The condensation of 2-methoxy-5-(2-bromopropionyl)benzenesulfonamide (I) with N-benzyl-2-(2 ethoxyphenoxy)ethylamine (II) in refluxing butanone gives the tertiary amine (III), which is reduced with sodium in ethanol to the alcohol (IV). Debenzylation of (IV) with H2 over Pd/C in methanol affords the hydroxyamine (V), which by reaction with SOCl2 in acetonitrile is converted to the corresponding chloro derivative (VI). Finally, this compound is dechlorinated by hydrogenolysis with H2 over Pd/C in methanol.
The condensation of 2-methoxyphenol (I) with ethylene oxide (II) gives 2-(2-methoxyphenoxy)ethanol (III), which is treated with SOCl2 to yield 2-(2-methoxyphenoxy)ethyl chloride (IV). The reaction of (IV) with benzylamine (A) gives N-[2-(2-methoxyphenoxy)ethyl]benzylamine (V), which is condensed with 2-methyl-5-bromoacetylbenzenesulfonamide (VI) affording N-[2-(2-methoxyphenoxy)ethyl]-N-[(4-methyl-3-aminosulfonylbenzoyl)methyl]benzylamine (VII). The reduction of (VII) with NaBH4 affords the corresponding protected carbinol (VIII), which is finally debenzylated by hydrogenation with H2 over Pd/C.
A new synthesis of YM-12617-1, the active R-isomer of YM-12617, has been described: The reductocondensation of 1-(4-methoxyphenyl)-2-propanone (I) with R-1-phenylethylamine (II) gives regioselectively the secondary amine (III) as the HCl salt, which by sulfonation with chlorosulfonic acid and treatment with NH4OH yields (R,R)-2-methoxy-5-[2-(1-phenylethylamino)propyl]benzenesulfonamide (IV). Eliminating the protecting group by hydrogenation, the free amine hydrochloride (V) is obtained, which is finally submitted to a reductocondensation with 2-(2-ethoxyphenoxy)acetaldehyde (VI) by means of sodium borohydride in methanol, and treated with HCl in ether.