Author Topic: 1-(2-phenethyl)-4-phenyl-4-acetoxypiperidine synth  (Read 1101 times)

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  • Guest
1-(2-phenethyl)-4-phenyl-4-acetoxypiperidine synth
« on: February 04, 2003, 02:08:00 PM »
I 'm going to present here a two step PEPAP synthesis.

Step 1: Synthesis of 1-(2-phenylethyl)-4-phenyl-4-piperidinol

A mixture of 2-phenylethylamine (121 g), an equivalent amount of concentrated hydrochloric acid (93 ml), alpha-methylstyrene (118 g) and aqueous 37 % formaldehyde (200 g) was stirred and heated at 80 °C for 3 hours.  The resultant clear solution was refluxed for 5 hours and left at room temperature overnight.  The product, consisting of 2 layers, was washed with benzene (3 x 100 ml), made alkaline with aqueous 50 % NaOH solution and extracted with benzene (3 x 100 ml).  After drying (K2CO3) approximately 200 ml of solvent was evaporated and the residue diluted with n-hexane until a faint permanent cloudiness was obtained.  The crystals which separated on cooling were collected and recrystallized from light petroleum (b.p. 80 - 100 °C) to give 1-(2-phenylethyl)-4-phenyl-4-piperidinol (36.7 g) needles, m.p. 102 - 103 °C.

Step 2: Acetylation

A mixture of 1-(2-phenylethyl)-4-phenyl-4-piperidinol (2 g), acetic anhydride (3 ml) and pyridine (3 ml) was refluxed for 3 hours and the solvents were removed under reduced pressure.  The residue was converted into a hydrochloride and recrystallized from ether-ethanol.

M.p. PEPAP.HCl: 214 - 215.5 °C


  • Guest
Re: subject
« Reply #1 on: February 04, 2003, 02:18:00 PM »
Got refs? What's the final yield?


  • Guest
Got refs? Sure. A.H. Beckett, A.F. Casey, G.
« Reply #2 on: February 04, 2003, 03:04:00 PM »
Got refs?


A.H. Beckett, A.F. Casey, G. Kirk, J. Med. Pharm. Chem. (1959) vol. 1 n° 1 p 37 - 58: Alpha- and Beta-Prodine Type Compounds.

What's the final yield?

No final yield was given, a whole bunch of analogs was synthesised, with M.P. & elemental analysis  ... but without yield (this is a VERY bad synthetic practice ... I guess they got inspired by patents, where all too often no yield is specified  >:( ).


  • Guest
Problem shooting
« Reply #3 on: February 04, 2003, 04:32:00 PM »
I forsee a problem with this synthesis however.

Check out Post 404190 (not existing).  As you can see, there were some serious health problems with MPTP in 1982.  Since my J. Pharm. Chem. article is from 1959, it is reasonable to say they didn't know about the neurotoxicity of the dehydro product.  Consequently, they didn't have to worry about it when they performed the acetylation.

Well, I do worry about the acylation: acetic anhydride is a dehydrating agent!  Refluxing the piperidol with Ac2O is rather unsafe, if you ask me ...

I 'd like to have a second oppinion about this: is the risk of elimination substantial?  How can we do the acetylation without dehydratation?  I thought about those amide coupling agents used in peptide chemistry, like dicyclohexylcarbodiimide.  Have to research this further, but any ideas are wellcome.


  • Guest
« Reply #4 on: February 04, 2003, 04:43:00 PM »
Dissolve the tert. piperidinol in ANHYDROUS ether (Et2O or TBME) and add dropwise with STRONG stirring 105% of theory acetyl chloride. Clouds of the desired ester-HCl are formed immediately. Let stand a few hours for complete crystallization and filter off, wash with ether.
I've done this several times with N-Ethyl-4-phenylpiperidin-4-ol and propionylchloride in TBME with yields between 90 and 95%. Further purification can be achieved with recrystallization in acetone.