Research updates on two potential anti-malarial drug candidates

11 Apr
Published by JimCronshaw

Jim Cronshaw here. Research on my side of the Todd Lab into the synthesis of two new anti-malarial drug candidates is progressing well. As a new honours student in the Todd group, unfamiliar with the ways of a research lab, I found myself inundated with the volume of new information coming my way, though I’ve settled in nicely now. This post is intended to summarise the work I’ve completed so far.

At this time, I’m but an NMR spectra away from confirmation that I’ve made my first anti-malarial drug candidate (the triazolourea singleton). The synthesis of this molecule (Figure 1.) has been fairly straight-forward, though a few time consuming bumps were encountered along the way. Attaching a benzyl protecting group to the sulfur atom on the side of the triazole proved to be an early hassle. Benzyl bromide and the thiol proved to be quite unreactive, even when benzyl bromide was in 10x excess, but when a base (potassium carbonate) was added to the reaction it proceeded in 50-60% yield. Following the protection, replacing the acidic hydrogen on the triazole with urea proved to be an easy task, with this reaction proceeding in up to 92% yield.

Figure 1. Triazolourea Singleton Synthetic Route

The second bottleneck in this synthesis was a chlorination reaction. Safety considerations and apparatus design and setup consumed a fair portion of time, though I remained proud of apparatus myself and Paul setup (Figure 2.).

Figure 2. Chlorination Apparatus

The sulfonyl chloride that was produced within this apparatus was far more stable than conventional wisdom might dictate. The 1H NMR spectrum alluded to earlier is what I need to confirm that this sulfonyl chloride was able to withstand an aqueous workup (as suggested by the literature). The second batch of sulfonyl chloride which I synthesised last week will, once an NMR spectrum is run, be ready to be transformed into analogues of this triazolourea singleton.

Research on the amino-thienopyrimidine series is not progressing quite as quickly as the triazolourea singleton.  Whilst waiting for certain chemicals to arrive I attempted to synthesise ethyl-3-aminothiophene-2-carboxylate (Figure 3.). The cyclisation of the ‘thiophane’ using ethoxide and methoxide reagents failed to lead to cyclisation, so an attempt was made using titanium tetrachloride and a base. This reaction did lead to the cyclisation to the thiophane, which was subsequently lost on a column. One success in this regard was that the lab was stunk up several times with thanks to the odourous reagents I was using.

Figure 3. Thiophene Synthetic route

Once the aminothiophene arrived from Alfa Aesar I set about synthesising the thienopyrimidine moiety found in this series (Figure 4). Sadly, it is also proving to be difficult to make, with the 6-membered heterocycle not fully cyclising under a range of conditions (Table 1), forming a half cyclised heterocycle (Figure 5).

     Figure 4                    Figure 5.

Experiment Yield
JRC 8-1 15% (crude mass)
JRC 8-2 28% (crude mass)

JRC 9-1

79% (crude mass)

Table 1: Experiments and results all leading to the half cyclised heterocycle seen in Figure 5.

The questions going foward now come down to: What analogues of the triazolourea singleton would be best to make, and; What conditions will complete the cyclisation of the thienopyrimidine moiety?

Links to my online lab notebooks are found below, and any feedback is welcomed.

Triazolourea Singleton Lab Notebook

Amino-thienopyrimidine Series Lab Notebook

Jim Cronshaw (11/04/2012)