Progress on pyrrole analogue of OSM-S-106

[mbhebhe]

I am currently still trying to synthesise the pyrrole analogue of OSM-S-106 to see if changing the scaffold improves the potency. The starting material (4-chloro-5H-pyrrolo[3,2-d]pyrimidine) was bought from combi-blocks. I tried brominating at the 6th position with n-BuLi and bromine and it brominated at the 7th position (MNB17). The same happened when bromination was done with NBS. Does anyone know how to brominate indole or something similar at the 6th position without having to use tert-BuLi? Indole can be brominated at the 6th position with tert-BuLi (J. Org. Chem., Vol. 57, No. 8, 1992). Once I brominate at the desired position, I should be able to carry on with the synthesis and make the pyrrole analogue of OSM-S-106.

In the mean time, I have synthesised the analogue brominated at the 7th position (MNB19). This underwent amination (MNB20) and I tried to couple that to the benzesulfonamide and I did not succeed (MNB21). I will give this one more go whilst trying to couple the chloro to the benzenesulfonamide and then aminate at the end to get to another analogue.

Strings for analogue
Smile: NC1=C2C(C=C(C3=CC(S(N)(=O)=O)=CC=C3)N2)=NC=N1
InChI=1S/C12H11N5O2S/c13-12-11-10(15-6-16-12)5-9(17-11)7-2-1-3-8(4-7)20(14,18)19/h1-6,17H,(H2,13,15,16)(H2,14,18,19)
InChl Key : XTMBLMGMAYOFBP-UHFFFAOYSA-N

[MFernflower]

@mbhebhe combi-blocks offers the brominated core but I cannot find a price as I am not a customer of them! http://www.combi-blocks.com/cgi-bin/find.cgi?QM-7302

Update it seems to be about 200 USD per 100 mg of compound

[mbhebhe]

I have looked into that, its expensive 1 g = USD 2480 and 5 g = USD 7490

[mbhebhe]

MNB19 underwent an amination to give MNB20. Coupling MNB20 to the sulfonamide (MNB5) does not give us the desired product (still trying to figure out what we got). So we thought coupling before aminating would work (MNB19 + MNB5 -> MNB23). This was trialed and the sulfonamide coupled to on the chlorine position. This was done with Pd(PPh3)4 instead of PdCl2(dppf) (traditional method in S3). PdCl2(dppf) is currently being used to see if coupling at the bromine position will occur.
More of the wrong coupled product needs to be resynthesised so that we can try and couple at the bromo position to form a di-sulfonamide molecule

Another method we are using to couple at the bromo position is to Boc protect the 7-bromo pyrrole (MNB19) to make MNB27. Then after the Boc protection hopefully we will be able to couple at the bromo position (MNB30). Then if that works we will deBoc and aminate in whatever order that works.

At the same time we are still trying to brominate at the 6th position of the chloro pyrrole. At the moment we have Boc protected the pyrrole to change the reactivity of the 6th position (MNB28). Next step is to try and brominate at 6th position with NBS and if that doesn't work then with n-BuLi and Br2 (MNB29). If that works then we will either deBoc, aminate and couple (in whatever order that works). Hopefully we will have our OSM-Pyrrole.