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Author: Subject: Theoretical synthesis of 2-benzyl proline
njl
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[*] posted on 13-4-2021 at 13:02
Theoretical synthesis of 2-benzyl proline


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

https://imgur.com/a/NvW8EL4

Attachment: BenzylProline.pdf (48kB)
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[*] posted on 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]
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[*] posted on 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.



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[*] posted on 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]
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[*] posted on 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.



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[*] posted on 14-4-2021 at 17:56


Quote: Originally posted by Newton2.0  
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
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[*] posted on 14-4-2021 at 18:53


http://www.swisstargetprediction.ch/result.php?job=378378258...



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[*] posted on 14-4-2021 at 20:31


I will just leave this here. https://www.ch.ic.ac.uk/ectoc/echet96/papers/081/index.htm
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[*] posted on 20-4-2021 at 08:38


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.



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