Advantages of High-Throughput Experimentation (HTE)

In recent years, High-Throughput Experimentation (HTE) - in which 100 or more experiments are conducted in parallel - has emerged as an important tool for the pharmaceutical industry at various stages of drug discovery and development.

Traditionally, one (or several reactions) were run at a time. The outcome of those experiments then guided the next round of experiments. This approach is not very efficient, as with an increased set of parameters to study, it may take months to find the best conditions for the desired transformation or (in a worst-case scenario) they may be missed entirely!

HTE experimentation transforms the sequential nature of experimentation to a higher level of parallel experimentation. With higher parallel experimentation, the scale is reduced to accommodate for space and limited material availability. There are several advantages associated with HTE, including:

Shorter development times

More experiments with limited precious materials

Data rich experimentation

Exploration of also less promising conditions

Better experiment to experiment comparability

Phase-Appropriate Goals

As with other experimentations, we rationally design HTE experiments to achieve phase appropriate goals. In this way, we can rapidly explore chemical space, optimize reaction parameters, and probe reaction mechanisms.

Often different reactants need to be explored in order to develop an efficient process. With HTE, we can:

Evaluate different substrates in parallel. Example: Ar-Cl, Ar-Br, and Ar-I in cross coupling reactions

Explore different parameters such as bases, additives, catalysts, and solvents.

Evaluating Multiple Parameters of Catalytic Transformations

At J-Star, we use HTE for catalytic and other chemical transformations that require the exploration of wide chemical spaces. These are most often found in catalytic transformations.

For any catalytic transformation, we need to evaluate multiple parameters in order to identify scalable process-friendly conditions (see the following Figure). We differentiate here between class reaction parameters and continuous reaction parameters.

Class reaction parameters include:

  • Catalysts
  • Solvents
  • Bases

Continuous parameters include:

  • Temperature
  • Concentration
  • Equivalencies

Typically, we start screening subsets of our large library of over 500 ligands, catalysts, and precursors. The experimental designs are guided by our rich experience, literature precedence and mechanistic consideration.

HTE & DoE for Rapid Development

It is also important to find the best operating ranges for continuous parameters like reagent equivalents, catalyst mol%, and concentrations. The initial optimization of those parameters can be accelerated with HTE and efficient use of DoE - a very powerful combined toolset for the rapid development of chemical transformations.

We can rapidly optimize reactions by maximizing product formation, minimizing specific impurities or other attributes like reducing the amount of catalyst needed.

A progression of DoE is kinetic DoE, typically conducted at low to medium throughput. With this, we can also optimize reactions on a time scale, setting criteria like full conversion while minimizing specific impurities.

Any of these techniques, coupled with mechanistic reasoning, can be utilized to probe reaction mechanisms and devise strategies for process improvement.

Our current technical capability encompasses the screening of reactions from sub-ambient temperature to high temperature reactions.

J-Star Research Catalytic Transformation Capabilities

We are skilled in a wide range of catalytic transformations and have developed processes for numerous transformations including the below:

Pressurized Reactions

  • Amination
  • Asymmetric Aza-Wacker
  • Carbonylation
  • Cyclopropanation, asymmetric
  • Deuteration (H/D exchange)
  • Hydroformylation
  • Hydrogenations (Ar, C=C, CO, ..) and hydrogenolysis
  • Aerobic oxidation

Non-Pressurized Reactions

  • 1,2-alkylation of aldehydes, asymmetric
  • 1,4-conj. arylation or reduction
  • a-arylation
  • Amide reduction
  • Asymmetric acylation
  • Baylis-Hillman
  • Borylation
  • Buchwald-Hartwig amination
  • C-H activation
  • C-O coupling (Aryl-ether formation) (Pd, Cu, Ni)
  • Cyanation
  • Direct arylation

Non-Pressurized Reactions (continued)

  • Epoxidation, asymmetric
  • Heck reaction
  • Hydroamination
  • Hydroxylation
  • Kumada coupling
  • Negishi coupling
  • Photocatalysis
  • Silylation
  • Sonogashira coupling (Pd, Fe)
  • Suzuki coupling, asymmetric
  • Transfer hydrogenation, asymmetric
  • Ullmann coupling
  • Urea coupling