Synthesis of the Ephedra Bases

The racemic base was resolved, by crystallization of the tartrates, into I- and d- -ephedrine. By isomerization of both forms, with hydrochloric acid, I- and d-ephedrine were obtained. 

In 1925 Spath and Roller described a new ephedrine synthesis. a-Phenylpropylene was reacted with bromine to l-phenyl-l,2-dibromo-propane. One bromine was then substituted by methoxyl, the other by NH CHa. On hydrolysis with fuming hydrobromic acid, racemic -ephedrine was formed. (Compare also Spath and Bretschneider, 261.) 

Kanao (71), in 1927, synthesized racemic ephedrine in excellent yields by methylating phenylpropanolamine or by reducing -methyl-aminopropiophenone. The first compound had been prepared by condensation of benzaldehyde with nitroethane followed by reduction. Two amines were obtained, which by methylation gave racemic ephedrine and racemic -ephedrine respectively. Nagai and Kanao (17) described the syntheses of the optically active ephedrines and those of the nor- and )V-methylephedrines and Ephedrines, following this method of preparation. Later, in 1947, Hoover and Hass (270) utilized the same reaction sequence to obtain the ephedrine bases. 

The ephedrine synthesis described by Manske and Johnson (74) and by Skita and Keil (77) in 1929 is founded on a different reaction. If a mixture of o -phenylpropane-a,/S-dione and methylamine, in absolute alcohol is hydrogenated catalytically in the presence of platinum oxide (Manske) or colloidal platinum (Skita), dl-ephedrine, with a little dJr -ephedrine is obtained. The reaction has been further elaborated by Coles, Manske, and Johnson (76), by Skita, Keil and coworkers (78, 79, 262, 263) and by Couturier (265). Manske and Johnson (75) synthesized some ephedrine homologs and resolved racemic ephedrine by means of d-and f-mandelic acid. The pure I form of this acid is prepared easily with the aid of natural ephedrine, as confirmed by Jarowski and Hartung (268). 

Fourneau and Benoit (55) investigated the action of methylamine on several forms of phenylpropylene oxide. A complicated mixture of ephedrines and isoephedrines was obtained. 

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