The benzyl-protected 2-(2-hydroxyethyl)phenol (I) was brominated in HOAc to give (II). Lithiation of aryl bromide (II) followed by in situ condensation of the resulting organolithium derivative (III) with diethyl oxalate under -95 C furnished the keto ester (IV). Subsequent ketone reduction by NaBH4 afforded hydroxy ester (V), which was further hydrolyzed to the mandelic acid derivative (VI). The condensation of racemic acid (VI) with (S)-2-amino-7-hydroxytetraline (VII) gave rise to a diastereomeric mixture of hydroxy amides from which the desired (S,R)-diastereoisomer (VIII) was isolated by column chromatography. Reduction of the amide function of (VIII) using borane-dimethyl sulfide complex yielded the amino alcohol (IX). Alkylation of the phenolic hydroxyl group of (IX) with 2-bromo-N,N-dimethylacetamide (X) provided the corresponding (aryloxy)acetamide (XI). Then, hydrogenolysis of the benzyl protecting groups over Pd/C furnished the target compound, which was finally isolated as the corresponding sulfate salt.

An alternative method, suitable for large-scale synthesis, has been described: The chloromethylation of 4'-hydroxyacetophenone (XII) using formaldehyde and HCl gave (XIII). Displacement of the chloride group with NaCN provided nitrile (XIV), which was further hydrolyzed to the carboxylic acid (XV). Esterification of (XV) with methanol and sulfuric acid yields (XVI), whose phenolic hydroxyl group was protected as the benzyl ether (XVII) by alkylation with benzyl chloride. Subsequent bromination of ketone (XVII) yielded the phenacyl bromide (XVIII). The chiral amino alcohol (XX) was prepared from (-)-camphor (XIX) by ketone oxidation in position alpha with SeO2, followed by condensation with hydroxylamine and reduction with LiAlH4. Asymmetric reduction of the bromo ketone (XVIII) with borane in the presence of aluminum triethoxide and the chiral auxiliary (XX) provided the desired (R)-bromohydrin (XXI). The hydroxyl groups of (XXI) were then protected by silylation with tert-butyldimethylsilyl chloride, yielding (XXII). Condensation of the silyl-protected bromide (XXII) with (S)-2[(2-amino-1,2,3,4-tetrahydronaphthalen-7-yl)oxy]-N,N-dimethylacetamide (XXIII) furnished adduct (XXIV).

The silyl protecting groups of (XXIV) were cleaved by acidic treatment yielding diol (XXV). Then, O-benzyl group hydrogenolysis in (XXV) using Pd/C, followed by salification with H2SO4, provided the title compound.

The optically pure (S)-amine (XXIII) was prepared as follows: Demethylation of the previously described (S)-7-methoxy-1,2,3,4-tetrahydronaphth-2-ylamine (XXVI) in concentrated HBr under reflux gave the amino naphthol (VII). After protection of the amino group of (VII) as the N-Boc derivative (XXVII), the phenolic hydroxyl was alkylated with 2-chloro-N,N-dimethylacetamide (XXVIII) to give (XXIX). Then, Boc group cleavage in (XXIX) by means of HCl in isopropanol furnished the intermediate amine (XXIII).