Parallel Synthesis

Parallel synthesis enables substantial time savings and compound differentiation by running multiple experiments simultaneously.

Parallel synthesis is used to accelerate the discovery of new compounds and to screen for optimal process conditions. In the pharmaceutical industry, parallel synthesis is used for the discovery and development of potential drug candidates. For example, this enables the synthesis of libraries with diverse chemical structures that can be screened for potential biological activity.

Parallel Synthesis applications run at different scales, including lead generation, lead optimization, and screening for optimal reaction conditions. Thus, in process scale-up and development, parallel synthesis methods speed process optimization by providing a better understanding of the effect of reaction variables including solvent systems, optimal temperatures and concentrations, correct reagents, reaction times, and selection of catalysts.

In drug discovery, a target molecule, such as a protein, is identified which has been associated with a disease process. Once the target molecule has been validated, scientists initiate a discovery process to find other molecules or substances that act on the target. The process of finding a molecule (i.e. lead molecule) that acts on a target can be daunting; thousands of compounds are likely needed to be screened to find one or more promising leads. Once a lead molecule is identified, it can be chemically modified to improve its efficacy against the target molecule. 

Parallel synthesis is vital in the step of screening for lead compounds. Parallel synthesis enables the rapid, logical synthesis of thousands of molecules, any one of which could provide a hit against the target entity. Prior to the use of parallel synthesis in combinatorial chemistry, the discovery of a lead molecules was a sequential  process that was time consuming and/or fortuitous. 

Combinatorial chemistry enables large sets of potentially novel and/or biologically active compounds to be created by combining all possible combinations of a smaller set of individual molecules under similar reaction conditions. The size of these resultant set of compounds (i.e., the library) can be enormous and entire families of novel compounds can be prepared in this manner for further testing to identify lead compounds.

Combinatorial chemistry was widely embraced some years ago, but the reality of actually identifying the compounds with biological activity from such a huge sample set proved daunting. Parallel synthesis with chemical reactors is a way to use the advantages of combinatorial chemistry in a manner that provides a more focused approach to the target molecules. This results in a smaller, more concentrated set of compounds, making the process of lead selection easier.

Parallel synthesis, which enables substantial time savings and compound differentiation by running multiple experiments simultaneously, can be performed in solution or in solid phase. In parallel solid phase synthesis, molecules are temporarily bound to an insoluble support and progressive synthesis of the product molecule is performed via a strategy of protecting and deprotecting key functional groups.

There are numerous advantages to parallel solid phase synthesis. Reactions are easily driven to completion using an excess of reagents or using reaction-enhancing techniques such as microwave irradiation. Purification is simplified since the final product is cleaved from the solid phase substrate. As in solution phase parallel synthesis, solid phase synthesis is highly amenable to automation, providing high efficiency, speed and overall final product throughput.

EasyMax parallel synthesis reactors provide an excellent platform for parallel synthesis in support of reaction optimization experiments. Since the two reactors of EasyMax are precisely and accurately controlled, parallel experiments can be run with confidence in quality of results. Design of Experiments (DoE) studies are accelerated by performing reactions simultaneously, using the defined reaction variables.

The EasyMax reactor system has two fully independent, variable-size reactors. In addition to dosing units, pH control, various stirrer types, and temperature control to 0.1° C, EasyMax reactors can be equipped with FTIR spectrometers, raman spectrometers, and particle size analyzers.

Urs Groth, Fabio Visentin, “Fast and Effective Synthesis of Peptides: A Statistical Approach Using EasyMax”, METTLER TOLEDO Application Note 2010-002.

Using a peptide synthesis from LONZA, the objective of this work was to:

• Identify the reaction parameters necessary to create a kinetic model
• Maximize yield and selectivity
• Minimize by-product formation. 

Four parameters were chosen related to concentration of reagents and temperature, and a Design of Experiments (DoE) consisting of 11 experiments were run in parallel in the EasyMax reactors.  

HPLC analysis showed that at a temperature of 10.0 °C, the conversion and yield after 90 minutes was at a minimum level, as expected.  However, the level of impurities was also minimized. Increasing temperature improved conversion and yield, but this caused a loss of selectivity and more impurities. Using a lower temperature and lower amount of one of the reagents (EDC) reduced the impurities. In contrast, low TEA concentrations resulted in higher impurities.

The combination of statistical experimentation using parallel synthesis reactors accelerated the optimization of this peptide synthesis.

Increasing temperature improved conversion and yield, but this caused a loss of selectivity and more impurities. Using a lower temperature and a lower amount of one of the reagents (EDC) reduced the impurities. In contrast, low TEA concentrations resulted in higher impurities.

The combination of statistical experimentation using parallel synthesis reactors accelerated the optimization of this peptide synthesis.