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18th February 2014 @ 23:19

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Synthetic chemistry for OSM in Jan/Feb 2014 has been focussed on two main targets in Series 4 (the triazolopyrazines) - the ether linked compounds and the amide compounds, shown below along with specific examples of known, potent compounds in each series.

Ether and amides in Series 4

The ether series is interesting because there are many active compounds with this generic structure, as can be seen from browsing the wiki. MMV670652 shown above was evaluated as a racemate, and Alice has been attempting a resynthesis with a view to the separation of enantiomers to evaluate the properties of the active enantiomer. Here's the original issue for the synthesis of compound MMV670652, as well as the first discussion of how we might separate the enantiomers, and a newer issue created after a recent meeting.

One of the complexities of the synthesis is the difluoromethylation step (original summary of problem is here). It's not clear that this group is needed - there are related structures that could be tried, and compounds lacking this group (and indeed the whole stereogenic centre) are still active. The key issue Alice has been wrestling with has been the union of the two halves of the molecule - an alcohol (2) and the heterocycle chloride (7), for example in this most recent reaction. The reactions don't appear to be proceeding cleanly - this reaction also proceeded in very low yield for the CRO that first did it - report was posted here, but is also attached to this post. The other difficulty is that the synthesis of the alcohol fragment, via 1requires a source of cyanide, and we're currently out of stock in Sydney. It might therefore be sensible to trial simpler alcohols (i.e. ArCH2CH2OH) in this step and assess the relative importance of obtaining exactly MMV670652 in the short term.

Synthesis of Series 4 ethers

Another synthetic challenge being addressed is the efficiency of the cyclization to give 7 from the precursor 6. This has been achieved, but not in the ca. 50% yields reported by the original CRO. A new Honours student in the group, Jo Ubels, is now looking at this step to work out what is going on and how we can make this reaction more efficient and this has been the subject of research by an Edinburgh student working with Patrick Thomson, Devon Scott. There appear to be significant issues to do with solubility of the material throughout the reaction. The synthesis of the precursor 7 is straightforward.

The amide series is interesting because there are potent compounds with such a structure that appear to have desirable PK properties, but potency needs to be enhanced. Following an analysis of commercially-available primary and secondary amines that could be incorporated, as well as those we had to hand in the building, synthesis was started (scheme below). It has been noted that an efficient approach here would be to use the same intermediate as for the ether series (7, above) and invent a new carbonylation method (here is Inga's lit survey, Alice's original appeal for a collaborator and a summary of the associated discussion. This is something that another new Honours student, Tom Macdonald, will start to look into experimentally. For the moment, however, it was decided to pursue an alternative route wherein the extra carbon atom is incorporated from the start using acid 9. This molecule is commercially available but is expensive, but we now have routes to it in the lab. Inga has planned and then completed a synthesis of it, as has Eduvie using the same approach (though we currently don't have all the data for these experiments). Sabin has successfully demonstrated his very nice alternative route to this coupound in one step from the methyl precursor. Tom is now scaling up the Eduvie/Inga approach to bring through more material. Tom and Alice have identified a clean coupling reaction to give the amide 10, and Alice has seen excellent preliminary results in the coupling of a related amide with hydrazine, condensation with aldehydes (this chemistry has been surveyed by Inga) and is now attempting the crucial cyclization reaction to give what would be the final amide. Should this work, we would then have access to a wide range of new members in the amide series. Here is one of Tom's current "Being Synthesised Now" Github posts in this series. Here is one of Alice's where she is altering the northeast part of the molecule.

Route to Amide-linked series

We've been lucky to have Debra come in and help maintain the Series 4 wiki, by making sure that all the data inherited at the start of the project are now included in the main page. You can see her handiwork in this section.

In addition to Series 4, we've been tying up Series 3 (the aminothienopyrimidines) with a view to publishing. Carmen Tran has been making a number of "halves" of the required compounds for this series during her summer project here in Sydney: the amino thienopyrimidine core and the boronic esters that will couple to them. She's starting to carry out the Suzuki couplings of these fragments to gain the final compounds needed for evaluation. What's left from that set would then just be the final "twisted" compounds (24 and 25 in the previous link) containing methyl groups that ought to help with solubility. The writing up of the Series 3 paper has been boosted by Jimmy Cronshaw coming in to collate data for all compounds made as part of that project, using our brand new procedure for adding compounds to the master list. Introduction of this system, which essentially differs from what we were doing before in that it assigns numbers to compounds that have been made but not evaluated, was found to be needed during the ongoing write up of the first OSM paper on Series 1, which is still continuing as a high priority.

(This post originally authored by Mat T) 


Attached Files
Example Targets.cdx
Example Targets.png
Route to Ether Linked.cdx
Route to Ether Linked.png
Route to Amide Linked.cdx
Route to Amide Linked.png
CRO Synth Series 4.doc