aspects of this reaction were explored.

Design and evolution of the BMS process greenness scorecard

An accurate and comprehensive assessment of the environmental, health and safety impacts of a chemical process is critical to the design and implementation of greener, more benign and inherently safer processes. Over the past 15 years at BMS, we have developed a Process Greenness Scorecard to capture and analyse a number of metrics and attributes for each step in the synthetic sequence used to produce an API. This manuscript describes the design and evolution of the scoring methodology and implementation of the resulting scorecard, from an initial Excel-based tool to the current web-based format.