Resolution of a Series 4 Frontrunner

[mattodd]

There has been interest in establishing the relative biological activity of the enantiomers of chiral Series 4 compounds (the "eudysmic ratio") - summarised here, and the subject of previous discussion in #111 #120 #167

Mark Butler and his team at the University of Queensland have kindly agreed to try to separate 20 mg racemic MMV669844 into the constituent enantiomers with preparative chiral HPLC, so we can investigate the blood stage efficacy of both. The Sydney lab will ship the racemate ASAP. Mark has kindly agreed to share the experimental protocols involved in the separation, too.

Note that according to the inherited data for this project, MMV669844 was enantioenriched, but we have no data to support this. As part of the frontrunner set (#400) we have synthesised the racemate (as a racemate) and this has the code MMV897709. I think this is the best compound to send to Mark because it's a chiral, in vivo active compound that is likely to be difficult to resolve by classical resolution.

Opening this issue for people's information and for any comments. Will close when we have obtained the separate enantiomers ready for evaluation.

Strings
FC1=C(F)C=CC(C@@HCOC2=CN=CC3=NN=C(C4=CC=C(C#N)C=C4)N32)=C1
InChI=1S/C21H15F2N5O2/c1-29-18(15-6-7-16(22)17(23)8-15)12-30-20-11-25-10-19-26-27-21(28(19)20)14-4-2-13(9-24)3-5-14/h2-8,10-11,18H,12H2,1H3
PERKBMZWWUEZNJ-UHFFFAOYSA-N

[MFernflower]

Awesome!!! - but why methoxy instead of dimethylamine??? @mattodd

[mattodd]

The dimethylamine is certainly an attractive compound, but we have relatively little data on it. The methoxy is a compound known to be in vivo active. In addition the amine might be resolvable with a classical resolution, given its aliphatic amine group. Such an approach would probably be harder (though not impossible) with the methoxy, meaning this is a better candidate for HPLC-based resolution.

[jrcamacho2000]

Dear all,

This article could be useful.

Future. Med. Chem. "Practical Applications of Matched Series Analysis" explores applications to SAR transfer, binding mode prediction and data point validation. You can download a preprint from https://lnkd.in/epP6XQM.

regards,

Jose Camacho

[mattodd]

MMV897709 (AEW313-1) shipped to UQ today for resolution.
Cover letter Mark Butler.pdf

[MFernflower]

Fantastic!

[alintheopen]

UPDATE: Resolution achieved on analytical column http://malaria.ourexperiment.org/uri/b0a
~1 mg will be available to test each enantiomer.
TO DO: Locate preparative Phenomenex Cellulose 3 and see if anyone is willing to resolve larger quantities.

[cdsouthan]

Suggest assign two new MMV numbers for the pure-ish enantiomers ?