合成路线1

The chiral amine intermediate (XV) has been obtained as follows: The alkylation of 4-fluorophenol (I) with allyl bromide (II) and K2CO3 gives the allyl ether (III), which by thermal rearrangement at 210 C yields 2-allyl-4-fluorophenol (IV). The silylation of (IV) with TBDMS-Cl and imidazole affords the silyl ether (V), which is submitted to hydroboration with BH3 and H2O2 to provide the propanol (VI). The oxidation of (VI) with Dess Martin periodinane (DMP) gives the aldehyde (VII), which is condensed with the phosphorane (VIII) to yield the pentenoic ester (IX). The reduction of (IX) with DIBAL affords the unsaturated alcohol, which is desilylated with TBAF in THF furnishing the diol (XI). The treatment of (XI) under the Sharpless asymmetric epoxidation conditions ((-)-DET and titanium tetraisopropoxide) gives, after cyclization with NaOH, 1(R)-(6-fluoro-3,4-dihydro-2H-1-benzopyran-2(S)-yl)-1,2-ethanediol (XII), which is selectively tosylated with TsCl and pyridine yielding the monotosylate (XIII). The reaction of (XIII) with sodium azide in DMF affords the azide (XIV), which is reduced to the corresponding amine (XV) with H2 over Pd/C in ethanol.

合成路线2

合成路线3