Sciencemadness Discussion Board

Theoretical Synthesis of 4-Piperidone/Piperidine

kyanite - 5-5-2005 at 16:36

:mad: AHH I PRESSED BACK! TWICE!
I'm afraid to press any buttons!:o
anyways...

I have no clue what the use of thiese chems are, or have the resources to try this out, but this idea's been bugging me for a while. Tell me what you think. :)

Basicly it's a cyclisation of a di-ester(?) amine to form a beta-keto ester, which is then hydrolysed and decarboxylated to 4-piperidone.



That's for 4-piperidone. Piperidine can be made by a reduction of this ketone.

Any info, flames, or ideas are welcome. :)

Edit: Here's some info on the Dieckmann rxn. http://themerckindex.cambridgesoft.com/TheMerckIndex/NameRea...

[Edited on 6-5-2005 by kyanite]

Sandmeyer - 6-5-2005 at 15:23

EDIT: It should be stressed that it would be a very bad idea to make such compounds, for several obvious reasons. But chemistry involved can be pretty interesting and worth discussion.

The step one, as proposed, will give complex mixture of products. While true that formaldehyde can't enolize and is extreamly electrophilic, it is simply too reactive, it will react more than once. The desired compound would be obtained in very low yield, major porduct being 4-hydroxy-3,3-bis(hydroxymethyl)butan-2-one from multiple additions of formaldehyde. Since aldol w/ formaldehyde is unsatisfactory, this could be solved with use of a Mannich (Me2NH, CH2=O w/ cat. HCl).

For Mannich route to 4-dimethylamino-butan-2-one, see

  • Spaeth; Geissman; Jacobs; J. Org. Chem; 11; 1946; 399,400,402.

    And a bit more rescent:
  • Coward,J.K.; Bruice,T.C.; J. Am. Chem. Soc.; 91; 1969; 5339-5345.

    The above Mannich product can then be treated with MeI and then with a base to via E1cB elimination provide acsess to the desired enone.

    For conversion of Mannich product to vinyl ketone, see:
  • Vogel's fifth edition, page 1053.
    Quote:

    haloform rxn, acidic work-up


    How to make acrylic acid from the above enone w/ hypohalites (haloform) as you said, see:

  • Wacker,A.; US 2146282; 1935.
  • Wacker,A.; FR 811215.
  • Wacker,A.; DE 670782
    Quote:
    esterfication with ethanol


    Then to esterify in quantitative yield with alcohol using I2, see:

  • Ramalinga, K.; Vijayalakshmi, P.; Kaimal, T. N. B.; Tetrahedron Lett.; 43; 5; 2002; 879 - 882.

    And classical with sulfuric, see following DuPont patents:

  • US 2408889; 1944.
  • GB 428223.
  • US 2111509;
  • US 2111510; 1932.


    As you see, according to your outline, this is redicilously too much work for such a simple chemical. It should, of course, be instead obtained from commercial sources, esp when 1 liter of methyl acrylate costs 15 U$A bucks.
    Quote:
    2 ester + NH3 -> di-something-amine (1,4 nuc addition)


    Using ammonia will result in 3 conjugate additions, hence, to use clumsy IUPAC name, product would be dimethyl 3,3'-(4-methoxy-4-oxobutylazanediyl)dipropanoate, so if you have chemdraw copy/paste and generate structure to get the idea.

    Since the purpose of making 4-piperidone are some fentanyl alalogues anyway, Instead of ammonia, phenetylamine could be used, (alternatively amphetamine for order of magnitude more potent compounds), hence it will look something like:


    Step 1:

    phenethylamine + acrylic acid methyl ester ---> 3,3'-phenethylimino-di-propionic acid dimethyl ester

    Refs:

  • US 2880211

  • Biggs,D.F. et al.; J. Pharm. Sci.; 61; 1972; 1739-1745.


    Step 2:

    3,3'-phenethylimino-di-propionic acid dimethyl ester --NaH/Benzene/90 min/70C--> 4-oxo-1-phenethyl-piperidine-3-carboxylic acid methyl ester

    Ref:

  • Alexidis, Alexandros N.; Rekka, Eleni A.; Demopoulos, Vassilis J.; Kourounakis, Panos N.; J. Pharm. Pharmacol.; 47; 2; 1995; 131-137.


    Step 3:

    4-oxo-1-phenethyl-piperidine-3-carboxylic acid methyl ester --HCl (aq), heat--> 1-phenethyl-piperidin-4-one


    Ref:

  • Greek group, same paper as for step 2

    [Edited on 7-5-2005 by Sandmeyer]

    Sandmeyer - 7-5-2005 at 02:54

    As a funny sidenote, replacement of phenyl group with a furyl in the end products would probably yield active compounds, esp as thiophene analogue is even more potent. Furfuraldehyde can be made from corn: http://www.orgsyn.org/orgsyn/orgsyn/prepContent.asp?prep=CV1...

    The aldehyde then condensed with nitromethan and reduced with Zn/HCl for amine to react with methyl acrylate as pointed out in above post.

    Pretty scary how OTC those cmpnds can be...

    sparkgap - 7-5-2005 at 04:50

    Were you referring to the "thiambutenes", Sandmeyer? ;) I can attest to that; when I tried injecting it on cats, the characteristic sigmoidal tail came out within a short time span (5 minutes, IIRC). Furethidine is quite potent as well.

    sparky (~_°)

    Sandmeyer - 9-5-2005 at 06:39

    i feel compleatly disgussed by myself for making posts in this thread, could a mod be kind to remove them, please..

