The reaction of 6-methyl-4-phenyl-3,4-dihydro-2H-1-benzopyran-2-one (I) with methyl iodide and K2CO3 in refluxing acetone/methanol or dimethyl sulfate and NaOH gives 3-(2-methoxy-5-phenylphenyl)-3-phenylpropionic acid methyl ester (II), which is reduced with LiAlH4 in ether or NaBH4 and AlCl3 to the corresponding propanol (III). The reduction of (III) with tosyl chloride and pyridine yields the expected tosylate (IV), which by condensation with diisopropylamine (V) in hot acetonitrile is converted into the tertiary amine (VI). Finally, this compound is treated with BBr3 in dichloromethane or HBr to afford the expected amine (VII) as a racemic mixture, which is resolved with L-(+)-tartaric acid.
A new process for the preparation of tolterodine has been described: The cyclization of trans-cinnamic acid (I) with p-cresol (II) by means of hot sulfuric acid gives 6-methyl-4-phenyl-3,4-dihydro-2H-1-benzopyran-2-one (III), which is reduced with DIBAL in toluene, yielding 6-methyl-4-phenyl-3,4-dihydro-2H-1-benzopyran-2-ol (IV). The reductocondensation of (IV) with diisopropylamine (V) by means of H2 over Pd/C in methanol affords racemic tolterodine (VI), which is finally submitted to optical resolution with L-tartaric acid in dichloromethane/water.
The condensation of 2'-bromo-4'-methylacetophenone (I) with benzaldehyde (II) by means of NaOMe in methanol gives the propenone (III), which is cyclized by means of PdCl2, PPh3 and K2CO3 in DMF, yielding 5-methyl-3-phenyl-1-indenone (IV). The enantioselective reduction of (IV) by means of borane/Me2S complex and (R)-3,3-diphenyl-1-methyltetrahydro-1H,3H-pyrrolo[1,2-c][1,3,2]oxazaborole [(R)-MeCBS] as chiral catalyst in THF affords 5-methyl-3(S)-phenylindan-1-ol (V), which is oxidized with 1,4-diazabicyclo[2,2,2]octane (DABCO) in refluxing THF/TEA to provide the corresponding indanone (VI). The oxidation of (VI) with MCPBA in dichloromethane gives 6-methyl-4(S)-phenyl-3,4-dihydro-2H-1-benzopyran-2-one (VII), which is reduced with DIBAL in toluene to yield 6-methyl-4(S)-phenyl-3,4-dihydro-2H-1-benzopyran-2-ol (VIII). Finally, this compound is reductocondensed with diisopropylamine (IX) by means of H2 over Pd/C in methanol to afford the target compound.
An asymmetric total synthesis of tolterodine has been described: The regioselective addition of 2-benzyloxy-5-methylphenyl bromide (II) to 4(R)-phenyl-3-[3-phenyl-2(E)-propenoyl]oxazolidin-2-one (I) by means of Mg/CuBr/dimethylsulfide in THF gives 3-[3(R)-(5-benzyloxy-2-methylphenyl)-3-phenylpropionyl]-4(R)-phenyloxazolidin-2-one (III), which is hydrolyzed with LiOH/H2O2 in THF/water to the corresponding free acid (IV). The reaction of (IV) with SOCl2/pyridine in benzene yields the acid chloride (V), which is treated with diisopropylamine to afford the corresponding amide (VI). The reduction of (VI) with LiAlH4 in ethyl ether gives the tertiary amine (VII), which is finally, debenzylated by hydrogenation with H2 over Pd/C in methanol.
The condensation of p-cresol (I) with phenylacetylene (II) by means of acid activated alumina in refluxing dichlorobenzene gives 4-methyl-2-(1-phenylvinyl)phenol (III), which is hydroformylated with CO, H2 and a Rh catalyst in hot toluene to yield 3-(2-hydroxy-5-methylphenyl)-3-phenylpropionaldehyde (IV), mostly in the hemiacetalic form (V). The reaction of (V) with diisopropylamine (VI) in hot toluene catalyzed by molecular sieves gives the enamine (VII), which is finally hydrogenated with H2 over PtO2 in refluxing toluene to afford the target racemic tolterodine. Alternatively, the reductocondensation of hemiacetal (V) with diisopropylamine (VI) by means of H2 over Pd/C in hot methanol provides directly the target racemic tolterodine.