Synthetic Design of Pyrazolopyrimidine

[Yuhang-CADD]

Hi all!

After understanding how pyrazolopyrimidine is bound to Pseudomonas aeruginosa MurC (#36), we decided to synthesise pyrazolopyrimidines (#35): AZ5595 (compound 9) and its corresponding amine derivative (compound 17). Here is the synthetic plan we want to ask for help (shown in Fig 1). For further details of procedures and references, please check my ELN.

Fig 1. General Scheme of Pyrazolopyrimidine Synthesis

3 Main Questions:

1. Protection steps: R-5 and R-5 alternative routes

1.1 Boc2O or t-Butylphenylcarbonate (compound 19), which one is better to use for the Boc protection of this diamine (compound 10)?

DOI: 10.1021/acs.jmedchem.5b01374

1.2 Cbz, or some other protecting groups to select (considering reactivity and the following deprotection steps), any suggestions for a better protecting group of amine? What about the following reaction?

DOI: 10.1055/s-2002-34859

2. Deprotection steps: R-7 and R-7 alternative rourtes

2.1 Potentially, is it possible that such an acid condition may cause ring-opening at the pyrazole ring or the pyrimidine ring, or disconnection at the NH bridge?

DOI: 10.1021/ol048771l

2.2 Would H2/Pd-C over reduce part of the pyrazole ring or the pyrimidine ring, or even the NH bridge?

Patent Link

3. CN group reduction: R-10

When applied the condition of H2/Raney Ni, AcOH, would over reduction happen to part of the pyrazole ring or the pyrimidine ring, or even the NH bridge? Any other potential side reactions?

Patent Link

Additionally, if anyone got any suggestion about modifying the entire synthetic plan, I would really appreciate it!

@mattodd @loriferrins

[mattodd]

Hi @WieselHenson - I think Boc deprotection ought to be fine, and the conditions can always be tweaked to make them more mild, or a tweak of reagents. Cbz protection is a good plan B. Reagent 19 looks good (unless we have (Boc)2O in the building...). The CN reduction is for a Plan B too, so we can worry about that if Plan A doesn't work. So @loriferrins sent compound 10 so first thing is to take an NMR to see what it looks like and for comparison to products. Then find the reagent for Boc protection and check that that looks OK by NMR, then do your risk assessment so you can set up the reaction with monitoring by TLC, and we are off! So we're good to go with making compound 11! That means we need compound 7, meaning we're buying 6 and making 5? For searching for chemicals, you're already trying the commercial vendors, but you can also look at things like Manifold and Mcule?

Stereoisomers - compound 9 in the paper was enantiopure? The enantiomers gave different results in the Hameed paper? That's important if so, and we need address this with compound 17. @loriferrins sent a racemate of 10, I assume?

This means we need to buy the "active" enantiomer of 8 for the resynthesis of 9. We could buy the less active enantiomer as a control compound, though.

[Yuhang-CADD]

In the Hameed paper, two stereoisomers exhibited different SAR properties (see the screenshot below, taken from the original paper for fair use of demonstration)

[mattodd]

Right @WieselHenson so the other enantiomer is an excellent negative control and we might well expect something similar for the proposed amine compound. Syntheses can use the racemic material if we're exploring the chemistry, and we'd certainly want to evaluate the rac amine compound to see if there is any activity, but single enantiomers can then be accessed by resolution or using enantiopure starting materials.

[lferrins]

Hi all, I just double-checked and I shipped S-phenylglycinol, not the racemate. I think this is what you want to make the AZ compound, right?

[Yuhang-CADD]

Hi Iferrins,

Thanks for your help! (S)-phenylglycinol would be a good negative control for the synthesis of AZ5595, so this compound is useful! Thanks for devoting this!

However, what we also need are as followings:

If you have the racemates separately, namely (R)-1-phenylethane-1,2-diamine and (S)-1-phenylethane-1,2-diamine, please ship them to us, we would really appreciate that! They are essential components to synthesise the compound 17, AZ5595 derivative.

If you have the racemic 1-phenylethane-1,2-diamine, please also send them to us! That would be a good startup for testing out the reaction conditions. May also be a good alternative step to obtain both of the stereoisomers of compound 17 if separated successfully.

Best regards,

Yuhang Many thanks!

[mattodd]

Yes, that's great, @loriferrins, thank you again. @WieselHenson you should pursue the chemistry with the racemate, to make sure it works, and then we can use the (more expensive) enantiopure material as a key comparator.