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One-pot synthesis of amphetamine from P2NP with NaBH4/CuCl2 (1kg scale)

William Dampier

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Reaction scheme:
GzjcutCFE8


Synthesis:
1. Solution IPA/H2O 2:1 (18 liters) was added to the reactor.
2. NaBH4 (1739 g) was added at once and stirring was started.
3. P2NP (1000 g) was added in small portions, so that the temperature of the mixture did not exceed 60 *С.
JoZSYpsRiU

4. CuCl2 (105 g) in water (200 ml) was added slow dropwise, so that the temperature of the mixture did not exceed 80 *С.
V0iAhpYWBw

5. Thereafter, reaction was then held at 80 °C for 30 minutes using external heating.
6. 25% water solution of NaOH (8 liters) was added to reaction mixture and the phases were separated.
7. The aqueous phase was there after extracted with 8 liters of IPA.
8. IPA was evaporated on vacuum to an oil.
9. The oil was dissolved in two liters of acetone.
10. Sulfuric acid (or orthophosphoric acid) dripped to pH - 6 (with constant stirring).
11. The mixture was put in the freezer for 12 hours.
12. After crystallisation the suspension was filtered and washed with dry cold acetone to yield 60-70%.
 
Last edited by a moderator:

Sasha89

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First off all thank you very much for these very interessting synthesis route.
Is a 30l glass reactor useable for this way? (Something like that u see on the picture)
And how do you realize the stirring? Are you using a electrical overhead stirrer?
 

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William Dampier

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First off all thank you very much for these very interessting synthesis route.
Is a 30l glass reactor useable for this way? (Something like that u see on the picture)
yes
And how do you realize the stirring? Are you using a electrical overhead stirrer?
need over-head stirrer for this flask type
 

rickyrick

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If scaling this reaction up do you scale everything or extracting the aqueous layer with IPA doesnt need to be linear scaled?
 

DocX

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This is a really nice synthesis without the mercury waste or possible mercury contamination generated by the Al/Hg reduction. I saw it on The Vespiary some months ago and was going to do a write-up here once I'd tried it myself. But as usual, you guys beat me to it :). Thanks for the excellent text!
 

diogenes

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Is it possible to scale this down? I have all the ingredients, but would rather try on a small scale first.
 

Uncle Lee

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This reaction is very good on a small scale
In a large reaction, trying to control the exotherm and the large amount of foam by putting the CuCl2 solution slowly into the flask will not give a high yield, there may be nothing but nitroalkanes and the concentration of nanoparticles will be too small to reduce the nitro, the largest flask possible should be used and the entire CuCl2 solution should be added at once
 

btcboss2022

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Reaction scheme:
View attachment 1411

Synthesis:
1. Solution IPA/H2O 2:1 (18 liters) was added to the reactor.
2. NaBH4 (1739 g) was added at once and stirring was started.
3. P2NP (1000 g) was added in small portions, so that the temperature of the mixture did not exceed 60 *С.
View attachment 1412
4. CuCl2 (105 g) in water (200 ml) was added slow dropwise, so that the temperature of the mixture did not exceed 80 *С.
View attachment 1413
5. Thereafter, reaction was then held at 80 °C for 30 minutes using external heating.
6. 25% water solution of NaOH (8 liters) was added to reaction mixture and the phases were separated.
7. The aqueous phase was thereafter extracted with 8 liters of IPA.
8. IPA was evaporated on vacuum to an oil.
9. The oil was dissolved in two liters of acetone.
10. Sulfuric acid (or orthophosphoric acid) dripped to pH - 6 (with constant stirring).
11. The mixture was put in the freezer for 12 hours.
12. After crystallisation the suspension was filtered and washed with dry cold acetone to yield 60-70%.
Hello,

Is normal to have a solid precipitate after point 6? I made twice with the same result I just filtered.
Thanks.
 

William Dampier

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Is normal to have a solid precipitate after point 6? I made twice with the same result I just filtered.
Yes, an insoluble precipitate should fall out. So, we remove excess salts, getting the base.
 
Last edited by a moderator:

Sasha89

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What is the best way to carry out an extraction with such big quantities, stir well and then decant?
and does the distillation have to be carried out in a vacuum or can the IPA also be distilled off in the normal way?

Sorry for the last writing in german, didnt see that autotranslator was on
 

William Dampier

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The alcohol (or other extraction solvent) must be evaporated, otherwise crystallization of the final product will be a problem.
 

Sasha89

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possible to do the vacuum distillation with a pump with the following specs:
Flow rate (max.): 5.5 l/min.
Ultimate vacuum (max.): 160 mbar (abs.)

and what would be the boiling point of the IPA with ussage of this pump
 

Montecristo

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Dec 29, 2021
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Reaction scheme:
View attachment 1411

Synthesis:
1. Solution IPA/H2O 2:1 (18 liters) was added to the reactor.
2. NaBH4 (1739 g) was added at once and stirring was started.
3. P2NP (1000 g) was added in small portions, so that the temperature of the mixture did not exceed 60 *С.
View attachment 1412
4. CuCl2 (105 g) in water (200 ml) was added slow dropwise, so that the temperature of the mixture did not exceed 80 *С.
View attachment 1413
5. Thereafter, reaction was then held at 80 °C for 30 minutes using external heating.
6. 25% water solution of NaOH (8 liters) was added to reaction mixture and the phases were separated.
7. The aqueous phase was thereafter extracted with 8 liters of IPA.
8. IPA was evaporated on vacuum to an oil.
9. The oil was dissolved in two liters of acetone.
10. Sulfuric acid (or orthophosphoric acid) dripped to pH - 6 (with constant stirring).
11. The mixture was put in the freezer for 12 hours.
12. After crystallisation the suspension was filtered and washed with dry cold acetone to yield 60-70%.
Any major risks with this synth?
 

William Dampier

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Any major risks with this synth?
The reaction with sodium borohydride may get out of control if you do not monitor the temperature. In addition, small-dispersed copper compounds can interfere with the purification of the final product.
 

Montecristo

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The reaction with sodium borohydride may get out of control if you do not monitor the temperature. In addition, small-dispersed copper compounds can interfere with the purification of the final product.
Thanks !
 

Mclssmxxl

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In small scale can the workup be replaced with salting out the ipa after alkalization and extracting with say toluene then dried over something appropriate? I dont see why not but maybe im missing something.I dont own a rotovap.
 

Sasha89

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What do you use for external heating to keep the temperature on 80 °c for 30 mins?
 

Mclssmxxl

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What do you use for external heating to keep the temperature on 80 °c for 30 mins?
Hotplate, heating mantle(might be too much even on low), deffo not open flame.
 

G.Patton

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First off all thank you very much for these very interessting synthesis route.
Is a 30l glass reactor useable for this way? (Something like that u see on the picture)
And how do you realize the stirring? Are you using a electrical overhead stirrer?
Worth using Batch chemical reactor for this scale.
 

Sasha89

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Mar 15, 2022
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After dozens of successful syntheses, it actually failed for me this time.
my glass reactor had a small crack which unfortunately led to a large one and has therefore become leaky. Luckily this happened shortly before the addition of CuCl2. I then stopped the synthesis, quenched the reaction with H2o and put it in a canister.
My question now: Can the mixture of NabH4 and P2NP be separated in any way so that both can be returned to their original forms? so that it can be used again for another new synthesis.
 
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