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mongler
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that is basically the same reaction that was referenced earlier, but using the diacid/diester instead of a simple ketone (eg: using a more activated
enolate source, compared with the ketone).
I mentioned this earlier. pretty much every standard text claims that an unsubstitued ketone has such a high pKa that reactions usually proceed very
slowly without the use of a strong non-nucleophilic base.
the previous reference used ammonia in glacial acetic acid, which was the only reason why the reaction occured.
had it been performed in aqueous ammonia, the enolate would not form in sufficient concentration to drive that reaction in any reasonable time scale.
but if you look at that wikipedia article, there is a referenced total synthesis using that di-acetal of the trialkyl amine...
that gives me hope. it means that it is at least possible to run the reaction with an unstabilized aldehyde (they used the acetal, which was a good
idea...)
I still think that the low cost of formaldehyde and ammonia should make this feasible, even with a precipitously low yield.
even the acetone dicarboxylic acid that would be the most effective starting material can be had from citric acid without too much fuss. that oft
repeated de carbonylation has good yields.
run this rxn on a mole scale, and even with a 10-20% yield (10% of you include the subsequent decarboxylation step that might yield something like
50%, so (0.2)(0.5)x100 = 10%).
the key is thinking like and INDUSTRY chemist. how can you avoid purification steps. purification/isolation = time, money, and lost material,
especially on larger scales. I designed my proposed convergent scheme around this concept (as welll as minization of watched reagent use)
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jon
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you can just save the trouble and buy the acetone dicarboxylic ester anywhere selling fine chemicals.
no you won't have any ray-bans showing up at your door.
glad i could help.
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Text still think that the low cost of formaldehyde and ammonia should make this feasible, even with a precipitously low yield.
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why use ammonia? i thought you were after n-substituted piperidones?
you know, as fragrance chemicals.
read page 304 of organic reactions vol 1
they react acetone formaldehyde and methylamine
but as i said thier stochiometry is off they used 2 moles ketone and got the aldol condensation product of 4-piperidone so this shows this scheme is
workable i would attach but it's 4 mb sorry.
here it is:
http://rapidshare.com/files/455330948/Organic-Reactions-v1.p...
[Edited on 31-3-2011 by jon]
[Edited on 31-3-2011 by jon]
[Edited on 31-3-2011 by jon]
[Edited on 31-3-2011 by jon]
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SciWiz
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Good PEA -> 1-2-Phenethyl-4-Piperidone NPP w/Refs
Since I've been digging around on piperidones lately, and I'm trying to learn how they work (I'm a Freshman, so I'm a total NOOOB). I spent the past
few days studying the transformations that take place during the steps from the starting materials to the final product 1-2-Phenethyl-4-Piperidone, or
as you guys call it, NPP. I know it's used for bad drugs. However, the chemistry of it is driving me crazy. People have been posting here for years
but I have yet to find a successful post by anyone, or more than a couple people say "Oh, yeah, that method works, AND HERE IS WHY." I really want to
understand as much as possible about the reactions and molecular changes that are taking place when it's made. Please take a peek, and if you know
this method, and have a couple minutes, I would love to know what's really happening to the ring, etc, here.
Some people say to start with the Piperidone HCL monohydrate and combine with Ethyl Acrylate, etc/, etc. But, it's got a lot of steps and there must
be a better way.
Here it is:
You can use this method to use the Double mannich
You can use this method to use the the mannich reaction to get 1-2-phenethyl-4-piperidone if you change the benzylamine for phenethylamine and the
3-methyl-2-butanone for acetone.
In theory, if you used MEK you could create a product 1000x stronger than Morphine (thats my opinion after all the reading I did).
Also, if you use MEK instead of acetone, the reaction should result in 1-phenethyl-3-methyl-4-piperidone, which is what the druggies prefer
(speculation), it's like 1000x more powerful, etc. It caused a ton of deahs, I read about them while doing research.
First, here is a link to the patent which makes this all possible, hopefully:
http://www.google.com/patents/US20030232833
Remember, replace the Benxylamine and the 3-methyl-2-butanone. Okay here is the process:
In a 1 liter 3-neck flask equipped with a mechanical stirrer, an addition funnel and a calcium chloride drying tube was added a 37% weight solution
of formaldehyde (168.5 mL, 2.25 mole) dissolved in 500 mL of absolute ethanol. The resulting solution was cooled in an ice-water bath to 10° C., and
benzylamine (109 mL, 1 mole) was added dropwise over a one hour period. In a separate 3-liter 3-neck flask equipped with a mechanical stirrer, an
addition funnel and two condensers was added 3-methyl-2-butanone (113 mL, 1.06 mole) dissolved in 500 ml of absolute ethanol and concentrated hydrogen
chloride (92 mL, 1.11 mole). The resulting solution was brought to reflux and the formaldehyde/benzylamine solution is added dropwise over a 2 hour
period. This solution was heated at reflux overnight, and then cooled to ambient temperature. Diisopropylethylamine (142.2 g, 1.1 mole) and
formaldehyde (22.46 mL, 0.3 mole) were added and the resulting solution was heated to reflux for six hours, and then cooled to ambient temperature.
