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3rd November 2013 @ 23:53

The team want to synthesise some amides based on the data from the CRO on the series four triazolopyrazines. Some synthesis data on known compound MMV670652 was available from the CRO, however, experimental procedures are not available for the amides (example below and here).

 

Patrick Thomson proposed this route on his blog and Github:

 

Sabin Llona-Minguez suggested a synthesis that started from 2-chloro-6-methylpyrazine 18 (£30/g Apollo) which could be oxidised to form 14 in a single step. 

The advantage to Patrick/Sabin's route is that the chemistry could all be performed by students in an undergraduate teaching lab, which might be an ultimate aim for this route. Patrick also highlighed that compound 13 might not be readily available commercially, which could make Sabin's suggestion more attractive.

Joie Garfunkle's elegant proposal would allow the amides to be synthesised by divergence from a common intermediate used in the synthesis of other series 4 compounds. Joie's suggestion was to use Pd-catalysed carbonyation of common intermediate 2 to furnish the methyl ester 19, which could then be transformed into the desired amide.

Patrick Thomson suggested that a collaboration with a group at the University of Edinburgh (his own institution) who specialise in high pressure carbon monoxide reactions could help to develop synthesis via carbonylation of common Cl-intermediate 2.

Update 14th Nov 2013

Joie Garfunkle analysed the weekly reports from the CRO and deduced a common route used for the synthesis of amide compounds, see below:

This route contains several analogies to a suggested improvement to the synthesis of the triazolopyrazine core by Stefan Debbert when he cited an ACIE paper that employs Chloromamine-T as oxidant in combination with 2-MeTHF solvent rather than CH2Cl2 and PIDA (DOI: 10.1002/anie.201001999). The ACIE paper also employs a Pd-catalysed coupling of an aldehyde derived hyrazone with a 2-chloropyrazine prior to oxidative cyclisation.

This route also demonstrates the importance of starting material 14 - a commercial source or cheap/quick synthesis is required. Additionally, it suggests that Patrick's route could be problematic as the hydrazine may react with the carboxylic acid in preference to displacement of the chloride. References for each of the steps need to be found but so far this route looks quite robust.

I still think that carbonylation is the most attractive route long term as it makes use of common intermediates. However, if optimisation is required then it might be quicker to go for a route involving more steps if they can a) be performed by undergraduates and b) require less time spent on reaction improvement.

What do you think of the propsed routes? If you have experience with similar syntheses or you would like to suggest a new one, please do so by posting on Github, facebook or commenting below. Alternatively, (although we would prefer to avoid email) email opensourcemalaria@gmail.com and one of the team will post your idea to GitHub.

Cheers, The OSM team

 

Attached Files
Sabin.png
Intermediate 2.png
MMV670652.png
amide and orig.png
Carbonylation.png
Amide synthesis_JG_OSM_Blog.png
Amide synthesis_JG_OSM_Blog.cdx
Amide synthesis_JG_OSM_Blog.png
Comments
Re: Synthetic Plan for Series 4 Amides by Alice Williamson
4th November 2013 @ 22:58
Comments from Jochen Robert Brandt (PhD) who posted to my personal facebook page when I shared the OSM post:
'Compound 11 has a Texas nitrogen ;)'
and then
'It won't let me comment below your post, so just a quick write-up from me: I would try to get to compounds 2/17/19 without the Ar group; that could make the synthesis easier. I bet that Baran's radical Minisci conditions would arylate in the desired position. Look at Fionn's (AEW edit - Fionn O'Hara, a postdoc that both Jochen and I completed our PhD with in the Gaunt Group and this is a paper that she published with Phil Baran during her postdoc) recent JACS paper for details on influencing the selectivity. http://pubs.acs.org/doi/pdf/10.1021/ja406223k Alternatively, using the Ester of 19 to direct a cyclometalation could also work.
and then
'Sorry for spamming: I don't see the transformation from 16 to 17. You break a C-N bond (N-Ar) and then form a C-C bond (C-Ar) using DCM (the only C1 source in the conditions)? There's no citation for that step in the blog post...'