Synthesis of 4-(5-(2-chlorophenethoxy)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)benzonitrile

[jamiescott11]

The second compound that I will be attempting to synthesise is shown below. This belongs to the triazolopyridine series 4 compounds (OSM series 4 info - http://openwetware.org/wiki/OpenSourceMalaria:Triazolopyrazine_%28TP%29_Series) The pyrazine core analogue (OSM-S-189) also achieved nice results from the hERG screening by AstraZeneca.

SMILES :

O=C(NC1=CC(Cl)=CC=C1)C2=CC=CC3=NN=C(C4=CC=C(OC(F)F)C=C4)N32

InChI String:

InChI=1S/C20H13ClF2N4O2/c21-13-3-1-4-14(11-13)24-19(28)16-5-2-6-17-25-26-18(27(16)17)12-7-9-15(10-8-12)29-20(22)23/h1-11,20H,(H,24,28)

[mattodd]

Ditto on links to context, e.g. wiki, other Github posts where we plan which compounds to make. And include the strings. Just edit the entry above, no problem.

Ditto also comment on solubility. What's the cLogP? We ought to aim for 3.5 as an upper limit, though in this case we are asking a specific question about the influence of a particular moiety, so the rule can be bent in these cases.

[jamiescott11]

An update on synthesis towards this molecule:

The first stage of synthesis involved taking di-chloropyridine and treating it with hydrazine to give the hydrazine derivative. This worked well after a few attempts at optimising conditions. (http://malaria.ourexperiment.org/triazolopyrazine_se/11161/)

The next stage involved forming the hydrazone in a condensation reaction (http://malaria.ourexperiment.org/triazolopyrazine_se/11177/) . This turned out nicely forming a crude solid that was used in the next stage.

The cyclisation with PIDA seems to be a bit of a stumbling block though (http://malaria.ourexperiment.org/triazolopyrazine_se/11191/) . It should work, this makes me think that perhaps the wrong isomer has been formed in the previous reaction. However, NMR seems consistent with the correct product being formed, perhaps purification should be done before the cyclisation reaction?

In order to solve the problem the same reaction was set up using chloramine-T rather than PIDA, the results of this will be analysed tomorrow : http://malaria.ourexperiment.org/triazolopyrazine_se/11203/

If anyone knows of problems cyclising with PIDA or has any ideas for me, please feel free to post them :+1:

[mattodd]

Hi Jamie - this is still a target, right? http://malaria.ourexperiment.org/triazolopyrazine_se/11311/Synthesis_of_452chlorophenethoxy124triazolo43apyridin3ylbenzonitrile_JS_131.html (though there's a mistake in that scheme I think)

Just want to update people on where we are, and which molecules are being made. Based on the Aldehyde Oxidase data we received from Pfizer, this compound is a good one to go for, so still very useful for the project.

[jamiescott11]

Hi Mat,

Yes indeed this is still a target! Synthesis has been successful up until the last step so far. This will be completed after Christmas! I will be updating the progress of synthesis soon. Yes I also noticed the error, I will correct it!

On Wednesday, 17 December 2014, Mat Todd notifications@github.com wrote:

Hi Jamie - this is still a target, right?

http://malaria.ourexperiment.org/triazolopyrazine_se/11311/Synthesis_of_452chlorophenethoxy124triazolo43apyridin3ylbenzonitrile_JS_131.html (though there's a mistake in that scheme I think)

Just want to update people on where we are, and which molecules are being made. Based on the Aldehyde Oxidase data we received from Pfizer, this compound is a good one to go for, so still very useful for the project.

— Reply to this email directly or view it on GitHub https://github.com/OpenSourceMalaria/OSM_To_Do_List/issues/267#issuecomment-67315972 .

[jamiescott11]

Hi all, just getting back into the project again after christmas break. I have successfully synthesized the ether compound shown at the very top of the page : http://malaria.ourexperiment.org/triazolopyrazine_se/11415/Synthesis_of_452chlorophenethoxy124triazolo43apyridin3ylbenzonitrile_JS_191.html

Going to send it for testing soon.

If you have any suggestions as to what other types of ethers to incorporate into this molecule then please let me know as I have some time left to synthesise a few derivatives now that i have the experimental procedures nailed.

[mattodd]

Wow, Jamie, that's great news, both on this compound and on #266 . Congrats! If you're sending for testing try to group your compounds together with any others that might need to be evaluated from your lab (minimises inter-assay variability). I'm guessing if Dundee are happy to test, then they will use similar control compounds to those other labs that have tested Series 4 compounds. Browse through recent Series 4 evaluations in the relevant ELN to check this: http://malaria.ourexperiment.org/biological_data

For the NMR spectra, and any other characterization in the lab notebook, are you able to post the raw data files in addition to the png files? It's great if we can post as much raw data as possible in addition to the human-readable pictures.

As for other ethers - might you be able to make the analogs of any of the current most-wanted compounds?

http://malaria.ourexperiment.org/the_osm_blog/11379/The_Christmas_2014_Open_Source_Malaria_Shortlist.html

That'd be pretty nice to compare.

[PatrickThomson]

These compounds came back about 10 times less potent than the series 4 analogues as per: http://malaria.ourexperiment.org/biological_data/11127/Evaluation_of_some_remaining_series_3_compounds_and_series_4_pyridine_analogues.html

Closing.

[mattodd]

Hi @jamiescott11 @PatrickThomson could you please quickly check whether the data for this compound is in the spreadsheet at https://docs.google.com/spreadsheets/d/1Rvy6OiM291d1GN_cyT6eSw_C3lSuJ1jaR7AJa8hgGsc/edit#gid=510297618 and whether the compound has been added to the wiki (http://openwetware.org/wiki/OpenSourceMalaria:Triazolopyrazine_%28TP%29_Series) in the strings section but also in the main body of the series so that the result is highlighted? If not, could one of you please start an Issue for these tasks so we don't forget to incorporate these new data?

[alintheopen]

Hi, I've added to Wiki and to G Sheet. Still need to generate MMV number but closing for now as we need to start a new issue on OSM-E numbers and MMV generation.