The solution was quenched with potassium hydroxide (61.6 g, 1.1 mole) in 200 mL of water, and then extracted 3 times with 500 ml ethyl acetate. The
organic layers were concentrated under vacuum to give 225 g of a red oil. The crude oil was dissolved in 1 liter of methylene chloride. This solution
was carefully poured over 1 kg of silica gel on a sintered glass filter. The silica gel was washed with 4 L of methylene chloride. The methylene
chloride was concentrated under vacuum to provide 142 g of a yellow oil which was crystallized in a freezer overnight. Yield=65.4%. MS(ion
spray)=218.3(M+1)
Then I found a good writeup of the "most" accepted method of using acrylate. Here it is:
rxn between acrylic acid ester and beta-phenethylamine..
N-Di-(2-carbethoxyethyl)-2’-phenylethylamine
Ethyl acrylate (300 g) was added with stirring to 2-phenylethylamine (121 g) in dry ethanol (200 ml) and the mixture refluxed for 48 h. The product
was fractionally distilled under reduced pressure to give N-di-(2-carbethoxyethyl)-2’-phenylethylamine (303 g) as a colourless oil, b.p. 166-168’
(0.3 mm)
Dieckmann condensation..
N-2’-phenylethyl-4-piperidone ethylketal.
N-Di-(2-carbethoxyethyl)-2’-phenylethylamine (70 g) was added to a stirred suspension of bird shot sodium (10.8 g) in xylene (250 ml) and the
mixture, protected from moisture, warmed to 50’ to initiate the reaction. A further quantity of base was then added drop-wise at a rate sufficient
to maintain the reaction. Stirring was continued for 3 h after addition of the base, the mixture cooled, and water (250 ml) added drop-wise. The
aqueous phase was separated, washed with ether (2 x 100 ml), and acidified with concentrated hydrochloric acid (congo red). The solution was saturated
with anhydrous potassium carbonate and the yellow oil which separated extracted with ether (600 ml). After drying (K2CO3), the ether was evaporated to
give crude N-2’-phenylethyl-3-carbethoxy-4-piperidone (103 g). The ketone was refluxed with aqueous 20 per cent hydrochloric acid (450 ml) for 3.5 h
(negative reaction with ferric chloride). The product was evaporated to dryness under reduced pressure, the free base liberated with aqueous 25 per
cent sodium hydroxide and extracted with ether. After drying (Na2SO4), the ether was evaporated and the residue treated with excess of alcoholic 10
per cent hydrochloric acid. The crystals (42 g) which separated were collected, the free base liberated with aqueous ammonia and extracted with ether.
The ether was dried (Na2SO4) and the ether evaporated to give N-2‘-phenylethyl-4-piperidone ethylketal (35 g) as a pale yellow oil which could not
be distilled. It gave a hydrochloride. needles from ethanol, m.p. 178-179' dec. The ketal gave a picrate, needles from ethanol, m.p. 136-137' dec.
and finally, decarboxylation..
N-2'-phenylethyl-4-piperidone.
A mixture of N-2'-phenylethyl-4-piperidone ethylketal (20 g) and dilute aqueous hydrochloric acid (150 ml) was refluxed for 2 h. cooled aid washed
with ether. The free base was liberated with aqueous ammonia and extracted with ether. After drying (Na2SO4), the ether was evaporated and the residue
(13.0 g) crystallized from light petroleum (b.p. 80-l00') to give N-2'-phenylethyl-4-piperidone (12.1 g), needles. m.p. 60.5-61.5'.
- phenethylman -
(No references attached to this second method)
This patent (first one)looks co\\\\mpletely legit to me, I believe this is a viable route.
Have any of you guys seen this patent before, has anyone has any success, or did it fail. My curiosity lies in the fact that this particular
piperdone has no valid synthesis. Literally, I'be looked at about 10 different N-arylations for this, and everyone has very conflicting results. It
seems like there is a ton of theory, but, now facts.
Have a great day everyone!!!
[Edited on 4-10-2013 by SciWiz]
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solo
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"Ethyl acrylate (300 g) was added with stirring to 2-phenylethylamine (121 g) in dry ethanol (200 ml) and the mixture refluxed for 48 h. The product
was fractionally distilled under reduced pressure to give N-di-(2-carbethoxyethyl)-2’-phenylethylamine (303 g) as a colourless oil, b.p. 166-168’
(0.3 mm)".....SciWisis
....the Hinsberg test for amines showed a secondary instead of a tertiary amine on the bi ester, I guess i have to test the b.p. to verify its the
tertiary amine.....as for the Dieckmann condensation..seems not to work for me ....using 25% sodium methoxide in methanol....will try it with
potassium methoxide see if i can get the condensation to ocurr....i also failed to heat the solution to 50˚C so i have a couple of hurdles to
cover.....solo
It's better to die on your feet, than live on your knees....Emiliano Zapata.
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