Chemical Synthesis of Pyrazolopyrimidine Derivatives

[dayang-us]

Hi all!

Previous issues on pyrazolopyrimidine derivatives:

30 Producing a protein-ligand interaction map

31 Help meeting the eNTRy criteria

32 Conformers and docking with Vina

Here's just a small update/detail on what I have gathered on the synthesis of pyrazolopyrimidine derivatives, specifically Compound 10 / AZ5595, extracted from the Supporting Information of Hameed et al, 2014 (DOI).

I have also tried using DataWarrior to look up Enamine building blocks:

• Could not find Compound IId – paper sourced it from Aurora Fine Chemicals LLC
• Compound I was found on the Enamine Database (numbered 2 in the table below)
• Could not find Compound 1V - paper sourced R-2-amino-2-phenyethanol sourced from Alfa Aesar
• Search for amine-containing analogues on Enamine Database via Datawarrior did not yield any results

Quick screenshot from DataWarrior:

Considerations for synthesis of primary amine-containing pyrazolopyrimidine derivatives: Would it be better/easier to... 1) Synthesise Compound 10 then aminate it? 2) Modify Compound 1V into 1-Phenylethane-1,2-diamine, then employ protection/deprotection strategies to ensure specificity?

Ultimately, we would like to build primary-amine containing fragments into R1 without elongating it too much that it becomes too flexible that it loses its wild-type activity (e.g. Compound 22 and Compound 26 in the paper has 11 and 10 rotatable bonds respectively. They have excellent IC50 but poor MIC). We also might consider rigidifying the phenyl ethanolamine moiety to keep rotatable bonds below 5 - perhaps with a ring structure?

I welcome any tips/suggestions/fact-checks, especially from experienced organic chemists here. Hope this will help in developing the molecule further!

[mattodd]

Absolutely great, thanks @dayang-us . So @eyermanncj @loriferrins what do you think? Easy resynthesis of the main compound, AZ5595? @WieselHenson do you think you can make it in lab? Are there any other sources of those first two building blocks?

[Yuhang-CADD]

I am not 100% sure about this, but I guess with all the details provided in the supporting information, I can try.

Also, here is what I found on how to synthesize two of the reactants in the synthesis of Compound 10 / AZ5595.

Not sure if this is totally feasible. But these two starting materials (with CAS number provided under each structure) are commercially available on the MERCK website: https://www.sigmaaldrich.com/united-kingdom.html

For the synthesis of compound IId, I guess I would use the methylation condition in the following paper https://www-sciencedirect-com.libproxy.ucl.ac.uk/science/article/pii/S0968089614001047.

As for the synthesis of 1V, I assume deprotection of its Boc derivative might work.

However, here I have a concern, which is the byproduct 1-phenylethen-1-amine (shown below) might be produced as to form a larger conjugated system (with benzene ring)...

Looking forward to suggestions from anyone who has expertise/interests in organic synthesis. Many thanks!

[lferrins]

@WieselHenson I think that you might run into some problems with the alkylation of the pyrazole nitrogen - I have a feeling that the bulky t-butyl will mean that you get (at best) a mix of regioisomers where the methyl ends up predominantly on the nitrogen closest to the amine. You could build it up instead? Make the b-ketonitrile and then close with methylhydrazine?

Alternatively, there are a few reports in SciFinder for the following transformation:

As for the deprotection, can you not by the (S)-2-amino-2-phenylethanol (CAS: 20989-17-7)? It is commercially available from Fisher Scientific in the US (looks like the suppliers include Acros, Alfa Aesar and TCI) - not sure if you also have access in the UK?

[Yuhang-CADD]

@lferrins Thanks a lot for the insights!

In the methylation of pyrazole nitrogen, I totally agree with what you suggested! I should have considered the t-Butyl's delocalisation effects on the conjugated Π system. I reckon the mechanism of why methylation would happen to the nitrogen near the amine group goes as follows:

As for the deprotection, I agree that there is no need to proceed this reaction as I just found the compound you mentioned (S)-(+)-2-Phenylglycinol (CAS Number 20989-17-7 ) available in the UK store of MERCK group.

Here is the link to it: https://www.sigmaaldrich.com/catalog/search?term=20989-17-7&interface=CAS%20No.&N=0+&mode=mode%20matchpartialmax&lang=en&region=GB&focus=product (Bug here: to open this page, you need to copy and paste this link in a new webpage window instead of clicking on it directly)

Thanks again for your detailed instructions and suggestions!