Sciencemadness Discussion Board - how could I synthesize this molecule

how could I synthesize this molecule

jmister28 - 19-12-2018 at 19:59

Hi, I have an attached image below of a molecule that I have been trying to synthesize. I'm having trouble finding the best precursors and catalysts. Any Ideas?

Σldritch - 20-12-2018 at 05:00

I hope it is nothing illegal:

Acetone ---> Dichloroacetone ---> Diaminoacetone ---> Diaminoacetonemonoacetate
---> Aminoacetoneacetamide or whatever it is called.

Not sure how acetone chlorinates though, perhaps you will just get 1,1-dichloroacetone instead of the desired 1,3-dichloroacetone. Be careful with chloroacetones.

CuReUS - 20-12-2018 at 05:17

can't you just do a ketonisation reaction between glycine and n-acetyl glycine ?

Σldritch - 20-12-2018 at 05:25

Perhaps under vacuum but i very much doubt it would not decompose into polymerized ketone and imine crap.

jmister28 - 20-12-2018 at 06:05

what reagents would you use for:

dichloroacetone --(???)--> diaminoacetone --(???)--> diaminoacetonemonoacetate --(???)--> Aminoacetoneacetamide

Σldritch - 20-12-2018 at 06:32

Besides the chloroacetone (which i suggest you find an alternative to such as iodoacetone) it is step by step:

Step 2: (Nucleophilic substitution) Aqueous ammonia in excess

Step 3: (Acid-Base neutralization) Acetic acid of any concentration

Step 4: (Dehydration) Nothing, just heat carefully. If it decomposes it may need catalyst and/or vacuum.

Really though it may be pointless because Haloacetones are nasty, i would not try it without a good fumehood and judging from your knowledge of these reactions; more experience.

https://en.wikipedia.org/wiki/Bis(chloromethyl)_ketone

http://www.sciencemadness.org/talk/viewthread.php?tid=18579

Maybe if you could protect a carboxyl group on citric acid you could get to diaminoacetone that way via Hofmann degredation but i can not think of any way to just protect the middle carboxylic acid.

[Edited on 20-12-2018 by Σldritch]

jmister28 - 20-12-2018 at 06:41

so using these I would end up with Aminoacetone acetamide?

Boffis - 20-12-2018 at 08:47

1,3-diaminoacetone is prepared from acetonedicarboxylic acid via 1,3-diisonitrosoacetone. It is described in Preparation of organic intermediates by Shirley. It is easily downloaded from t'internet. Good luck with the acetonedicarboxylic acid! I have a lot of experience with it, most unsuccessful.

Chemi Pharma - 26-12-2018 at 03:39

I would start from glycine --> BOC protection of glycine amino group --> acid chloride from glycine with cyanuric chloride and TEA (see here: http://www.sciencemadness.org/talk/viewthread.php?tid=80658&...) or TCCA and triphenylphosphine (see here: http://www.sciencemadness.org/talk/viewthread.php?tid=80658&...) --> reaction with acetamide --> BOC deprotection of the amino group and you would get your molecule.

[Edited on 26-12-2018 by Chemi Pharma]

CuReUS - 26-12-2018 at 09:47

Quote: Originally posted by Chemi Pharma

I would start from glycine --> BOC protection of glycine amino group --> acid chloride from glycine with cyanuric chloride and TEA (see here: http://www.sciencemadness.org/talk/viewthread.php?tid=80658&...) or TCCA and triphenylphosphine (see here: http://www.sciencemadness.org/talk/viewthread.php?tid=80658&...) --> reaction with acetamide --> BOC deprotection of the amino group and you would get your molecule.

firstly, you can't acylate amides that way -https://pubs.acs.org/doi/abs/10.1021/ja01535a032

and secondly,even if it worked,you still would be missing the carbon in the middle.

Chemi Pharma - 26-12-2018 at 10:48

Quote: Originally posted by CuReUS

Quote: Originally posted by Chemi Pharma

firstly, you can't acylate amides that way -https://pubs.acs.org/doi/abs/10.1021/ja01535a032

and secondly,even if it worked,you still would be missing the carbon in the middle.

@Cureus, You're right. I can't believe I didn't see the carbon in the middle. Forget all what I've said about the synthesis. May be other way would be start with 1,3 dichloroacetone (sold by Merck/Sigma Aldrich), make a delepine reaction with HMTA to obtain the ketone diamine and reacts the last with a stoichometric amount of acetyl chloride to N-acylate only one aminogroup, giving the OP's desired product.

On the other hand, I think is possible to do an N-acylation on the amide with an acid chloride, the same way the literature show examples of the N-alkylation and N-arylation with alkyl chlorides and aryl halides cause the mechanism is the same. See: https://www.organic-chemistry.org/synthesis/C1N/amides2.shtm... Also, this article tell about the diacylation of amides with acyl chlorides: https://pubs.acs.org/doi/abs/10.1021/ja01156a115. Could you explain to me why you think the N-acylation won't work in this case?

[Edited on 26-12-2018 by Chemi Pharma]

Jon snow - 31-12-2018 at 14:33

I don't frequently browse the forum so please correct me if I'm wrong but I don't think it's generally a good idea spoon-feeding information regarding drug manufacturing and the production of drug precursors like the molecule op mentioned

Loptr - 31-12-2018 at 15:14

Quote: Originally posted by Jon snow

I don't frequently browse the forum so please correct me if I'm wrong but I don't think it's generally a good idea spoon-feeding information regarding drug manufacturing and the production of drug precursors like the molecule op mentioned

What is this a precursor for?

Jon snow - 31-12-2018 at 15:28

It's a precursor to a variety of Imidazobenzodiazepines like climazolam and midazolam if I remember correctly, the other precursors being the corresponding 2-aminobenzophenones

Loptr - 31-12-2018 at 16:01

I would hardly consider this a "precursor". Also, after looking at the structures of those compounds you mentioned, while i see some similarity, I dont see a direct conversion of this to those medications.

Jon snow - 31-12-2018 at 16:18

I'm not an expert on the chemistry behind the synthesis of benzodiazepines but I'll provide a link to a patent regarding the synthesis of midazolam from the compound in discussion, it looks pretty direct to me but I'm not sure because it looks like poorly translated and English isn't my first language

https://patents.google.com/patent/WO2016146049A1/en

Loptr - 31-12-2018 at 16:32

I see what you're saying. I knew that I would eat my words.