I had an idea for the synthesis of benzyl proline and decided to write it down before I forgot. This compound is likely active as a stimulant but as
far as I know is not illegal. That said, I don't really have any interest.
The synthesis would start with either racemic or entantiomerically pure n-methyl proline methyl ester (commercially available). If this is unavailable
as it is for me currently, it could be prepared in one step from proline and methyl iodide or another agent suitable for both n and o alkylation. A
quaternary salt is formed with the proline and benzyl bromide. A stevens rearrangement then takes place directed to the carbon adjacent to the ester
carbonyl. After workup the ester is hydrolyzed and the resulting carboxylate heated to expel CO2.
This is obviously not detailed but I would like to note some things
1. Benzyl bromide could be replaced with chloride or iodide
2. The stevens rearrangement is usually messy and might not even work with sodium methoxide in this case, but I am hoping it would be successful since
the carbon adjacent to the ester has one strongly electron withdrawing group and the amine is occupied as a quaternary salt (does not contribute much
electron density).
3. I don't know if it would be as kinetically favorable, but I think there is a chance that the methyl group on the quaternary nitrogen will migrate
rather than the benzyl group due to the relatively large carboxylate
Attachment: BenzylProline.pdf (48kB) This file has been downloaded 380 timesNewton2.0 - 13-4-2021 at 13:55
Very interesting! I would expect this thing to have similar pharmacological profile to BZP. It is a ring-constrained amphetamine. Very interesting
little thing! Have you run it through Swiss to check its activity?
[Edited on 13-4-2021 by Newton2.0]njl - 13-4-2021 at 16:17
I don't know anything about swiss, details?? As for pharmacology, I'd hesitate to make any concrete claims but I think a rather uninteresting
anorectic could come out of it. The BZP I know about is benzylpiperazine, not piperidine. Classic benzylpiperazine
is not a constrained amphetamine. Benzylpiperidine can be depending on isomerism, and is the core of the structure of methylphenidate. Newton2.0 - 13-4-2021 at 17:22
I was not clear, sorry. Here's what my post meant to say:
Your compound of interest is a ring-constrained amphetamine-type molecule.
BZP has a very rough similarity to your compound. Obviously the piperidine and piperazine rings are very different.
Swiss Target Predictions is a website which allows one to predict the pharmacological properties of a compound a user inputs. It is very useful and I
have determined that your compound most likely is a stimulant similar to a classical stimulant. It most likely affects DAT, SERT, NET, and TAAR1 much
like a classical stimulant.
[Edited on 14-4-2021 by Newton2.0]njl - 14-4-2021 at 04:35
Very interesting, I'll have to look into that. This prep was inspired by the work of David Nichols on constrained tryptamines, one of which
(5-meo-MPMI) showed potent activity as a 5HT2 ligand. His teams synthesis is rather unfriendly though. This was simply a look at a slightly simpler
compound. I could see this process working with an n-protected 3-halomethyl indole instead of a benzyl halide to yield their product, although it
would not be as elegant as their original preparation. draculic acid69 - 14-4-2021 at 17:56
Very interesting! I would expect this thing to have similar pharmacological profile to BZP. It is a ring-constrained amphetamine. Very interesting
little thing! Have you run it through Swiss to check its activity?
[Edited on 13-4-2021 by Newton2.0]
Can you please provide link to this Swiss you speak of. It sounds very interesting njl - 14-4-2021 at 18:53
An alternative and unrelated synthesis based on this paper may be possible. Here an alkyl azide undergoes a Schmidt reaction with a nearby carboxylate to form a cyclic amine.
