November Compound Hitlist at Sydney

[david1597]

32 molecules, 30 days.

Following a quick meeting of the OSM team here at Sydney we decided to aim to get one more batch of compounds sent away for potency evaluation before the end of the year. These are the structures we - @edwintse (green), myself (red), @maratsydney (blue), @rjmacdonald (purple), @mbhebhe (orange) - are targeting. We'll post a weekly (at least) update on progress. Shipping Fri 1st Dec. See you in the lab, team!

[MFernflower]

Perhaps 34 if possible? 💊
I was thinking of some new compound ideas and I would really like to see these two added in to the batch for testing if time permits!

Reference for compound 1: http://pubs.acs.org/doi/abs/10.1021/acs.jmedchem.6b00306 (this drug was just FDA approved!)

Synthetic plan for 4-quinuclidinyl ethan-2-ol precursor (A cage I really want to see tested!)

(compound ideas re posted from my twitter page) - @mattodd is it okay to communicate over twitter or should we centralize everything to github?

[david1597]

Update: 10 Nov

8 compounds ready. Those with bold boxes around them.

@edwintse is currently making the methylated amine (thanks to @MFernflower for spotting this is incorrectly drawn in the first post) and repurifying the boc-protecting amine from the greens. Awaiting the other three precursors to be shipped. I am somewhere midway through the syntheses of each of the reds. The first ones should be ready by next weeks update. @maratsydney has made the set of four compounds shown. @mbhebhe and @rjmacdonald are progressing with the series 3 compounds.

[MFernflower]

@david1597 A bit unrelated but may I request a new compound in the "blue" series? Do you guys have 4-(Dimethylamino)phenylboronic acid on hand? @maratsydney

@david1597 Did you talk to anybody (if time permits) about the possible synthetic method I posted for 4-quinuclidinyl ethan-2-ol ? I'd love to see this cage tested as all of our cage compounds were just hydrocarbons

[edwintse]

@MFernflower re:quinuclidine - before we try to make that kind of cage, we need to know if a nitrogen in the para-position is any good (i.e. is a pyridine replacement ok). I had a go at making this compound earlier this year using 4-pyridineethanol but didn't have much success. I will take a look at it again in the near future though.

[MFernflower]

@edwintse Your morpholine and methylpiperazine compounds should show us if we can even stick a saturated cyclic with a nitrogen atom in the first place - If they pass it should be proof to try quinuclidine ethanol

Also regarding my phosphine oxide compound (OCHF2 replacement) - How would would that be to produce????

Also this sounds rather silly but would it be possible to acetylate some of that bare piperazine compound at the free N atom with some acetyl chloride?

[david1597]

Update: 17 Nov

8 compounds still. Nothing extra this week.

@maratsydney (blue) has been working at getting the C-N couplings working. I (red) have a somewhat parallel synthesis; three compounds are just one step each away from the final molecule. Excitingly, there should be some bonus compounds included in the next update, from @ErinSheridan, @alintheopen and the SGS team which is great! Structures and details of these next week.

[david1597]

11 compounds ready,

Just a few days left before we ship. Various other compounds are just one step away, or awaiting purification of the final compound and/or characterisation.

The final update and which compounds were shipped to Dundee will be posted on Friday.

[mattodd]

Four days left. Pass the popcorn.
@MFernflower - all the things you mention are possible, but as always it's just a question of resources and time. If you want to suggest something should be made you will always need to provide a strong justification for it (rather than just the structure itself) if the suggestion is to displace something in the above (all of which are either asking a question (e.g. cage replacements), are part of a series (e.g. how good is the cage replacement), are validating some new synthetic chemical route (Suzuki, in this case) or are predicted to help solve remaining Series issues to do with solubility or clearance). The current set also includes the Pfizer compound David is making (to check it's what we think it is), and exploring the new chemical space we have as a result of that compound being potent.

[MFernflower]

@mattodd Understood. Tonight I will be migrating all of my compounds to a labarchives ELN as to avoid crowding up github space! Of the large amount of compounds I have proposed in the last 4 months I would strongly recommend the dimethylphosphine oxide ochf2 swap as that has precedent in a FDA approved drug! http://pubs.acs.org/doi/abs/10.1021/acs.jmedchem.6b00306

My ELN: https://mynotebook.labarchives.com/share/O_S_M%2520Proposed%2520Molecules/MC4wfDI2Mjc0OS8wL1RyZWVOb2RlLzQyMDU2MzI0Njh8MC4w

[david1597]

Just to close this issue (the final update was never posted)...

At the end of November the compounds in boxes had been made and were shipped to Dundee for potency evaluation. Further info and the results from these tests are here. Synthesis of some of the remaining structures in this graphic continued after November; some were sent to Dundee in Feb 2018, with further compounds planned for April 2018.

Final Nov compounds.zip