Questions regarding alprazolam/flualprazolam synthesis

[Mulch4065]

My reference material is 10.1007/s00044-016-1585-z and the small scale alprazolam synthesis that I found here - I do understand the basic process.

I do have a few questions though, and can't really find answers to them online elsewhere.

1. The precursor of 2-amino-5-chlorobenzophenone is for alprazolam, but I assume this can be replaced with 2-amino-5-chloro-2'-fluorobenzophenone for flualprazolam? Or is it a different substitution?
2. Can the chloroacetyl chloride be substituted for ethyl chloroacetate?
3. Is acetic anhydride the only option? I thought acetyl chloride could work here too, except the HCl would be released as a gas (obviously harder to work with). It's still easier than trying to source AA though.
4. Is the hydrazine hydrate directly replaceable with hydrazine sulfate? It's easier to source, safer to work with, and the product is cleaned at the end anyway. If not, I think it can be turned into hydrazine hydrate, so it's at least still easier to source.

Everything else required for this synthesis is obtainable, although I do have some questions regarding scaling the reaction up. My main concern is the final step, where 25ml of AcOH was used. Is this an arbitrary amount?

The small-scale synthesis on here suggested that you use pear-shaped flasks for all of this reaction - I assume a boiling flask will work just fine?

Apologies for the seemingly noobish questions, and thank you! I am a bit out of my comfort zone with this one, so any reading material on the subject would suffice just as well

I drew up a synthesis (using ethyl chloroacetate, acetyl chloride and hydrazine sulfate - I don't know if hydrazine sulfate will work, but the rest seems fine). Hydrazine hydrate is probably obtainable, so that's not the hardest part of this synthesis.

 

[G.Patton]

Hello, yes
I'm not sure, there is different group on the carboxylic carbon.
Probably you are right
Probably yes, but you have to increase amount of NaOAc because you have to get basic space there. -SO4 will react with Na from NaOAc.
It was taken from an article.
what do you mean boiling flask?? Round bottom flask? It is ok. Pear shaped flask more convenient for handling in small scale synthesis.

 

[Mulch4065]

Thank you for the reply!

In regards to the acetyl chloride, are you suggesting that it should work? I'm a little confused with your answer in that regard.

I'll do some more research into the ethyl chloroacetate substitution, as it's definitely easier to get ahold of.

I did mean an RBF, apologies for not being clearer and thank you for the insight. The pear-shaped flask choice had me pretty confused.

Cheers

 

[G.Patton]

Sorry, I wanted to say that not sure that it will work. But you can try and share us by your result. Our forum will be appreciated to you =)
You have to try, I think you'll recommend it after your first synthesis as me!

 

[Mulch4065]

Thank you for the help!

I am unsure over the ethyl chloroacetate, but I strongly believe the acetyl chloride should work in place of acetic anhydride - it is a LOT more reactive, but hopefully not too much.

Anyway, due to how easy it is to get acetyl chloride here, it's only a quick reaction and distillation away from being acetic anhydride

Going to do some more research as ethyl chloroacetate is a lot easier to get than chloroacetyl chloride.

 

[madmoney69]

Did you do any progress on it?