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11th September 2013 @ 12:06

The team has received some experimental details used for the synthesis of a representative triazolopyrazine (11). I am planning to use this route as a basis for the synthesis of triazolopyrazine analogs but it would be great to hear any ideas about how to improve this synthesis. You can post comments below, send a tweet or a G+ post or as a last resort email opensourcemalaria@gmail.com.

Synthesis of triazolopyrazine core

The synthesis of the triazolopyrazine core commences with the reaction of commercial 2,6-dichloropyrazine 1 with hydrazine hydrate and subsequent condensation with an aromatic aldehyde to give imine 3. Treatment with the oxidant phenyliodonium diacetate causes 3 to undergo cyclisation to generate the triazolopyrazine core 4.

 

Side chain synthesis

Synthesis of the side chain commences with the nucleophilic addition of cyanide to an aromatic aldehyde 5 and concomitant silylation to give 6. Deprotection under acidic conditions and esterification gives 8 which can be treated with freon gas to provide the fluorinated ester 9.

QUESTION I'm not entirely sure if we are able to used freon in Australia...does anyone know if the gas is still allowed or an alternative way to alkylate the alcohol with a difluoromethyl group?

Hydrolysis of the ester reveals acid 10 which can be driectly coupled with the chlorotriazolopyrazine 4.

 

 

 

 

 

 

 

At some stage it might prove interesting to synthesise 11 (or other analogs) in an enantiomerically pure form. One possible synthesis could make use of some chemistry that I developed during my PhD along with Dr. Aurelien Bigot. Enantioselective copper-catalysed arylation of a silylketenimide (derived from a commercial N-acyloxazolidinone) with a diaryliodonium salt installs the required chiral centre. 

Attached Files
Series4_1.png
Chiral Synthesis.png
Series4_2.png
Series4_3.png
FINAL REPORT MMV670652.doc
Comments
Re: Synthetic Plan for Series 4 by Jochen Brandt
13th November 2013 @ 09:52
To do the difluoromethylation you don't have to use freon, instead you can use Hartwig's method to start from the (toxic yet) convenient TMSCF3: DOI: 10.1002/anie.201209250

There are no examples of aliphatic alcohols in the paper but I assume that's because of the low yield. Aliphatic difluoromethyl ethers made with freon have yields in the 30-40% range, so you probably have the same problem here. After all, you generate the same carbene in both cases.

Alternatively, this paper could open another pathway, but I don't know how easy the reagent can be obtained: 10.1246/cl.2011.1189
Re: Synthetic Plan for Series 4 by OSM ELN
19th February 2014 @ 03:21
Tagging this post to make it more discoverable: CRO, synthesis, synth, Series 4, MMV670652, CR302-6082-84C