search

OpenSourceMalaria / OSM_To_Do_List

Action Items in the Open Source Malaria Consortium
82 stars 13 forks source link

Synthesis of 3-(7-aminothiazolo[4,5-d]pyrimidin-2-yl)-4-methyl-benzenesulfonamide #161

Closed PatrickThomson closed 9 years ago

PatrickThomson commented 10 years ago

target second

As per a discussion somewhere pre-GitHub that I can't actually find, I'm synthesising this structure as opposed to compound 25 because the route is significantly shorter and the outcome is the same (ortho-methyl gives twisted geometry).

PatrickThomson commented 10 years ago

As per US2006199817 (page 53) The following route is known and will be followed.

scheme

[edit] reagents for steps 1 and 2 assembled or purchased.]

PatrickThomson commented 10 years ago

To complete this synthesis it would be helpful to get a sample of the following molecule. If it cannot arrive in the UK by March 27th, for whatever reason, I will make it instead. @alintheopen ?

aminothienopyrimidine

mattodd commented 10 years ago

The original discussion for the need for this compound is here: http://malaria.ourexperiment.org/the_osm_blog/7974 The precursor mentioned above is OSM-S-139: http://malaria.ourexperiment.org/osm_procedures/9080/Preparation_of_OSMS139.html Question: Do we still need/can we send some of this compound? @alintheopen @PatrickThomson ?

PatrickThomson commented 10 years ago

My seed funding is due to expire so I spent a bit of money on the precursors for OSM-S-139 - I can whip up a batch and make everything quickly.

PatrickThomson commented 10 years ago

Boronic acid and bromo-chloro-thienopyrimidine are being made now.

mattodd commented 10 years ago

We can leave this open, for now, right Patrick? When we close it, we need to try to ensure we don't orphan the issue, since there is useful content. This is a generic problem with closing issues (and the lack of a search feature). So we need to either install a link to this issue in the Series 3 wiki (which needs some TLC - spending all available time on Series 1 and 4 at the moment) or needs to be installed on the relevant ELN experimental procedures page for this molecule, but I'm guessing it doesn't have one, yet?

mattodd commented 10 years ago

Keeping cross-links active until this is closed - #58

PatrickThomson commented 10 years ago

Yes, the synthesis is on-going - I'm doing a big push this week for the meeting.

PatrickThomson commented 10 years ago

Completed the ortho-methyl boronate ester. I'm doing the final cross-coupling now, using the microwave/IPA conditions.

PatrickThomson commented 10 years ago

I believe this is done. Experimental data here. Tentative NMR interpretation: http://malaria.ourexperiment.org/data/files/12272.png

A & E assigned by analogy to previous compounds (A moves a lot when changing amine -> chlorine) and chemical shifts (ortho to two ring nitrogens)

B & C assigned on the basis of long-range "W" coupling of ca. 1Hz between B & C only, then ortho-coupling of C & D. Also chemical shifts are consistent with B & C being ortho to EWG.

Nominal mass spectroscopy is consistent, accurate has been submitted.

mattodd commented 10 years ago

Aw come on, you can't say "the most beautiful tan solid I've ever seen" without a photo...

PatrickThomson commented 10 years ago

You had to be there... it crashed out on the rotavap about five minutes before I was ready to admit defeat and go to the meeting empty-handed, after having made minor but potentially-serious messups with both columns in both steps on the same day... That having been said: img_20140704_122135

PatrickThomson commented 10 years ago

Accurate mass is consistent.

http://malaria.ourexperiment.org/data/files/12324/PT-22-C1%20ESI%20Accurate.jpg

If you have a burning desire, I can grow crystals or try to send some for EA, or run through-space NMR, but I'm happy as it is!

mattodd commented 10 years ago

Very nice, Patrick. Crystals would provide interesting structural info that's relevant here, and EA would help speed publication. If you've time.

PatrickThomson commented 10 years ago

Sent to Dundee for evaluation.

https://docs.google.com/document/d/1vnAqw7wz_E0py3u8_Lb4ygK5yJL-1czxCZumKwHhcPw/edit?usp=sharing

mattodd commented 10 years ago

Awesome, Patrick. Dundeed. They are happy to screen? Numbering: In writing the paper I have assigned OSM-E-9 already http://malaria.ourexperiment.org/osm_procedures/10609/Preparation_of_OSME9.html As it stands, we're up to 14: http://malaria.ourexperiment.org/osm_procedures/meta/OSM/value/OSM-E-10_to_OSM-E-19 I should have flagged this, but did it only recently. Any chance you can, when you refer to this compound again, re-number? No need to trouble Dundee with this, but for anything public-facing?

PatrickThomson commented 9 years ago

Ok, I'll un-name this. Should I be naming and loading the intermediates as well then, i.e. calling the boronate precursors OSM-E-15, 16, etc?

mattodd commented 9 years ago

Yes, generally speaking we need to name intermediates too since this makes tracking the synthesis in the project far easier. You'll see this when we circulate the first OSM paper in the coming days. I know this adds a layer of things to do. I have been thinking increasingly in recent days about how to solve this compound registration problem. The approach that is under consideration is adapting Labtrove to aggregate content automatically when suitably tagged. The alternative is convincing a company to let us have a CRS (free or paid) where any contributor can add molecules. The former is far neater and more impactful, in terms of building a resource for the community. Imagine a Chemistry Department that uses Labtrove, where an index of all the molecules in the building (and all the attempts at those molecules) is automatically captured and is searchable. That's useful.

On 29 August 2014 09:52, PatrickThomson notifications@github.com wrote:

Ok, I'll un-name this. Should I be naming and loading the intermediates as well then, i.e. calling the boronate precursors OSM-E-15, 16, etc?

— Reply to this email directly or view it on GitHub https://github.com/OpenSourceMalaria/OSM_To_Do_List/issues/161#issuecomment-53877992 .

MATTHEW TODD | Associate Professor School of Chemistry | Faculty of Science

THE UNIVERSITY OF SYDNEY Rm 519, F11 | The University of Sydney | NSW | 2006 T +61 2 9351 2180 | F +61 2 9351 3329 | M +61 415 274104 E matthew.todd@sydney.edu.au | W http://sydney.edu.au/science/chemistry/research/todd.html | W http://opensourcemalaria.org/

CRICOS 00026A This email plus any attachments to it are confidential. Any unauthorised use is strictly prohibited. If you receive this email in error, please delete it and any attachments.

PatrickThomson commented 9 years ago

Compound is inactive with partial inhibition at the highest concentration (70% at @50mM). There are two more axial twisted molecules by @tpefoley pending testing this week to confirm this, but it looks like throwing out the planarity is a bad idea, even if it did help the solubility a bit.