Merck Sharp & Dohme Corporation, Rahway/Kenilworth, NJ, USA
Accounts of Chemical Research, ACS Publications
Conspectus: The structural complexity of pharmaceuticals presents a signiﬁcant challenge to modern catalysis. Many published methods that work well on simple substrates often fail when attempts are made to apply them to complex drug intermediates. The use of high-throughput experimentation (HTE) techniques oﬀersameanstoovercomethis fundamental challenge by facilitating the rational exploration of large arrays of catalysts and reaction conditions in a time-and material-eﬃcient manner. Initial forays into the use of HTE in our laboratories for solving chemistry problems centered around screening of chiral precious-metal catalysts for homogeneous asymmetric hydrogenation. The success of these early eﬀorts in developing eﬃcient catalytic steps for late-stage development programs motivated the desire to increase the scope of this approach to encompass other high-value catalytic chemistries. Doing so, however, required signiﬁcant advances in reactor and workﬂow design and automation to enable the eﬀective assembly and agitation of arrays of heterogeneous reaction mixtures and retention of volatile solvents under a wide range of temperatures. Associated innovations in high-throughput analytical chemistry techniques greatly increased the eﬃciency and reliability of these methods. These evolved HTE techniques have been utilized extensively to develop highly innovative catalysis solutions to the most challenging problems in large-scale pharmaceutical synthesis. Starting with Pd- and Cu-catalyzed cross-coupling chemistry, subsequent eﬀorts expanded to other valuable modern synthetic transformations such as chiral phase-transfer catalysis, photoredox catalysis, and C−H functionalization. As our experience and conﬁdence in HTE techniques matured, we envisioned their application beyond problems in process chemistry to address the needs of medicinal chemists. Here the problem of reaction generality is felt most acutely, and HTE approaches should prove broadly enabling. However, the quantities of both time and starting materials available for chemistry troubleshooting in this space generally are severely limited. Adapting to these needs led us to invest in smaller predeﬁned arrays of transformation-speciﬁc screening “kits” and push the boundaries of miniaturization in chemistry screening, culminating in the development of “nanoscale” reaction screening carried out in 1536-well plates. Grappling with the problem of generality also inspired the exploration of cheminformatics-driven HTE approaches such as the Chemistry Informer Libraries. These next-generation HTE methods promise to empower chemists to run orders of magnitude more experiments and enable “big data” informatics approaches to reaction design and troubleshooting. With these advances, HTE is poised to revolutionize how chemists across both industry and academia discover new synthetic methods, develop them into tools of broad utility, and apply them to problems of practical signiﬁcance.
‘’Automation of our foundation formulations has provided a significant gain of time once the initial color definition has been established and iterations and fine tuning are needed. An estimated increase of productivity by a factor of three was fulfilled thus considerably reducing the Time to Market. Notable and important point is the excellent reproducibility of the Chemspeed Technologies automated foundation formulation solution leading to exploitable scalable formulations for our development and pilot activities.’’
January 2018 – The Laboratory of Molecular Simulation (LSMO) at EPFL Valais Wallis
“The Laboratory of Molecular Simulation (LSMO) at EPFL has selected Chemspeed Technologies in order to accelerate their research work in discovering novel nanoporous materials. The overarching goal of this project is to identify a ‘wonder’ material that can outperform existing materials reported and available in the market for energy, environmental and sensing applications!
High-throughput methods represent a very promising approach for accelerating the discovery of metal-organic frameworks (MOFs) as a large number of automated and integrated reactions can be prepared in one batch by screening a wide variety of parameters: metal source and solvent mixtures, concentrations, ratio between the metal and ligand, pH of the reaction, heating temperature, time and others. The utilization of RoSy (Robotic Synthesiser ISYNTH SWAVE) at EPFL Valais Wallis is an ideal tool for the discovery of new materials as it allows the LSMO researchers to run a series of 50 (or more) simultaneous experiments for the synthesis of MOFs (automated dispensing of solids – ligands, metal salts and liquids with high quality; automated capping and crimping of the reaction vials without manual interference; microwave heating; confirmation of the product formation with the integrated camera). The experimental results (successful and failed) are then utilized to rank each synthetic reaction with the Genetic Algorithms (GAs) – an approach that the computational scientists in LSMO have developed. After this ranking, a set of new synthetic conditions is generated and run experimentally using RoSy. This can lead in multiple generations of MOFs (set of 50 reactions) and it continues until the best conditions are identified. Recent advances from this research activity include the discovery of new MOFs and the optimisation of the synthetic conditions for the synthesis of stable, originally reported as unstable MOFs. Additionally by establishing this robust iterative method, the design and synthesis of specific MOF for the capture / storage of strategically critical gases (CH4, CO2, H2) can be achieved!”
