Advances in organic synthesis : expedient radiosynthesis of substituted indoles for pharmaceutical lead development within microreactors

Wahab, Ben

Abstract

Microreactors are miniaturised chemical reaction apparatus that exhibit excellent thermal control, accurate and predictable mixing, and improved safety when compared to classical batch chemistry. Better stoichiometry and reduced waste are also demonstrated when using microreactor systems for synthetic chemistry. The use of microreactors within applied organic synthesis is growing, with certain applications benefiting greatly from the ability to create small aliquots of highly pure materials in short time periods. One such niche of applied organic synthesis currently investigating the potential benefits of microreactor systems is that of radiochemistry for pharmaceutics and diagnostics.

Radiochemistry for pharmaceutics is the highly skilled chemical discipline of using radioisotopes in the synthesis of materials (such as drug leads) so as to make the materials traceable (via detection of radiation) when they are in vivo or excreted after metabolism within living organisms. The radiolabel is strategically deployed into a potential drug lead so that the progress of the drug and its metabolites can be traced around the body (in ADME / pharmacokinetics studies). This requires the use of small aliquots of highly pure radioactive materials produced rapidly and within rigorous safety protocols, and microreactor technology appears a novel and expedient way in which to achieve these synthetic goals.

Procedures have been developed to produce substituted indoles employing three different practical approaches (with the optimised systems capable of producing substituted indoles quantitatively at up to 20 mgh⁻¹ within a single microreactor), as well as further reacting the indoles in order to build larger molecules (by way of C3‐ bromination and N1‐ alkylation) utilising the well known indole pharmacophore as the core building block. The optimised bromination reactions were capable of producing 3‐bromoindoles quantitatively at up to 15 mgh⁻¹ per reactor. N1‐ reaction of the indoles was less successful and the implications are discussed; with the main problem being solubility of intermediates and products. In‐ line reactions are outlined, with an example of a coupled indolisation‐bromination reactor array capable of creating ethyl bromo‐1H‐indole‐2‐carboxylate from ethyl pyruvate (46 % across both steps). An investigation into the use of microreactors for radiosynthesis was conducted using [¹⁴C]‐labelled reagents as a test of system viability, and the implications are examined, and discussed with regards to future work and possible avenues in which to improve integration of microreactors for radiochemistry.

Citation

Wahab, B. (2010). Advances in organic synthesis : expedient radiosynthesis of substituted indoles for pharmaceutical lead development within microreactors. (Thesis). University of Hull. Retrieved from https://hull-repository.worktribe.com/output/4217285

• Thesis Type: Thesis
• Deposit Date: Nov 6, 2015
• Publicly Available Date: Feb 23, 2023
• Keywords: Chemistry
• Public URL: https://hull-repository.worktribe.com/output/4217285
• Additional Information: Department of Chemistry, The University of Hull
• Award Date: Mar 1, 2010