mattodd
commented
7 years ago Yes, that's absolutely great, Chase. Interesting write-up (full marks awarded for linking to the lab book pages). So you're all set on bio evaluation, ideally vs standard controls so that we can be sure we can compare the data for the first Series 4 paper.
The fact that that amidation works implies we could access a bunch of other compounds that way, should yours prove to be active. Given the change you're making to the electron density of the ring, it'd be very nice to have them evaluated in the Aldehyde Oxidase assay. Might you be able to send some to Scott Obach when we do, as per #485 ?
MedChemProf
MFernflower
This is a long overdue update on our synthetic attempts to synthesize a few analogs of the 'Reversed Amides' as part of the overall SAR of Series 4. It has taken us much longer than originally expected to make these compounds. The Reversed Amide has been discussed previously in issue #301, #352 and #358. Our initial approach was to synthesize the azide which was then planned to be reduced to give the amine. This strategy worked on small scale and is detailed in ELN experiments CCS-3-2 and CCS-4-1.
On scale-up of the amine however, none of the amine was obtained, instead the intermediate iminophosphorane was isolated. Experiments TL-4-2 and TL-4-3.
Attempted hydrolysis of the iminophosphorane using the more common basic methods (heating with either aq. NaOH / THF or NH4OH / MeOH) failed to force the reaction to completion. (Experiment CCS-5-1). It was later discovered that the hydrolysis could be forced using acidic conditions, but the reaction was very slow (Experiment NA-7-2).
Prior to finding the acidic hydrolysis conditions, the reduction of the azide was also achieved using either catalytic hydrogenation or borohydride reduction. Both of these methods did provide the amine product, but the yields were low and the product difficult to isolate during purification from a complex mixture of by-products. (Experiments BM-5-1 / NA-2-1 and NA-2-4).
It was decided to just hydrolyze the iminophosphorane since it produced pure amine product instead of trying to find more optimal reduction conditions for the azide. The amine however, proved to be unreactive with standard coupling conditions. Forcing conditions did produce some product which could be identified by NMR and LCMS, but the material was significantly contaminated with by-products. While the product was identified in the mixtures, we were unable to purify adequately via silica gel column chromatography or via preparative TLC. We did not have access to a Prep HPLC which would have allowed us to isolate the clean product. The figures below list the temperature being raised to 65C, but they were also repeated at as high as 110C-120C with mostly additional decomposition and resulted in very little extra product being formed.
Above attempts are detailed in Experiments CCS-6-1, NA-3-1, NA-3-2, FG-5-1, FG-5-2, FG-5-3, FG-5-4. An attempt to produce the urea also did not result in any reaction. Starting material only remained (Experiment VD-4-1).
It was then decided to abandon the acylation of the amine for the time being and focus on a different synthetic route to the desired Reverse Amides. Toward this end, a new core was synthesized containing a para-cyanophenyl group instead of a para-chloro. This was done in order to avoid any competition with a metal catalyzed substitution at that position versus the chloride on the pyrazole ring. (Experiments JH-5-1, JH-5-2 and JH-7-1).
We are now back in touch with my contact at the Broad Institute and OSM-W-6 and OSM-W-7 will be sent for testing in the very near future.