Synthesis of 6-chloropyrazine-2-carboxylic acid

[sabinllm]

[sabinllm]

Clean conversion and the yield is decent (see experimental procedure in the blog). The starting material is relatively cheap and readily available (Apollo, 1g, £30.00)

http://malaria.ourexperiment.org/osm_procedures/8901/Preparation_of_6chloropyrazine2carboxylic_acid.html

@alintheopen or @mattodd I believe this might not be the place for this post, could you please move it to #121 ? Cheers.

[mattodd]

That's great. Could you insert a link in the above to the relevant eln post? I can't see it. Ah - found it here: http://malaria.ourexperiment.org/osm_procedures/8901/Preparation_of_6chloropyrazine2carboxylic_acid.html. That location is intended for summaries of procedures only. Would you mind hiding it? I think you need to log in to do that. You probably can't delete it outright, but making it not appear should work. Then re-post in the Series 4 ELN? here: http://malaria.ourexperiment.org/triazolopyrazine_se. Thanks Sabin

[mattodd]

It's really very good that this works, Sabin - a neat transformation. It's 75+% on a 50 mg scale. Do you have an idea of what you want to do next? Some possibilities:

1. Scale-up to a gram to check?

2. Based on the general synthetic approaches we've talked about (see here for one place where the relevant slide is: malaria.ourexperiment.org/the_osm_blog/8480) we need to use the molecule you've made in some amide couplings. @tscmacdonald is going to be trialling this Monday/Tuesday we think - Tom's just joined the project in my lab here. We need decent conditions for that coupling.

3. At the moment the synthetic scheme involves making the amide at an early stage - i.e. next. Given that that is our point of diversity, that seems a shame. It's done because it's assumed that the coupling with the hydrazone will be ineffective if the acid or an ester is present, but the amide should withstand it. @alintheopen and I were wondering about that. What if we converted the acid you've just made into a salt, and then try to attach the hydrazone at the Cl-substituted position?

So - a question for you, Sabin. What's your interest, and what do you have capacity for at the moment?

[sabinllm]

1. This was just a test reaction. Someone else in the team can scale it up if required.
   I was planning on keeping the methyl, building the heterocyclic core with a suitable RHS and introduce the diversity point as a final step. Not sure which RHS would be best to use, since -OCHF2 will probably react under strong acidic conditions. -CN or -Cl perhaps?

If this route does not work, we can go the long way.
I am quite busy at the moment, but I will keep you posted of any new developments.

2. For that amide coupling I would use amine(1.1eq)/T3P(2.2eq)/Et3N(2.5eq) in EtOAc or DCM, rt, overnight. Wash organic layer with bicarbonate and dil. HCl.

3. I cannot hide/delete post http://malaria.ourexperiment.org/osm_procedures/8901/Preparation_of_6chloropyrazine2carboxylic_acid.html Any suggestion?

4. Could you send me the login details required to edit the master file?

[tscmacdonald]

(I'll make a separate issue for this when I've actually done something)
@sabinllm: I'm still very new to this, but was planning on doing an acyl chloride SOCl2-based coupling to form the amide, as the rest of the structure looks fairly robust. Would you advise against that?

[sabinllm]

@tscmacdonald There's absolutely nothing wrong with using SOCl2. Everyone has it's own favourite amide coupling method ;) Just make sure you azeotrope residual SOCl2 with toluene, that would be my only advise.

[mattodd]

Well, other people have recently been suggesting T3P to me for other
reactions so perhaps we should give it a try here. For the first attempt
let's go with what we have to hand, but we can think of other reagents if
need be. Tom: Paul Ylioja and others have used thionyl chloride a fair
amount in previous OSM amide bond formations - make sure you scan previous
lab notebooks to read through some of that work to pick up the kinds of
techniques that Sabin just referred to.

On 2 February 2014 22:02, sabinllm notifications@github.com wrote:

@tscmacdonald https://github.com/tscmacdonald There's absolutely
nothing wrong with using SOCl2. Everyone has it's own favourite amide
coupling method ;) Just make sure you azeotrope residual SOCl2 with
toluene, that would be my only advise.

Reply to this email directly or view it on GitHubhttps://github.com//issues/146#issuecomment-33897667
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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

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This email plus any attachments to it are confidential. Any unauthorised
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[mattodd]

Hi @sabinllm for the new write up (http://malaria.ourexperiment.org/triazolopyrazine_se/8929) could you please change the OSM number? As this is the first KI compound, the number should be "1". We've also been tending to use city letters, i.e. this would be ST for Stockholm, rather than KI for the institute. Up to you, though, if you like KI instead. But the number needs to be "1". Thanks for this - if you log back in as yourself you should be able to alter the title of the post without trouble. We can't do that for you.

[alintheopen]

I have tried an EDCI, HOBt coupling method and also a T3P method. The compound is beautifully clean and the reaction worked a treat so I would suggest following this prep: http://malaria.ourexperiment.org/uri/4e3. Please excuse the fact that my spectra aren't uploaded just yet, there was a delay in transfer from the 400 MHz NMR today, so I'll process and upload tomorrow. As stated at the top of the experiment, in future reactions I would used 1 equiv of the amine or a very slight excess as I had problems separating aniline and amide on a column despite different Rfs.

[mattodd]

That's great - assuming the NMRs show that the product's the product :) .
Looks experimentally simple, and without pyridine.

On 9 February 2014 20:07, alintheopen notifications@github.com wrote:

I have tried an EDCI, HOBt coupling method and also a T3P method. The
compound is beautifully clean and the reaction worked a treat so I would
suggest following this prep: http://malaria.ourexperiment.org/uri/4e3.
Please excuse the fact that my spectra aren't uploaded just yet, there was
a delay in transfer from the 400 MHz NMR today, so I'll process and upload
tomorrow. As stated at the top of the experiment, in future reactions I
would used 1 equiv of the amine or a very slight excess as I had problems
separating aniline and amide on a column despite different Rfs.

Reply to this email directly or view it on GitHubhttps://github.com//issues/146#issuecomment-34569113
.

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

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.

[alintheopen]

Spectra are now uploaded.

[mattodd]

Hi @sabinllm - this synthesis was successful, and the data are in the lab notebook, so we're able to close this issue, correct?

[mattodd]

Data for this method in ELN (http://malaria.ourexperiment.org/triazolopyrazine_se/8929), and general methods to all the compounds towards this acid are being collated in #164 . Discussed in March 2014 meeting http://malaria.ourexperiment.org/osddmalaria_meeting_/9470 and summarised in wiki http://openwetware.org/wiki/OpenSourceMalaria:Triazolopyrazine_%28TP%29_Series#Synthesis_of_the_Amide-Linked_Series

Closing.