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Already available anilines for amide formation #151

tscmacdonald opened this Issue Feb 11, 2014 · 7 comments

4 participants


While we're waiting for our new amines (issue #123), I had a look through the inventory for anilines we already have that may be worth trying. Here's a list, together with clogP values of the final triazolopyrazine (as calculated with chemdraw):
available anilines 11

Thoughts on these? I think the 2-methyl-3-chloro aniline might be interesting, as we know the 3-chloro is active. Also, it seems to have a lower clogP than the unmethylated version, which is surprising. Can anyone tell me why? Is this just an artefact of the "c" part of logP?
Also of potential interest are the brominated compounds. They're a bit greasier than the chlorinated ones, but not excessively so (I suspect they might be metabolised more quickly, though).

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mattodd commented Feb 11, 2014

The top row compounds are interesting. The meta/Me can be compared with what you've already made and the para/N-Me is a good comparison with MMV670246 (inactive) and MMV669105 (active) - see amide section on wiki ( If you can find a reference that says that aromatic bromides are OK as drugs then we can explore the bottom set, but one must ask why we see such structure so rarely?

My offline suggestion of using pyrrolidine was a bad one - been done: MMV669022 (inactive).


I think I might make the 2-methyl-3-chloro compound, as it'll be an interesting comparison if nothing else (although I suspect the sterics might disrupt whatever the chlorine seems to be binding to). The parachloro N-Me might be worth looking into, but given the inactivity of the parachloro compound I don't know if it's worth bothering with; waiting for N-Me compounds of primary amines we know to work is perhaps more sensible.

I haven't found much information on aromatic bromides as drugs, which seems to confirm that they're generally a bad idea. For the sake of learning if nothing else, can anyone else add to that?

Finally, it occurred to me that this series of aryl chloride amides might cause troubles when we try to couple a hydrazone with with the pyrazine chloride, but not the aryl chloride on the amide linkage:
Has this been considered?


Bromphenriramine, bromfenac, mebrofenin, flusalan, bromazepam, brimonidine... they all contain aromatic bromides. There's nothing "particularly" wrong about adding a bromine to your molecule, aside from adding MW and logP

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...well done, self. So, our desired product is definitely favoured (although I'm not sure how much by; some playing with temperatures might be in order). I think I'll start making the 2-methyl compound tomorrow. Issues going up!

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mattodd commented Mar 26, 2014

This analysis is complete, and a link to this issue has been installed in the wiki
so closing.

@mattodd mattodd closed this Mar 26, 2014
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