The reaction of 4-phenyl-1-butanol (I) with 1,6-dibromohexane by means of NaH in THF gives the ether derivative (III), which is then condensed with 5-(2-amino-1-hydroxyethyl)-2-hydroxybenzyl alcohol (IV) by means of KI and triethylamine in hot DMF.

The reaction of 4-phenyl-1-butanol (I) with 1,6-dibromohexane (II) by means of KOH and tetrabutylammonium bisulfate gives the butyl hexyl ether (III), which is condensed with 2-aminoacetaldehyde dimethylacetal (IV) in refluxing toluene yielding 2-[6-(4-phenylbutoxy)hexylamino]acetaldehyde dimethylacetal (V). The protection of the amino group of (V) with N-(benzyloxycarbonyloxy)succinimide and triethylamine in acetone affords the carbamate (VI), which is treated with TsOH in acetone to provide the acetaldehyde derivative (VII). The condensation of (VII) with 6-bromo-2,2-dimethyl-1,3-benzodioxan (VIII) (obtained by cyclization of phenol (IX) with acetone and AlCl3) by means of Mg in THF gives the expected carbinol (X), which is deprotected with H2 over Pd/C in methanol yielding the aminoethanol derivative (XI). Finally, this compound is treated with HCl in methanol/water to open the 1,3-dioxane ring and afford the target compound.

The condensation of N-benzyl-N-[6-(4-phenylbutoxy)hexyl]amine (I) with 5-(bromoacetyl)salicylaldehyde (II) by means of TEA in isopropanol gives the adduct (III), which is debenzylated and reduced with H2 over Pt/C and Pd/C in ethanol to afford the target triol.

The Friedel-Crafts condensation of 2-hydroxybenzoic acid methyl ester (I) with 13C-labeled acetyl chloride (II) by means of AlCl3 in dichloromethane gives 5-acetyl-2-hydroxybenzoic acid methyl ester (III), which is brominated with Br2 in CHCl3 yielding the bromoacetyl compound (IV). The condensation of (IV) with the secondary amine (V) by means of DIEA in THF affords the tertiary amine (VI), which is reduced with LiAlD4 in refluxing ethyl ether to provide the trideuterated triol (VII). Finally, this compound is debenzylated by hydrogenation with H2 over Pd/C in ethanol.

The condensation of 1,6-dibromohexane (I) with 4-phenyl-1-butanol (II) by means of NaOH under phase transfer catalysis gives 6-(4-phenylbutoxy)hexyl bromide (III), which is condensed with benzylamine (IV) by means of Cs2CO3 in hot DMF to yield the secondary amine (V). The condensation of (V) with methyl alpha-bromo 4-acetylsalicylate (VI) by means of DIEA in refluxing THF affords the tertiary amine (VII), which is submitted to a reductive deuteration by means of deuterated LiAlD4 in THF to provide the trideuterated intermediate (VIII). Finally this compound is deprotected by hydrogenation with H2 over Pd/C in methanol to give rise to the target trideuterated salmeterol.

The condensation of 4-phenyl-1-butanol (I) with 1,6-dibromohexane (II) by means of NaH in THF gives the ether (III), which is condensed with benzylamine (IV) by means of NaI and TEA in DMSO to yield the secondary amine (V). The condensation of (V) with 5-(bromoacetyl)-2-hydroxybenzaldehyde (VI) in refluxing acetonitrile affords the tertiary amine (VII). The reduction of both carbonyl groups of (VII) by means of NaBH4 in methanol affords the dihydroxy amine (VIII), which is finally debenzylated by means of h2 over Pd/C in the same solvent to provide the target salmeterol. The intermediate 5-(bromoacetyl)-2-hydroxybenzaldehyde (VI) has been obtained by Friedel Crafts condensation of 2-hydroxybenzaldehyde (IX) with bromoacetyl chloride (X) by means of AlCl3 in dichloromethane.