December 2017 – French National Institute for Agricultural Research, BIBS Platform
The French National Institute for Agricultural Research (INRA) is celebrating its 5th successful year of automating demanding sample preparation/derivatization with Chemspeed technology!
INRA is Europe’s top agricultural research institute and the world’s number two centre for the agricultural sciences. Its scientists are working towards solutions for society’s major challenges. The Biopolymères, Biologie Structurale (BIBS platform) – of INRA, Nantes, France is part of Biopolymers Interactions Assemblies (BIA) of the characterization and development of agricultural products (CEPIA).
BIBS has been certified ISO 9001 and is recognized as a strategic platform of INRA. The Chemspeed’s SWING system is at the heart of the BIBS platform and is being used for the automation of demanding sample preparation/derivatization workflow campaigns for screening structural properties of agricultural derived biopolymers.
Research Engineer of INRA states, “The Chemspeed system allows us to perform more sample preparation screening campaigns while freeing up our staff from very constraining and repetitive manipulations that require the use of highly toxic chemicals. In addition, the system eliminates analyst to analyst variation and performs highly complex chemical synthesis-like sample preparations that only highly trained staff can manage.”
October 2017 – PTT Global Chemical Limited, Rayong, Thailand
Senior Researcher, R&D-Scale-up and Process Technology, states: “It is known that research is a seriously tough job, it e.g. always needs to satisfy the expectation of every people and management level involved. Moreover, it always takes time. Normally, it might take around 10 years from laboratory scale to commercial scale. Besides, in polyolefin research it is more than 60% of the whole journey that falls into lab scale phase. Nowadays, more and more automation is involved and relieves such constraints. Thus, I am very pleased to expand the implementation of high-output research in PTT Global Chemical Limited (Public), Thailand. Chemspeed Technologies has been an excellent company providing us a convincing solution for the highly challenging automated polyolefin catalyst synthesis, catalyst screening, and polymerization testing. I believe that these tools will provide a strategic advantage to our R&D organization in our effort to rapidly develop novel polyolefin products for local and global use. In addition to accelerating and standardizing experimentation, the Chemspeed solution also enables R&D data preservation and evolution in one informatics platform which will help PTTGC researchers to be more productive and innovative.”
September 2017 – Clariant, Frankfurt, Germany
“To help reduce the time to market for new products, Group Technology & Innovation has developed an advanced laboratory centered on high throughput experimentation (HTE) techniques. The lab provides accelerated synthesis, formulation, application and testing for all business units across the product landscape.
Accelerating the development of new products and reducing their time to market is a critical factor in Clariant’s success. Developing a product often requires multiple formulations and testing, making this process very labor-intensive and time-consuming.
To accelerate scientific research, Clariant has set up a central High Throughput Experimentation (HTE) laboratory at its Clariant Innovation Center (CIC) in Frankfurt-Hoechst, Germany. HTE uses automated instrumentation, specialized software tools, and alternative research techniques to increase the output of experimentation, application, and testing, all of which help improve the efficiency and productivity of the development process.“
August 2017 – Oil & Gas Science and Technology – Rev. IFP Energies nouvelles
Catalysis, irrespective of its form can be considered as one of the most important pillars of today’s chemical industry. The development of new catalysts with improved performances is therefore a highly strategic issue. However, the a priori theoretical design of the best catalyst for a desired reaction is not yet possible and a time- and money-consuming experimental phase is still needed to develop a new catalyst for a given reaction.
August 2017, Merck & Co., Inc., Rahway, NJ, USA
Reaction Chemistry & Engineering, The Royal Society of Chemistry
Knochel – Hauser bases, derived from 2,2,6,6-tetramethylpiperidinyl (TMP) metal amides, offer exceptional selectivity and functional group tolerance in the regioselective metalation of arenes and heteroarenes. The selectivity, stability and yield of these reactions are highly dependent on the nature of the base, additive and deprotonation temperature.
July 2017 – Polymer Chemistry, The Royal Society of Chemistry
Reversible addition–fragmentation chain transfer (RAFT) copolymerization was used to prepare copolymers of N-isopropyl acrylamide (NIPAM) and vinyl acetate (VAc) with mole fractions of NIPAM ranging from 0.1 to 0.6 and targeted degrees of polymerization of 100 and 250. The measured kinetic parameters and obtained experimental results revealed that this copolymerization system leads to a “one pot” synthesis of amphiphilic gradient copolymers,
A series of dual pH- and ultrasound responsive statistical copolymers were synthesized via the reversible addition–fragmentation chain transfer (RAFT) polymerization of 3,4-dihydro-2H-pyran (DHP) protected HEMA 2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl methacrylate (THP-HEMA) and 2-(dimethylamino)ethyl methacrylate (DMAEMA)