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Synthesis of Racemic Ephedrine

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Synthesis of Racemic Ephedrine1

A mixture of 50 mL of absolute ethyl alcohol, 7.4g of 1-phenyl-1,2-propanedione (50 mmol) and an alcoholic solution of methylamine containing 1.6g (50 mmol) was reduced catalytically with hydrogen in the presence of 100 mg of platinum oxide3. In some experiments there was a long induction period and then the yield was low. This behavior could be obviated by reducing the catalyst first and then adding the reactants. When reduction no longer proceeded, the catalyst was removed by filtration and about half the alcohol removed under reduced pressure. By this means any excess of methylamine was removed. The solution was made just acid with alcoholic hydrogen chloride and evaporated to dryness. The solid hydrochloride was washed with cold acetone and dried. A small amount of pseudoephedrine hydrochloride could be extracted from this by means of hot chloroform and by working up a number of extractions sufficient was obtained for definite identification (mp 164°C; free base, mp 118°C)2,3.

The dl-ephedrine hydrochloride was purified by recrystallizing once from alcohol-acetone and melted at 189°C2. The free base was recrystallized from chloroform-petroleum ether and melted at 75°C. The yield was 2.5-4.0 g.


Resolution of Ephedrine with Mandelic Acid

Resolution of dl-Ephedrine4

A mixture of 13.8g of dl-ephedrine and 7.7 g. of d-mandelic acid was dissolved in 30 cc. of hot 95% alcohol. On cooling the d-ephedrine-d-mandelate crystallized out. After two recrystallizations from a small volume of alcohol the product consisted of colorless, rhombic plates, melting at 170°C with previous sintering at 167°C. The combined mother liquor yielded a further small amount of this product. The salt as thus obtained was basified with potassium hydroxide and the base was extracted with ether. The ethereal solution was evaporated to a small volume and treated with alcoholic hydrogen chloride. The d-ephedrine hydrochloride as thus obtained melted at 218-218.5°C and had [α]24D +35.6° in a 2% aqueous solution; yield, 5.3 g.

The mother liquor from the mandelate of the d-base was basified and the extracted base treated with 7.7g of l-mandelic acid. The crystalline mandelate was twice recrystallized from a small volume of alcohol; mp 170°C with previous sintering at 167°C. The l-ephedrine hydrochloride obtained from the mandelate melted at 218-218.5°C, alone or admixed with a purified specimen from Ma Huang, and had [α]24D -35.5°C in 2% aqueous solution; yield, 6.7 g.

It was now possible to obtain a further amount of d- and then l-base from the mother liquor from the mandelate crystallizations by alternate treatment with d- and l-mandelic acid, respectively.

Resolution of dl-Mandelic Acid4

Considerable quantities of mandelic acid were required in the resolution of ephedrine and as far as the authors are aware the most convenient source of d-mandelic acid is from the sparingly soluble cinchonine salt. This process was described almost simultaneously by McKenzie5 and by Rimbach6. McKenzie prepared a number of salts of d- and l-mandelic acid with various alkaloids and recorded their melting points among other physical properties. Rimbach did not record melting points. Recently Ward, Chrisman and Nicholas7, while in agreement with McKenzie in so far as the resolution is concerned, pointed out a discrepancy in the melting points as recorded by the latter for the quinine salts of the d- and l-acids. The present authors found for the melting point of cinchonine-d-mandelate 176-177°C. McKenzie gives 79-80°C. Probably this author interchanged a number of his figures.

Undoubtedly the simplest method of preparing l-mandelic acid is by resolution with l-ephedrine when this base is available. For this purpose 12 g of l-ephedrine and 12 g of dl-mandelic acid are heated together in 40ml of 95% alcohol. The crystals obtained on cooling are twice recrystallized from a small volume of alcohol. The optically pure mandelic acid obtained by acidification, extraction with ether and recrystallization by spontaneous evaporation of an acetone solution melted at 133.5°C and had [α]20D -156.9° in 2% aqueous solution. The yield was 5.9 g.

Some d-mandelic acid was obtained from the combined mother liquor from which no more crystalline salt was obtainable. The acid after several recrystallizations from water melted at 132°C.


  1. J. Am. Chem. Soc. 51, 580 (1929)
  2. Monatsheft 41, 319 (1920)
  3. J. Am. Chem. Soc. 45, 2171 (1923)
  4. J. Am. Chem. Soc. 51, 1906 (1929)
  5. J. Chem. Soc. 75, 966 (1899)
  6. Chem. Ber. 32, 2385 (1899)
  7. J. Chem. Soc. 2186 (1928)