Novel technique to automate production of pharmaceutical compounds

The discovery and development of new small molecules for therapeutic use involves a considerable investment of time, effort and resources. Putting a new spin on conventional chemical synthesis, a team of researchers at the National University of Singapore (NUS) has developed a way to automate the production of small molecules suitable for pharmaceutical use. This method can potentially be used for molecules that are typically produced by manual processes, reducing the labor required.

The research team that achieved this technological breakthrough was led by Assistant Professor Wu Jie of the NUS Department of Chemistry and Associate Professor Saif A. Khan, from the Department of Chemical and Biomolecular Engineering at NUS.

In demonstrating this new technique on prexersatib, a pharmaceutical molecule used in cancer treatment, the NUS team achieved a fully automated six-step synthesis with an isolated yield of 65% in 32 hours. In addition, their technique also produced 23 derivatives of prexersatib in an automated fashion, demonstrating the method's potential for drug discovery and design.

These results, which were first published in the journal Nature Chemistry on April 19, 2021, can potentially be applied to the production of a wide range of pharmaceutical molecules.

Simplifying the production of pharmaceutical compounds

Recent advances in end-to-end continuous flow synthesis are rapidly expanding the capabilities for automated syntheses of small-molecule pharmaceutical compounds in flow reactors. There are well-defined production methods for molecules such as peptides and oligonucleotides that have repeating functional units. However, it is difficult to achieve continuous flow and multi-step synthesis of active pharmaceutical ingredients due to problems such as solvent and reagent incompatibility.

The new automated technique developed by the NUS research team combines two chemical synthesis techniques. These are continuous flow synthesis, where chemical reactions are carried out in a continuous process, and solid-state synthesis, in which molecules are chemically bound and grown on an insoluble support material.

Their new technique, called solid-phase synthesis or SPS-flow, allows the target molecule to be grown on a solid support material while the reaction reactant passes through a packed-bed reactor. The entire process is computer controlled. Compared to existing automated techniques, the SPS-flow method allows for broader reaction schemes and longer linear end-to-end automated synthesis of pharmaceutical compounds.

The researchers tested their technique on a cancer-inhibiting molecule, prexasertib, because of its ability to bind to the solid resin used as a support material. Their experiments showed a 65% yield after 32 hours of continuous automated execution. This is an improvement over the current method of producing prexasertib, which takes about a week and requires a six-step manual process and purification procedure to achieve 50% yield.

The new method also allows for synthetic modifications early in the process, which allows for greater structural diversification compared to traditional methods that only allow for late diversification of a molecule's common basic structure. Using a computerized chemical recipe file, the team was able to produce 23 molecules derived from prexasertib. The derivatives produced are molecules with parts of the molecular structure that differ slightly from the original molecule.

"The ability to easily obtain these derivatives is crucial in the drug discovery and design process, as understanding the relationship between the structures of the molecules and their activities plays an important role in selecting promising clinical candidates," says Associate Professor Khan.

Creating new opportunities for drug development

The NUS team plans to demonstrate the versatility of its SPS-flow technique by conducting further research on best-selling pharmaceutical molecules.

"Our new technique provides a simple and compact platform for automated on-demand synthesis of a drug molecule and its derivatives. We estimate that 73% of the top 200 selling small molecule drugs could be produced using this technique," said Assistant Professor Wu.