Synthesis of N-(3-chlorophenyl)-3-(4-(difluoromethoxy)phenyl)-[1,2,4]triazolo[4,3-a]pyridine-5-carboxamide

[jamiescott11]

The first target I will attempt to synthesise is compound 1, this belongs to the triazolopyridine series 4 compounds ( OSM series 4 info http://openwetware.org/wiki/OpenSourceMalaria:Triazolopyrazine_%28TP%29_Series ) . This has been chosen to investigate the influence of swapping the pyrazine for a pyridine core. The pyrazine analogue (OSM-S-202, http://malaria.ourexperiment.org/osm_procedures/9880/OSMS202.html ) gained relatively good results from screening by AstraZeneca for hERG binding.

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)

SMILES

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

[mattodd]

Great, Jamie - welcome aboard! It's great to have you working with us all.

So that people new to the project can get up to speed with where you are, try to include a couple of links/sentences of context, as well as a molecule code (SMILES and InChI) so that the page is machine-discoverable. So I'd recommend a link to the Series 4 wiki, ideally pointing out the relevant data, a link to the page for OSM-S-202 (assuming we made one) and then the SMILES/InChi codes. This allows people to check out the rationale for replacing the pyrazine with pyridine.

Also, the comment about hERG. I think we're seeing some issues with the amides. The cumulative data are here:

http://malaria.ourexperiment.org/biological_data/11081

The amides aren't great, but we're not sure if that's a logP problem. Poor aqueous solubility can frequently bring with it a hERG problem. Removing your N on that aromatic ring will worsen solubility, so I'd worry that you're headed for hERG nastiness. Any way you can improve solubility of the molecule with side chain tweaks? In data we just received for the most recent compounds evaluated (not posted yet - slight issue with one data point just being sorted out) we see that pyridines in the northeast aren't great. Any other way of getting the cLogP down to 3.5 or lower?

[jamiescott11]

Hi Matt, will update the posts shortly. Thanks for your help. Unfortunately we can't calculate the cLogP here at Edinburgh as Patrick informs me we don't have the software. Information on how to lower the cLogP through structural changes would be greatly appreciated though!

[mattodd]

Hi Jamie - don't you use Chemdraw for drawing your structures? That software can calculate a value. It may not be the best, but is what we've been using as an approximation to date.

On 17 October 2014 00:10, Jamie Scott notifications@github.com wrote:

Hi Matt, will update the posts shortly. Thanks for your help. Unfortunately we can't calculate the cLogP here at Edinburgh as Patrick informs me we don't have the software. Information on how to lower the cLogP through structural changes would be greatly appreciated though!

— Reply to this email directly or view it on GitHub https://github.com/OpenSourceMalaria/OSM_To_Do_List/issues/266#issuecomment-59445164 .

MATTHEW TODD | Associate Professor School of Chemistry | Faculty of Science

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[drc007]

Hi,

If you don’t have access to cLogP you could use the virtual computational chemistry lab. (http://www.vcclab.org)

Cheers

Chris On 17 Oct 2014, at 09:57, Mat Todd notifications@github.com wrote:

Hi Jamie - don't you use Chemdraw for drawing your structures? That software can calculate a value. It may not be the best, but is what we've been using as an approximation to date.

On 17 October 2014 00:10, Jamie Scott notifications@github.com wrote:

Hi Matt, will update the posts shortly. Thanks for your help. Unfortunately we can't calculate the cLogP here at Edinburgh as Patrick informs me we don't have the software. Information on how to lower the cLogP through structural changes would be greatly appreciated though!

— Reply to this email directly or view it on GitHub https://github.com/OpenSourceMalaria/OSM_To_Do_List/issues/266#issuecomment-59445164 .

MATTHEW TODD | Associate Professor School of Chemistry | Faculty of Science

THE UNIVERSITY OF SYDNEY Rm 519, F11 | The University of Sydney | NSW | 2006 T +61 2 9351 2180 | F +61 2 9351 3329 | M +61 415 274104 E matthew.todd@sydney.edu.au | W http://sydney.edu.au/science/chemistry/research/todd.html | W http://opensourcemalaria.org/

CRICOS 00026A This email plus any attachments to it are confidential. Any unauthorised use is strictly prohibited. If you receive this email in error, please delete it and any attachments. — Reply to this email directly or view it on GitHub.

[jamiescott11]

An update on progress so far toward synthesis of this compound:

The first reaction (http://malaria.ourexperiment.org/triazolopyrazine_se/11131/) went very smoothly giving the amide in 97% crude yield ( very minor impurity ).

Trying to then replace the chlorine atom with hydrazine proved difficult giving pure product with low yield (http://malaria.ourexperiment.org/triazolopyrazine_se/11188/) . Or high yields with impure products (http://malaria.ourexperiment.org/triazolopyrazine_se/11200/).

It would appear that hitting the amide with high concs of the hydrazine causes more impurities. At the moment several of the flasks containing pure product and impurities will be combined and put through a column to gain the final product pure.

From the small amount of pure product gained in JS 5-3 , the condensation reaction was performed - (http://malaria.ourexperiment.org/triazolopyrazine_se/11192/) . The final product was impure but did contain the desired compound, column chromatography would have been performed but for the lack of actual material , ~25 mg starting material. Likely that doing a column would just result in loss of product.

So at the moment with the synthesis of the molecule above, optimizing the reaction with hydrazine is on-going. After that has been achieved the condensation will be carried out again and then purified.

[jamiescott11]

After finally realising that ClogP can be calculated by ChemDraw i identified this compound as a potential target :

seems to have nice values and the synthesis is very similar to the initial target shown above. Any thoughts on this target ? or any others that might be interesting to synthesise ?

[mattodd]

How's this strand going? The amides in series 4 seem to be a bit more susceptible to AO oxidation than the ethers, so this means we ought to prioritise the ethers. http://malaria.ourexperiment.org/biological_data/11208 However, this compound is a nice control point for your ether compound. It also serves as a nice comparison with MMV670246 (structure in the post I just linked to). So you're still pursuing?

[mattodd]

Actually @alintheopen would you recommend -Cl, -OCF3 or -OCHF2 in the para position of the phenyl ring rather than -CN? Jamie you might still have time to change that?

[PatrickThomson]

This compound came back inactive 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 ditto for this, obv #267