GU Project 1: Synthesis and reactions of 3-bromo-5-chloro-[1,2,4]triazolo[4,3-a]pyrazine

[mcoster]

GU Project 1 will focus on optimising the synthesis of 3-bromo-5-chloro-[1,2,4]triazolo[4,3-a]pyrazine and, if time allows, an exploration of the chemistry of this molecule, as outlined below:

The project is being undertaken by Cohan, who is working in a lab with excellent access to analytical instruments (LC-MS, GC-MS) and variable temperature NMR, but is less well-equipped for organic synthesis. Cohan is interested in analysing reactions in detail with a view to optimising yields, and minimising reaction and purification times.

Links: AEW 85-x EGT 225-1 JT 2-1 JT 8-1 Earlier discussion of Griffith Uni OSM contributions - GHI #508 Jasper Tyler's halogenation project - GHI #493 OSM Synthetic Branches - OSM-BrCl

Files: Cohan - synthetic plan.zip

Strings: 3-bromo-5-chloro-[1,2,4]triazolo[4,3-a]pyrazine InChIKey=UGKMQVWBWSZEBB-UHFFFAOYSA-N InChI=1S/C5H2BrClN4/c6-5-10-9-4-2-8-1-3(7)11(4)5/h1-2H ClC1=CN=CC2=NN=C(Br)N12

(edit: added zip, fixed compound name in text, but not in title, fixed scheme - was missing pyrazole N's) (edit 2: added compound strings)

[MFernflower]

Love the use of the microwave! if time permits what would you replace the Br atom with? I would think simple N-linked cycles like morpholine, azetidine, pyrrolidine, etc? @mcoster

[mcoster]

Yes, definitely interested in N-linked hetercycles and seeking feedback/suggestions about what to aim for.

[MFernflower]

Azetidine and morpholine seem like good choices - @mattodd Got anything else to chime in with?

[mattodd]

These are the Norcross compounds. Still high-value, and the primary reason this chemical need was developed. Anything non-aromatic that helps solubility would be good. Aromatic groups in that northeast position need something in the para position for potency. Given that the N-linked groups would have a different positioning, I'd expect the same requirement not to be there for any cyclic aliphatics we include.

[juliasmith2]

We are Julia and Guadalupe from the Broadrup Lab at Haverford College. Based on our NMR analysis we believe we have synthesized 3-bromo-5-chloro-[1,2,4]triazolo[4,3-a]pyrazine. If interested, our lab notebook is here: http://malaria.ourexperiment.org/synthesis_of_3_brom We are interested in exploring possible chemistry with this intermediate.

[drc007]

@juliasmith2 Looking at the NMR it appears to have extra peaks?

[edwintse]

@juliasmith2 @drc007 It looks like there's still a bit of NBS (2.96) left so the yield might not be as high. Also some water, DCM, EtOAc, hexanes/grease and succinimide.

[MFernflower]

I wonder if it is worth doing the coupling on the impure product and then dealing with the garbage at a later step?

@edwintse

[rbroadrup-HC]

We can look at recrystallization when students return from August research recess to see if that may quickly remove some of the non-volatile impurities.

On Sat, Jul 29, 2017 at 12:10 PM, MFernflower notifications@github.com wrote:

I wonder if it is worth doing the coupling on the impure product and then dealing with the garbage at a later step?

— You are receiving this because you are subscribed to this thread. Reply to this email directly, view it on GitHub https://github.com/OpenSourceMalaria/OSM_To_Do_List/issues/518#issuecomment-318840932, or mute the thread https://github.com/notifications/unsubscribe-auth/AS409mcK_gId8sLvImGBemCoAp9flbSYks5sS1lvgaJpZM4OcRuF .

[mcoster]

Much belated update. Cohan worked hard at this project during the trimester, putting particular effort into developing chromatographic methods that allow following these early steps and determination of compound purity. As an aside, this experience sets him up well for his chosen Honours project next year, which is in the forensic chemistry area dealing with profiling of organic synthesis routes.

We did not have a chance to look at many of the original aims of the project. In our hands, step 2 - the acid-mediated reaction with triethyl orthoformate, did not give high yields or purity. Some preliminary results suggested that trimethyl orthoformate may be more productive, although this needs to be followed up and verified.

Below are Cohan's research report and poster that he presented for this project. I'll close this issue and any further efforts at Griffith will be reported in mew issues.

Triazolo Pyrazine Report_1.pdf

Draft Poster 2.pdf

[mattodd]

Thanks, great to get the reports @mcoster . We need, I think, a repository of these standalone student reports. I wonder if Figshare or something would be a useful backup? Or a labarchives ELN page? If Github itself, then I need to activate a repository for such things - reports, posters, any other docs. Some student reports are linked here, and you could add?

Separately, are there any key findings from the reports that could be extracted and added in to the synthetic chemistry section of the S4 wiki, e.g. here or related pages?

[mcoster]

@mattodd I think Figshare would be my first choice because I'm hoping to use it for non-OSM things in future, and it would be good for me to get started.

This first stab at contributing to OSM has given us some good experience with the chemistry and how to run this sort of project, but we don't have much to contribute to the actual science thus far. I am planning a post to summarise our findings and discuss our future plans. I'll link back to all these closed "GU Project" issues. Should I put our summary and future plans post up on "Series 4" or "OSM_To_Do_List"?

[mattodd]

If all related to Series 4 chemistry then I think on the Series 4 repo issue list. Sounds v good.

[mattodd]

One more "loose end" action. If you were able to install some link on the DKNYS page of the wiki (if it's not there already) that'd be very good. Just to ensure that none of the relevant effort towards a target is ever orphaned.

[mcoster]

Ah, good point!

On 4 Dec. 2017 2:42 pm, "Mat Todd" notifications@github.com wrote:

One more "loose end" action. If you were able to install some link on the DKNYS https://github.com/OpenSourceMalaria/Series4/wiki/Desirable-Compounds-Not-Yet-Synthesised page of the wiki (if it's not there already) that'd be very good. Just to ensure that none of the relevant effort towards a target is ever orphaned.

— You are receiving this because you were mentioned. Reply to this email directly, view it on GitHub https://github.com/OpenSourceMalaria/OSM_To_Do_List/issues/518#issuecomment-348859262, or mute the thread https://github.com/notifications/unsubscribe-auth/Aa-O5ANqQnlFYaR55ArRE1rNYuvDOVEWks5s83g_gaJpZM4OcRuF .

[david1597]

Thanks for updating and closing these points, @mcoster. Great to know the outcomes. I'd been looking back just this morning at all the 'Being Synthesised Now" issues and wondering where each was up to. Thanks!

[mcoster]

The DCNYS page of the wiki has now been updated. Thanks for the suggestion.

[mattodd]

Since this page itself wasn't in the DCNYS page, because it's methodology, I installed a link in one of the methodology pages for now. Also will upload reports to a github repo. Ideally the reports would also be available on the relevant student ELN?