Constitution of ephedrine - Desoxyephedrine

A. Ogata
Chemical Abstracts 14, 745 (1920)

Corresponding to J. Pharm. Soc. Japan, 451, 751-54 (1919)

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  1. PhCH(OH)CHMeNHMe
  2. PhCH(NHMe)CHMeOH
  3. PhCH(OH)CH2CH2NHMe
  4. PhCH(NHMe)CH2CH2OH
  5. PhCH2CH(OH)CH2NHMe
  6. PhCH2CH(NHMe)CH2OH

Ephedrine was discovered in Ephedra vulgaris by Prof. Nagai. It is known to contain a benzene nucleus, a side chain with three carbon atoms, a hydroxy and a methylamino group. The main point of uncertainty is the positions where the hydroxyl and methylamino groups are linked. The six possibilities are:

Through a study of the structure of desoxyephedrine, Ogata attempts to show that A is the correct formula for ephedrine. From the work of E. Smidt, Miller, Bumming, and Nagai, Ogata concludes that the hydroxyl is linked to the phenyl group. If the methylamino group is linked at the last carbon atom, the removal of the hydroxylic function from ephedrine ought to produce optically inactive desoxyephedrine but the fact is that the resulting product is dextrorotatory. If it is present at the next to the last carbon atom, then the resulting compound should be identical with synthetic phenylisopropylmethylamine. Ogata has prepared desoxyephedrine by reducing the condensation product of PhCH2COMe and MeNH2.

Experimental

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 sodium metal 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 134-135°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.

Isomer Freebase bp HCl Salt mp
dl
209-210°C
131-5°C
d
208-210°C
170-175°C
l
210°C
170-171°C

In all respects, this product is very similar to phenylisopropylamine obtained by Nagai by reducing ephedrine and its analysis shows it to be C10H15N. 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: