3) Complete synthesis of key pyridine carboxylic acid

[alintheopen]

Following the online meeting the team decided to put the carbonylation approach to the synthesis of the amides (using the same intermediate synthesised for MMV670652) on hold. Reasons - the CRO weren't successful in their approach and perhaps now is not the right moment to invest time in method development rather than rapid synthesis of analogs.

Instead, the synthesis of the key pyridine carboxylic acid (1 on the slide).

[alintheopen]

Sydney have ordered 5g. Is @patrickthomson working on this? @sdebbert will update on progress according to the scheme shown on the slide.

[PatrickThomson]

We have a group here in edinburgh who do some carbonylation, but given the CRO attempts and multiple routes to "1" already, I'll only work on this if it's highly desirable and only then after my two students have finished and I have more time (March/April).

[PatrickThomson]

From preliminary mass spectroscopy, it looks as if reacting 1 directly with hydrazine will also form an acylhydrazone from the carboxylic acid.

[mattodd]

Yes - is this acid being actively synthesised right now, rather than being bought? I'm guessing it is by Eduvie? @sdebbert ? @sabinllm ? Please verify/link to make sure. This Issue is tagged as "Being Synthesised Now" - is that correct? Related entry https://github.com/OpenSourceMalaria/OSM_To_Do_List/issues/101

[sabinllm]

The chemical store at SciLifeLab is up an running again. I will give it a go, starting from the methyl-pyrazine.

[PatrickThomson]

Yes, Eduvie has made several grams of 1 via the N-oxide/chlorination route. The mCPBA is probably the expensive link in the chain. Even if Sabin's procedure uses chromatography it'll be better.

[mattodd]

Great! Happy to post the work to the lab notebook? Alice has made a super easy-to-use guide that others have already gone through quickly. All How-tos are listed here: http://malaria.ourexperiment.org/osm_logos_and_templ/group/How%20To

On 17 January 2014 07:54, sabinllm notifications@github.com wrote:

The chemical store at SciLifeLab is up an running again. I will give it a go, starting from the methyl-pyrazine.

— Reply to this email directly or view it on GitHubhttps://github.com/OpenSourceMalaria/OSM_To_Do_List/issues/121#issuecomment-32545876 .

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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[mattodd]

Great, Patrick. Could you just link to an ELN entry or two by editing the above, and I'll delete this comment.

On 17 January 2014 08:05, PatrickThomson notifications@github.com wrote:

Yes, Eduvie has made several grams of via the N-oxide/chlorination route.

— Reply to this email directly or view it on GitHubhttps://github.com/OpenSourceMalaria/OSM_To_Do_List/issues/121#issuecomment-32546820 .

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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[mattodd]

Steven Oliver (http://uk.linkedin.com/pub/steven-oliver/1/424/978) from Merck emailed to suggest the following:

"Carry your acid as a furan to the end and blast open with permanganate or RuCl3/NaIO4 in the final step. Depending on your Ar group, may trash your compound, but could be quick to try. The heterocycle itself should be stable enough. Would have to start from the following compound: ClC1=NC(C2=CC=CO2)=CN=C1. Should be an easy Suzuki to make it from the 2,6-dichloro.

If you want to stick with the carbonylation route, I’d recommend reading: JOC, 2008, 7096 (http://pubs.acs.org/doi/abs/10.1021/jo800907e). You probably need to use an alkyl substituted bis-phosphine ligand as described in this paper for this coupling. The phenoxide product is also probably even more useful to you than the acid you’re trying to make, because it can obviously get you to your amides directly."

Also posted on the original post: http://malaria.ourexperiment.org/uri/49d

[mattodd]

Muneer Ahamed (https://www.facebook.com/ahamed.muneer.3), formerly of the Todd group, says on Facebook "Why not CO2? which will open up lot of new possibilities. http://dx.doi.org/10.1021/ja303514b and http://dx.doi.org/10.1021/ja803435w. May be you are aware of this."

[sabinllm]

I will attempt to obtain these intermediates, all useful for further functionalization.

[mattodd]

That's awesome Sabin - any chance you could start an Issue for a molecule you're making and tag it with "Being Synthesised"? See this link for why: http://malaria.ourexperiment.org/osm_logos_and_templ/8576/Maximising_Benefit_from_this_ELN_and_Github.html

On 20 January 2014 05:42, sabinllm notifications@github.com wrote:

I will attempt to obtain these intermediates, all useful for further functionalization.

[image: untitled]https://f.cloud.github.com/assets/5659304/1950143/c917a3c4-8137-11e3-992f-23a057bbecdf.png

— Reply to this email directly or view it on GitHubhttps://github.com/OpenSourceMalaria/OSM_To_Do_List/issues/121#issuecomment-32715934 .

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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[mattodd]

Closing since data now on wiki. Discussed in March 2014 meeting (http://malaria.ourexperiment.org/osddmalaria_meeting_/9470) and the procedures are being collected together in #164 (compounds in this sequence have IDs OSM-S-147 through 150)