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Process for the Manufacture of
Phenyl-methylaminopropanol (Synthetic Ephedrine)

Brit. Pat. 302,940

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This invention relates to the manufacture of phenylmethylaminopropanol, also known as synthetic ephedrine, by means of alpha-bromopropiophenone, its conversion to alpha-methylaminoethyl phenyl ketone as reductive amination to yield the final product, ephedrine.

A single method, described by Eberhardt appears to give sufficiently satisfactory results as far as the production of ephedrine is concerned1, but this method, however, which consists in reducing methylaminopropiophenone with hydrogen in the presence of palladium, likewise furnishes a large proportion of psuedoephedrine. Later, Eberhardt took up the question again; he reproduced the results of his first work and likewise obtained mainly pseudoephedrine melting at 114?C. He points out, however, the presence of a base melting at 76?C which is ephedrine, but upon which he lays no stress.

In accordance with the present invention, racemic ephedrine is obtained exclusively and substancially free from pseudoephedrine.

The process of manufacture of the invention is by effecting the reduction of methylaminopropiophenone, not with hydrogen in the presence of palladium, but with hydrogen in the presence of platinum. In view of the simplicity of execution and the good yield obtained, the present process is far superior to those known in the art up to the present time.

The starting material, methylaminopropiophenone, can be prepared from bromopropiophenone.

Alpha-Bromopropiophenone is prepared either by causing bromopropionyl bromide to react with benzene in the presence of aluminum chloride, which gives a yield of 80% brominated ketone boiling at 135-138?C/20mmHg or else by direct bromination of propiophenone in a suitable medium.

Alpha-methylaminoethylphenyl ketone can be prepared by causing methylamine in benzene or alcohol to react with bromopropiophenone. It is to be recommended to cool with ice, as an elevation in temperature takes place after a certain time in a very abrupt manner. The products undergoing the reaction are allowed to stand for a short time at ordinary temperature. At the end of 24 hours, the HBr salt of monomethylamine is formed and separates. The excess of benzene is evaporated (if such is the solvent employed) and the residue neutralized with hydrochloric acid while cooling with ice. The acid solution is then washed with a small amount of ether, the base liberated from the hydrochloric acid solution and extracted with ether after which the base is distilled in a vacuum. It boils between 90-100?C/1.5mmHg.

The distilled base is accurately neutralized with hydrochloric acid when cold. The solution is evaporated and the residue becomes a crystalline mass which purified by crystallization in boiling alcohol.

In accordance with the process of the present invention, phenylmethylaminopropanol (ephedrine) can be obtained by reduction of the hydrochloride of the above aminoketone with hydrogen in the presence of platinum black prepared according to the method of Lowe2. The hydrochloride is dissolved in alcohol and the catalyst, the quantity of which depends upon the speed with which the total reduction is desired to be obtained, is thereupon introduced. A suitable quantity is in the neighborhood of a quarter of the substance to be reduced.

The operation takes place in a receptacle in which agitation can be effected. The air of the receptacle is driven out by a stream of carbonic acid which gas is subsequently driven out by hydrogen. The solution of the base to be reduced is then agitated energetically in the presence of platinum under slight pressure of hydrogen and when the theoretical amount of hydrogen has been absorbed, the operation is interrupted. It is not desirable to pas this point as total reduction may take place. The whole is filtered for the recovery of the catalyst and the concentrated alcoholic liquor furnishes the hydrochloride of ephedrine which is absolutely pure, with yields which exceed 70%.

In the mother liquor practically no pseudoephedrine is to be found but only a small amount of unchanged acetone and also a base which is produced by the total reduction of the ketone group, that is to say, phenylmethylaminopropane.


  1. Eberhardt, Arch. Pharm. 253, 62 (1915)
  2. Lowe, Ber. 23, 289 (1890)