Fentanyl question

[Bandil]

The page

https://www.thevespiary.org/rhodium/Rhodium/chemistry/fentanyl.html

describes nicely how to produce fentanyl, but there are some things that are not quite clear.

1:
In the preparation of N-Phenethyl-4-piperidone, there is not mentioned anything about the amount of reagents used. Only how much acetonitrile and carbonate is to be used. Anyone have a clue on how much was inteded?

2:
The commercial piperidone hydrochloride, comes as the hydrated version, with the ketone group as the diol(like formalin). I suppose it cant be any different, since there are no alternatives available without the hydrate. Will this interfere with the reaction in some way?

Thanks!

Regard
Bandil

[Rhodium]

1) I believe Siegfried left that part out as to create an obstacle for the unskilled chemists out there, who would otherwise be able to hurt/kill themselves, as the synthesis is otherwise easy enough for some of them to actually succeed.    I would guess that the reaction in his example is intended for a molar run.

2) No it won't, just like it seldom does in the case of formalin, it reacts just like an aqueous solution of formaldehyde.

[Bandil]

In the last reaction with propionyl chloride, pyridine is used as solvent. As far as i can tell, they use pyridine, because it acts as an acid scavenger. It is also unable of reacting with the propionyl chloride, because it is a tertiary amine.

Isn't it possible to use another tertiary amine as solvent for this reaction? Something like triethylamine, diisopropylethylamine or another tertiary amine?

Regards
Bandil

[SPISSHAK]

pyridine, DMAP is even better (have an aldrich account?)
you see the tertiary amines will scavange the acids, but the pyridine works by forming a pyridynium-chloramide intermedate and the reaction goes thru a differrent mechanism, which accelerates the reaction and buffers the acid produced.

[Rhodium]

It is not only an acid scavenger, it also forms a complex with the propionyl chloride which is even more nucleophilic than the acid chloride alone.

Compare with the reaction mechanism in Fig. 2 on page 196 in

https://www.thevespiary.org/rhodium/Rhodium/pdf/heroin.synthesis.pdf

where acetic anhydride is used with the highly active acylation catalyst 4-dimethylamino-pyridine (DMAP) to acetylate morphine in superior yields. The reaction mechanism is similar to that of pyridine itself (it just lacks the tautomer depicted in the upper right corner).

Aliphatic tertiary amines also catalyzes acylations in a similar fashion, but pyridine is superior to any of them, and DMAP further still.

[SPISSHAK]

DMAP accelerates acylation reaction 10,000 fold over pyridine and probably allow for gentler conditions, I also know it has the advantage of being able to catalyze acylation of stericly hindered tertiary alcohols quite well.
The only problem being: Most ordinary folks don't have an account with Fluka, Fisher, or Sigma-aldrich and the like.
But the discussion is fun at least.

[Rhodium]

One idea:


Pyridine --SOCl₂--> N-(4-Pyridyl)-Pyridinium Chloride HCl --[DMF,180°C]--> 4-Dimethylamino-pyridine (DMAP)



N-(4-Pyridyl)-Pyridinium Chloride HCl

Organic Syntheses, CV 5, 977

(http://www.orgsyn.org/orgsyn/prep.asp?prep=cv5p0977)

In a 2 L RB flask is placed 395g (5 moles) of dry pyridine (dried 24h over BaO and distilled immediately before use). As this flask is cooled by swirling in a bath of cold water, there is added during a few minutes 1190g (10 moles) of a good commercial grade of thionyl chloride. After completion of the addition, the flask is protected by a drying tube, and the reaction mixture is allowed to stand at room temperature under a hood for 3 days. During this period, the color of the mixture changes from deep yellow through brown to black.
The flask is fitted with a Claisen head, and excess thionyl chloride is distilled at reduced pressure (water pump) and collected in a receiver cooled in a mixture of dry ice and acetone (since thionyl chloride ruins all rubber tubing with which it comes in contact, efficient cooling of the receiver is recommended). The flask is heated with a water bath that is slowly raised from room temperature to about 90°C, then held at that temperature until no more distillation occurs and a black residue remains.
The black residue is cooled to 0°C, and 100 ml. of ice-cold ethanol is added very cautiously to react with residual thionyl chloride. An additional 400 ml of ice-cold ethanol is added, and the solid mass left at the bottom of the flask is broken up with the aid of a rod. The resultant light-brown powder is collected by suction filtration, preferably on a sintered glass funnel, and washed with five 150-ml. portions of ethanol. The yield of crude N-(4-pyridyl)-pyridinium chloride HCl is 230–257g (40–45%). This product is very deliquescent and should be used immediately or stored over P₂O₂.


4-Dimethylamino-pyridine (DMAP)

Patent DE2517774

229g (1 mole) of crude N-(4-Pyridyl)-Pyridinium Chloride HCl were dissolved in 146.2 g (2 moles) of dimethylformamide at about 140-150°C, and the solution was heated, while stirring, for 2 hours at a bath temperature of 180°C, and 90 ml of crude pyridine (boiling point 111-122°C) distilled off. The resulting dark resldue was allowed to stand with 100 g of sodium hydroxide in 1 litre of water, filtration was carried out to remove the black insoluble residue and the residue and solution were exhaustively extracted with methylene chloride. After drying the methylene chloride extract with sodium sulfate and treatment with a small amount of decolorizing charcoal there were obtained 68.3 g (56% yield) of crude 4-dimethylamino-pyridine (DMAP), which melted at 112-113°C after recrystallization from diisopropyl ether.

[slappy]

Be careful with DMAP. It is very toxic and can tend to be extremely hard to completely remove from your products, especially if it is an amine.

[SPISSHAK]

In demethylation of codeine too, any suggesstions?
Could you vacum sublime, chromatograph it, or subject the product to vacum and isolate the DMAP by evaporation?