kyanite
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Theoretical Synthesis of 4-Piperidone/Piperidine
 AHH I PRESSED BACK! TWICE!
I'm afraid to press any buttons!
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.
acetone +formaldehyde -base-> beta-hydroxy ketone (crossed-aldol rxn)
beta-hydroxy ketone -H2SO4-> alpha,beta-unsaturated ketone (dehydration)
haloform rxn, acidic work-up
esterfication with ethanol
2 ester + NH3 -> di-something-amine (1,4 nuc addition)
di-something amine -MOEt(where M is w/e metal)-> beta-keto ester (Dieckmann rxn)
Hydrolysis with acid, and reflux to decarboxylate
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]
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Sandmeyer
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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]
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Sandmeyer
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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...
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sparkgap
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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 (~_°)
"What's UTFSE? I keep hearing about it, but I can't be arsed to search for the answer..."
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Sandmeyer
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i feel compleatly disgussed by myself for making posts in this thread, could a mod be kind to remove them, please..
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sairuss
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A convenient one pot synthesis of fentanyl
LINK
PLS post
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dr. nick
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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 ...
of course you can well i couldn\'t before
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basstabone
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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
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Sandmeyer
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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... 
[Edited on 19-7-2009 by Sandmeyer]
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entropy51
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| 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...
[Edited on 19-7-2009 by Sandmeyer] |
How many more years before you stop being an organic chemistry newbie?
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ergoamide
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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
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Maxwell
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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...
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Satan
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| 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... |
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solo
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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 2934 times
[Edited on 31-8-2015 by solo]
[Edited on 31-8-2015 by solo]
It's better to die on your feet, than live on your knees....Emiliano Zapata.
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Chemi Pharma
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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 1877 times
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