Synthesis of the Amide Linked Series
Route 1: Initial Amide Bond Formation:
It was decided (GHI121, GHI101) to pursue a route involving initial amide bond formation with the chloro-pyrazine acid shown below (OSM-S-150). This molecule is commercially available but is expensive, but there are now routes to it in the lab. Patrick and Inga planned this synthesis and then Inga completed it, as has Eduvie using the same approach (data missing in the lab notebook, but reports are available). [http://malaria.ourexperiment.org/triazolopyrazine_se/9189 Tom scaled up the Patrick/Eduvie/Inga approach and has been completed on a 15 g scale in four steps: 1 2 3 4. An assessment of the relative costs of synthesis vs. purchase was discussed (GHI163, GHI164) but not properly completed.
Sabin has successfully demonstrated an elegant alternative route to the starting pyrazine acid in one step from the methyl precursor (data).
For the subsequent coupling of the pyrazine acid with an amine, Tom and Alice have identified reliable conditions for the amide coupling using T3P that worked much better than an attempt to go via the acid chloride. There was an analysis of commercially-available primary and secondary amines that could be employed, the likely physical properties of the resulting compounds as well as an analysis of those amines available locally.
Hydrazone synthesis was surveyed by Inga) and is working reliably. (Discussion about making hydrazone first, then coupling with pyrazine: GHI152) Following work by Jo Ubels on optimizing the cyclization step for the ether series (above), hypervalent iodide PIDA may now be used to form the triazolopyrazine, as in this example.
Route 2: Carbonylation An efficient alternative synthetic approach would be to use the same chloro-triazolopyrazine core as for the ether series (above) and invent a new carbonylation method to introduce the amide as the final sequence (GHI101, GHI126, Inga's lit survey, Alice's original appeal for a collaborator, a summary of the associated discussion, Alice's framing of the relevant reactions (GHI205) and Tom's lit survey. The most recent results (GHI259) indicate there is a significant competing SNAr reaction when an alcohol was used as a nucleophile. The most recent reaction to date in this series was in Sept 2014.