Reductive amination of phenyl-2-propanone with Sodium Cyanoborohydride (1kg scale)

[WillD]

Reaction scheme:​

​

Synthesis:
1. A mixture of phenyl-2-propanone (1000 g), ammonium acetate (6000 g), and sodium cyanoborohydride (600 g) in 15 liters of IPA was stirred at room temp for 48 h.
2. The pH of the mixture was maintained at neutrality by dropwise addition of concentrated HCl during the course of the reaction.
3. The reaction mixture was evaporated to dryness to yield a yellow semisolid that was suspended in water (25 ml) and then acidified to pH 1 by slow addition of concentrated HCl.
4. The acidic suspension was washed with methylene chloride, then made basic (pH 10) by the addition of NaOH pellets.
5. The resulting basic aqueous suspension was extracted with methylene chloride.
6. The combined methylene chloride extracts were washed with water, dried over magnesium sulfate, and evaporated to dryness to yield amphetamine as a yellow oil.
7. Dissolve oil in three amounts of acetone.
8. Dropwise sulfuric (or orthophosphoric) acid to pH - 6 when stirring.
9. Put in a freezer for 12 hours.
10. Filtrated and dried.​

 

[caesare.robot]

what are the yields of this method?

 

[btcboss2022]

Reaction scheme:
View attachment 1479


Synthesis:
1. A mixture of phenyl-2-propanone (1000 g), ammonium acetate (6000 g), and sodium cyanoborohydride (600 g) in 15 liters of IPA was stirred at room temp for 48 h.
2. The pH of the mixture was maintained at neutrality by dropwise addition of concentrated HCl during the course of the reaction.
3. The reaction mixture was evaporated to dryness to yield a yellow semisolid that was suspended in water (25 ml) and then acidified to pH 1 by slow addition of concentrated HCl.
4. The acidic suspension was washed with methylene chloride, then made basic (pH 10) by the addition of NaOH pellets.
5. The resulting basic aqueous suspension was extracted with methylene chloride.
6. The combined methylene chloride extracts were washed with water, dried over magnesium sulfate, and evaporated to dryness to yield amphetamine as a yellow oil.
7. Dissolve oil in three amounts of acetone.
8. Dropwise sulfuric (or orthophosphoric) acid to pH - 6 when stirring.
9. Put in a freezer for 12 hours.
10. Filtrated and dried.

William DampierIs possible to replace sodium cyanoborohydride by NaBH4 in less amount? Sodium cyanoborohydride is a reducing agent weaker than NaBH4 if I'm not wrong.

Thanks.

 

[caesare.robot]

swim used methanol and nabh4. after vacuum distillation ~50% yielding

 

[btcboss2022]

swim used methanol and nabh4. after vacuum distillation ~50% yielding

caesare.robotIn what amounts did it?

 

[Jamroz]

In second step u mean that pH is changing for 48h when reaction is going and i need to control it? Or maybe its enough to make it neutral one time and it stay at neutral level when reaction is going.

 

[caesare.robot]

In what amounts did it?

btcboss202290g p2p.
reaction might be sensetive to water

 

[btcboss2022]

90g p2p.
reaction might be sensetive to water

caesare.robot90gr of P2P ok and the amounts of NaBH4 and Methanol? Same timing and process as posted?
Thanks.

 

[caesare.robot]

90gr of P2P ok and the amounts of NaBH4 and Methanol? Same timing and process as posted?
Thanks.

btcboss202252g NaBH4 added in portions ca. 30min,
2 hours after on stirring 25°C.

while evaporation of methanol from RM a lots of salts are taking of?!? any suggestions.

and what is the point to keep reaction neutral?

swim is thinking about bubbling ammonia into iced and dried methanol and use it straight in reaction? using mollecular sieves? will it higher the yields?

 

[caesare.robot]

does anyone know the NH3 ratio to P2P in moles?

 

[Davidrobinson]

does anyone know the NH3 ratio to P2P in moles?

caesare.robotIt will just be 1 mole NH3 to 1 mole p2p. Stoichiometric Ratio

 

[OrgUnikum]

This gives very very low yields. The only known way to get Amphetamine by borohydride reduction and ammonia or a salt of ammonia is by adding at least one equivalent titanium-(IV)-isopropoxide.
I personally think aluminium-(III)-isopropoxide or tin-(IV)-isopropoxide might work too, but thats just a guess. And no water in the reaction. None at all.

Reason: Ammonia is in this reaction much less reactive then the formed Amphetamine, about 20 times less reactive and so most phenylacetone (P2P) will preferably react with any Amphetamine formed and one ends up with almost only the di-alkylated product what is P2P joined to Amphetamine and thats not fun.

Titanium-(IV)-isopropoxide forms a complex with the Amphetamine and prevents it from reacting with P2P.

Kindly stop making stuff up which you "think should work".
thx