Synthesis of Amphetamines


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Phenyl-2-nitropropene [1]

0.2 Mole of benzaldehyde, 0.2 mole of nitroethane and 0.02 mole of n-amylamine were mixed and set aside at room temperature in the dark. After a day water began to separate from the mixture; after several days the mixture became quite solid. After two weeks, the mixture was dissolved to a homogeneous solution by warming with 50 ml of ethanol and then on cooling 0.15 mole of phenyl-2-nitropropene melting at 65-66°C was obtained as a fine crystal product. The melting point of this compound has been reported as 64°C (Ber. 43, 189 (1910)).

Amphetamine [1]

0.1 Mole of phenyl-2-nitropropene dissolved in a catholyte of 100 ml of ethanol, 50 ml of acetic acid and 50 ml of 12 N sulfuric acid was placed above a 40 cm2 mercury cathode in a porous cell surrounded by a 3 N sulfuric acid anolyte with a water-cooled lead anode. Four amperes was passed for twenty hours and the temperature in the catholyte was kept between 30-40°C.

The resultant catholyte was partially evaporated, then made strongly alkaline and the separated basic layer taken up with benzene. The desired amine was then extracted from the benzene by just neutralizing with dilute hydrochloric acid and separating the aqueous layer. This was then evaporated and the product crystallized. From phenyl-2-nitropropene, 0.02 mole of dl-beta-phenylisopropylamine hydrochloride (Amphetamine) melting at 144-145°C was obtained. The melting point of this compound has been reported as 145-147°C (4).


Methamphetamine from Phenylacetone [2]

To 100 g of alcoholic MeNH2, 40 g. of phenylacetone is added and left at room temp. for 4 weeks in a stoppered bottle. Then 150 g. of alcohol is added, and 30 g of Na is used for reduction, collecting the large amount of MeNH2 in HCl. After the reduction, H2O is added, the excess of alcohol is evaporated off, steam distillation is conducted till the distillate is no longer alkaline. HCl is used for neutralization. The insoluble portion is extracted with ether and the extract is concentrated and precipitated with HgCl2. The Hg salt is decomposed with H2S, giving 15 g of the HCl salt. After purification with alcohol, plate-shaped crystals are obtained with a mp of 134-5°C. The free base, which has an amine odor, is a liquid and has a bp of 209-210°C and 93°C at 15 mmHg.

Separation of the d- from the l-form was accomplished easily by the tartaric acid method. The further characteristics of the different isomers are as follows:

  • dl form: bp 209-210°C, HCl salt mp 131-135°C.
  • d form: bp 208-210°C, HCl salt mp 170-175°C.
  • l form: bp 210°C, HCl salt mp 170-171°C.

References

[1] G. A. Alles, JACS 54, 271-274 (1932)
[2] A. Ogata, J. Pharm. Soc. Japan 451, 751-54 (1919), CA 14, 745 (1920)