pHarmacist (Hive Bee)
10-07-02 20:41
No 365566
      Fentanyl Pre-cursor...?  Bookmark   

After admiering Siegfried's excellent fentanyl approach, I decided to give people an idea of an alternative approach of producing NPP (N-Phenethyl-4-piperidone), this is used as a importnat pre-cursor for many goodies, once NPP is in the flask, the way to china-white isn't that hard... this is crazy so go ahead and flame me... But here it comes:



Greetings: Siegfried


[pH]armacist - Never underestimate the power of retrosynthesis. Svenskar suger p fotboll!
 
 
 
 
    Rhodium
(Chief Bee)
10-07-02 22:05
No 365582
      I doubt that the grignard addition to the enamine ...  Bookmark   

I doubt that the grignard addition to the enamine could be that selective. Do you have references?
 
 
 
 
    Cyrax
(Hive Bee)
10-07-02 22:32
No 365592
      About the precursor thing: ...  Bookmark   

About the precursor thing: N-Phenethyl-4-piperidone ain't the problem, 4-piperidone is.  You can't just go to Aldrich and order a few grams 4-piperidone.HCl ...

However, synthetically speaking, you should convert the 4-piperidone to the 1,4-dioxa-8-aza-spiro[4.5]decane (which is a cyclic ketal, obtained by reacting the 4-piperidone with ethylene glycol / H+), before the grignard on the imminium ion is done.  This is rather tedious, don't you agree?

What's wrong with phenethanol mesylate?
If you want to use ( peu prs) the same starting products,
you 'd better react the benzylmagnesiumbromide with formaldehyde, followed by the reaction of the alcohol with methanesulphonyl chloride.
 
 
 
 
    pHarmacist
(Hive Bee)
10-08-02 00:11
No 365634
      Rhod  Bookmark   

Rhodium : No, no refs, a dream of mine... selective? we got delta + (partial positive) on the methylene, seems to me that the nucleophile dosen't have much choice dosen't it...

[pH]armacist - Never underestimate the power of retrosynthesis. Svenskar suger p fotboll!
 
 
 
 
    PrimoPyro
(Hive Prodigy)
10-08-02 00:44
No 365654
      I dont think it will work  Bookmark   

You are forgetting the carbonyl carbon. The benzyl carbanion will add to this carbon to give the tertiary alcohol, which is prone to dehydration to give a compound similar in structure to MPTP, only being one carbon atom longer in the chain (from 0 to 1 that is) and being N-desmethyl.

You show in your picture that the nitrogen bears the positive charge, meaning that the methylene must be slightly carbanionic, and will be unreactive toward the benzyl carbanion of the grignard reagent. The Grignard would be attracted to the nitrogen atom, and I honestly have no idea what type of reaction would take place, because any intermediate formed would be highly unstable. Maybe some sort of elimination would occur?

But the addition of Grignard Reagents to the piperidone ring at the carbonyl is a known reaction.

PrimoPyro

Firm supporter of the "Purge The Couch!" movement. Vote for the purge today.
 
 
 
 
    Rhodium
(Chief Bee)
10-08-02 00:45
No 365655
      Troubleshooting  Bookmark   

You have a <delta>-positive on the two carbon atoms next to the nitrogen in the ring too, due to resonance, and the carbonyl in the other end of the molecule is also reactive. Also, what keeps the 4-piperidone from polymerizing in the first step where you add the formaldehyde? And lastly, what improvement over existing, proven, syntheses like the one suggested by Cyrax does it offer?

Too many possible errors in just this single synthesis proposal, I think, which of course can be remedied by you looking up similar reactions in the chemical literature before suggesting a synthesis that won't be of much use to other people anyway without any specified plausible reaction conditions (again, lifted from the literature on similar compounds). It is nice with people being as enthusiastic as you, but I would advise you to think of the suggestions above before you swamp us with more hypothetical syntheses... wink
 
 
 
 
    pHarmacist
(Hive Bee)
10-08-02 01:25
No 365675
      ...  Bookmark   

But the addition of Grignard Reagents to the piperidone ring at the carbonyl is a known reaction.

PrimoPyro: of course.. you re right.. rhod.. you 2


[pH]armacist - Never underestimate the power of retrosynthesis. Svenskar suger p fotboll!
 
 
 
 
    Cyrax
(Hive Bee)
10-08-02 02:45
No 365721
      An additional problem in this synthesis is that ...  Bookmark   

An additional problem in this synthesis is that the starting product, 4-piperidone, isn't a stable product.  It tends to polimerize.  Think about it, this molecule has both a ketone and an amine.  The amine freebase can grab a proton next to the carbonyl, and the enolate reacts with the carbonyl of another 4-piperidone molecule.  What makes you think that the amine freebase will react with formaldehyde alone?  I forsee that the aldol condensation will be an important side reaction.  Or even worse: the formaldehyde can react with the enolate, yielding a beta-hydroxy ketone (i.e. the CH2OH group next to the ketone).   For this reason alone, I would protect the carbonyl trough conversion to the ethylene ketal (which is an irritating liquid), before doing any other reaction with it.  Note that the 4-piperidone is supplied as a monohydrate hydrochloride (i.e. C(OH)2 instead of C=O) to prevent polimerization.
 
