合成路线1

The bromination of 1-acetyl-5-propionylindoline (I) with pyrrolidone hydrotribromide (PTBr) and sulfuric acid in THF gives the alpha-bromo derivative (II), which is reduced with triethylsilane in TFA yielding the 2-bromopropyl compound (III). Nitration of (III) with HNO3 in HOAc affords the 7-nitroindoline (IV), which is reduced to the corresponding amine derivative (V) with H2 over PtO2 in ethanol. The reaction of amine (V) with NaNO2/HCl, followed by treatment with CuCN, provides 1-acetyl-5-(2-bromopropyl)indoline-7-carbonitrile (VI), which is treated with NaN3 in hot ethylene glycol monomethyl ether/water to yield the 2-azidopropyl derivative (VII). Reduction of (VII) with H2 over Pd/BaSO4 in ethanol affords the expected 2-aminopropyl compound (VIII), which is condensed with 2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl bromide (IX) by means of NaHCO3 in ethanol to provide the secondary amine (X). The intermediate 2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl bromide (IX) has been obtained as follows: Alkylation of 2-methoxyphenol (XVIII) with 2,2,2-trifluoroethyl iodide (XIX) by means of K2CO3 in hot DMF gives 1-methoxy-2-(2,2,2-trifluoroethoxy)benzene (XX), which is demethylated by means of BBr3 in dichloromethane to yield the corresponding phenol (XXI). Finally, this compound is alkylated with 1,2-dibromoethane (XXII) and NaOH in water at 120 C (1,2).

合成路线2