    A convenient one pot synthesis of fentanyl

    sairuss - 11-12-2006 at 10:31

    LINK

    PLS post

    dr. nick - 4-1-2007 at 10:29

    well, disgusting, indeed (:)), but i'd really like to know a bit more on the Mannich with Phenetylamine+Acetone+Formaldehyd, especially on the needed temperatures and the time it would take - this is going through my head for years now and i couldn't find any good info that fits good enough for this special kind of reaction.

    The Organikum-Standard Procedure for aliphatic Ketones says to reflux for 12 hours but i'm not sure if that's also true for Piperidone ...

    basstabone - 19-7-2009 at 14:34

    Quote: Originally posted by Sandmeyer  

    Step 1:

    phenethylamine + acrylic acid methyl ester ---> 3,3'-phenethylimino-di-propionic acid dimethyl ester

    Refs:

  • US 2880211

  • Biggs,D.F. et al.; J. Pharm. Sci.; 61; 1972; 1739-1745.


    Step 2:

    3,3'-phenethylimino-di-propionic acid dimethyl ester --NaH/Benzene/90 min/70C--> 4-oxo-1-phenethyl-piperidine-3-carboxylic acid methyl ester

    Ref:

  • Alexidis, Alexandros N.; Rekka, Eleni A.; Demopoulos, Vassilis J.; Kourounakis, Panos N.; J. Pharm. Pharmacol.; 47; 2; 1995; 131-137.


    Step 3:

    4-oxo-1-phenethyl-piperidine-3-carboxylic acid methyl ester --HCl (aq), heat--> 1-phenethyl-piperidin-4-one


    Ref:

  • Greek group, same paper as for step 2

    [Edited on 7-5-2005 by Sandmeyer]


    • For some reason i can't find the patent for step one. Obviously it is two portions of the methyl acrylate and I know it is done in methanol. But that is just about it.

    Another possibility for step two is to use sodium ethoxide which would be much easier to make/obtain than sodium hydride.

    Just a suggestion and was wondering about that patent.

    ~Bass

    Sandmeyer - 19-7-2009 at 15:24

    I was organic chemistry newbie at the time I made those posts, besides as you can read I thought better of it and regreted posting on this subject.

    The thread is 4 years old... :D

    [Edited on 19-7-2009 by Sandmeyer]

    entropy51 - 19-7-2009 at 15:44

    Quote: Originally posted by Sandmeyer  
    I was organic chemistry newbie at the time I made those posts, besides as you can read I thought better of it and regreted posting on this subject.

    The thread is 4 years old... :D

    [Edited on 19-7-2009 by Sandmeyer]


    How many more years before you stop being an organic chemistry newbie?:P

    ergoamide - 30-7-2009 at 18:30

    This thread might be 4 yrs old but I feel I must point out a mistake that everyone seems to say. It's commonly said that the thiophene analogue is more potent but that is actually false. I have never found information about the thiophene analogue of fentanyl but the commonly called thiofentanyl/thiofentanil should be more appropriately called thioCARfentanil. This compiund is 6000x morphine in potency while ordinary carfentanil is 10000x morphine in potency. So as you can see the replacement of the benzene ring with a thiophene decreases potency not increases as commonly thought.

    Ergo

    Maxwell - 2-8-2010 at 15:29

    Скорее всего возможно синтезировать пиперидоны-4 следующими путями пиридин кватернизуется алкид галогенидом затем восстанавливается борогидридом натрия и полученный ТГП переводится в диол или эпоксид который в кислой среде должен дать пиперидон...

    Satan - 3-8-2010 at 01:58

    Quote: Originally posted by Maxwell  
    Скорее всего возможно синтезировать пиперидоны-4 следующими путями пиридин кватернизуется алкид галогенидом затем восстанавливается борогидридом натрия и полученный ТГП переводится в диол или эпоксид который в кислой среде должен дать пиперидон...


    Quote: Originally posted by Maxwell translated  
    Most likely possible to synthesize piperidones -4 by the following ways pyridine is quaternized alkyd by halide then it is restored by boron hydride of sodium and obtained [TGP] is transferred into diol or epoxy which in the acid medium it must give the piperidone...

    solo - 30-8-2015 at 15:16

    Reference Information



    Piperidone synthesis using amino acid: A promising scope for green chemistry
    C. Soundarrajan a,⁎, K. Saraswathi
    Microchemical Journal
    98 (2011) 204–206



    Abstract
    Piperidone is a family of organic chemicals characterized by a 6-carbon ring substituted with nitrogen and a double-bonded oxygen atom. Piperidones are named by the location of the nitrogen or amine group on the ring. It differs from piperidine by the presence of oxygen molecule (from ketone). It is used in pharmaceutical companies and chemical manufacturers as intermediates having anti microbial activity. It is usually synthesized using ammonia both in laboratory and industry. In present study, amino acid namely aspartic acid is used instead of ammonia. The amino acid incorporated piperidones is purified and analyzed using NMR spectroscopy. It has antimicrobial activity against Pseudomonas aeruginosa and Salmonella aboni



    Note; it seems it produces 4-piperidone....rather easy!






    Attachment: Piperidone synthesis using amino acid- A promising scope for green chemistry.pdf (284kB)
    This file has been downloaded 2573 times

    [Edited on 31-8-2015 by solo]

    [Edited on 31-8-2015 by solo]

    Chemi Pharma - 26-9-2017 at 11:14

    However this is an old topic, I think interesting bring to all some paper telling more about the mannich condensation between ketones, aldehydes and amines (or ammonea) to afford 4-piperidones.

    4-piperidones are widely used to sinthesize fentanyl related drugs.

    The patent I bring below study this kind of mannich reaction and comes with an experimental section showing a little more about the work up and reaction conditions.

    Attachment: 4-piperidones-one-pot-1 (fentanyl).pdf (341kB)
    This file has been downloaded 1607 times