 
 
 
    pHarmacist
(Hive Bee)
10-08-02 09:30
No 365888
      ...  Bookmark   

Cyrax: Yeah, I can also keep on posting smart things about  all possible errors in the mechanism, when i (now) see the actuall errors and when primopyro and rhod came with their remarks... I came up with it and within a minute i did a mechanism and posted it, without looking in the literature... maybe next time i should think and look in the books before i do that... of corse, it contains errors, even in the first step, why bother, it sucked, lets move on and concentrate on something that can be useful.. no hard feelings Cyrax, i saw your work, and you look like a smart individual.. take care..

off to school now...

[pH]armacist - Never underestimate the power of retrosynthesis. Svenskar suger p fotboll!
 
 
 
 
    PrimoPyro
(Hive Prodigy)
10-08-02 12:16
No 365936
      Hey pHarmacist  Bookmark   

Dont get down. I get ideas blown out of the water all the time! Ask anyone! Shit there was a time when I was posting something "new" every day only to find out it couldn't work. laugh

Im sure you will find a way to get what you are seeking. I have done a lot of thinking in this area, and have come up short on most occasions. It's a tricky goal, the synthesis of fentanyl compounds via novel methods, you know?

PrimoPyro

Firm supporter of the "Purge The Couch!" movement. Vote for the purge today.
 
 
 
 
    pHarmacist
(Hive Bee)
10-08-02 13:58
No 365981
      PrimoPyro: You're right as always :) Cyrax: ...  Bookmark   

PrimoPyro: You're right as always :)

Cyrax: Re-reading my previous post, I can see that it may seem to you that i'm trying to put you down or being arrogant, that is however not the case, I've came across some of your earlier posts and i learned a lot of things from them. You seem to be a good and dedicated chemist...

[pH]armacist - Never underestimate the power of retrosynthesis. Svenskar suger p?fotboll!
 
 
 
 
    Tricky
(Stunning)
10-08-02 17:50
No 366061
      Why?  Bookmark   

Why don't you want to try the next rxn:
4-piperidone + Phenethylbromide???
Last one is avaiable at Aldrich and not so expensive.



Wanna make laugh the GOD? - Tell him about your plans.
 
 
 
 
    Rhodium
(Chief Bee)
10-08-02 17:58
No 366064
      DYI  Bookmark   

1 mole Phenethylalcohol and 2 moles 48% HBr is several times cheaper, and just a few hours work to get from point A to point B.
 
 
 
 
    SPISSHAK
(Hive Bee)
10-11-02 08:21
No 367204
      Piperidone  Bookmark   

Isn't easy to get, I'm sure it's red-flag chemical.
Would it be possible to sythesize it by action of methyl acrylate and ammonia, followed by cyclization to a keto ester with sodium/toulene, and lastly saponification with acid like in the synthesis of 1,3 dimethyl piperidone, as a prodine precursor, in this case they react methylamine with methyl-methacrylate, then methyl acrylate, then cyclizize as mentioned above, followed by the sapononification step?
Probably not.
But Hat's off to cyrax, he should write a book on the subject.
I'd buy it.
 
 
 
 
    Rhodium
(Chief Bee)
10-11-02 11:59
No 367260
      Yes, it is possible indirectly, for example by ...  Bookmark   

Yes, it is possible indirectly, for example by doing the acrylate ester condensation etc. on benzylamine, followed by hydrogenolysis of the final N-Benzylpiperidone. Other N-protecting groups can also be used.
 
 
 
 
    PrimoPyro
(Hive Prodigy)
10-11-02 12:01
No 367261
      Aha!  Bookmark   


Other N-protecting groups can also be used.




I asked this very question once! Could formamide or acetamide, etc be used in a Michael Condensationn with ethyl acrylate? I got no definitive answer. laugh

Thank you Chief. Keep up the ramblings at the ends of your posts, they answer old questions that never got the desired attention at their time.

PrimoPyro


Firm supporter of the "Purge The Couch!" movement. Vote for the purge today.
 
 
 
 
    Rhodium
(Chief Bee)
10-11-02 12:27
No 367266
      I don't think amides are nucleophilic enough to ...  Bookmark   

I don't think amides are nucleophilic enough to add acrylate esters, I'm not 100% sure however.
 
 
 
 
    Cyrax
(Hive Bee)
10-11-02 12:29
No 367267
      4-piperidone  Bookmark   

The direct synthesis of 4-piperidone can be acomplished by the following method.  The only problem is that the yields suck and the synthesis is really tedious.

1) Neutralisation of beta-bromopropionic acid with sodium bicarbonate, followed by the reaction of the salt with ammonium hydroxide.  Then esterification with EtOH, and distillation to separate primary amino esters from the beta,beta'-dicarbethoxydiethylamine.  Yield 23 - 26 %.  This distillate is consequently gassed with HCl in ether and crystallized.
2) The pure beta,beta'-dicarbethoxydiethylamine is then used in the preparation of the 3-carboethoxy-4-piperidone by reaction of the secudary amino ester with sodium in xylene.  Yield: 11 %.
3) Hydrolysis of the ester and decarboxylation by refluxing the last product in a 20 % hydrochloric acid solution.   Yield: 72 %.

Ref.: JACS (1931) vol 53 p 2692

Indeed Rhodium, the way to do it is to use the benzyl as a protecting group, which can be efficiently removed with Pearlmann's catalist.  Nope, amides are definitely not nucleophilic enough to add to 2 moles of methyl acrylate in a Michael addition.

PrimoPyro, ethyl acrylate is carcinogenic! Use methyl acrylate.