合成路线1

Condensation of 6-chloro-5-fluoroindole (I) with L-serine and Ac2O in AcOH at 80 °C yields 2-acetamido-3-(6-chloro-5-fluoroindol-3-yl)propanoic acid (III), which by kinetic resolution using L-aminoacylase provides the desired (R)-enantiomer (IV). Hydrolysis of N-acetylated compound (IV) by means of HCl yields the free amino acid (V), which is then esterified with MeOH in the presence of SOCl2 at 0 °C to afford the corresponding methyl ester (VI). N-Protection of the amine group of compound (VI) with Boc2O by means of NaHCO3 in THF/H2O generates carbamate (VII), which by ester reduction with LiAlH4 in refluxing Et2O at 0 °C produces the primary alcohol (VIII). Activation of alcohol (VIII) as its mesylate (IX) using MsCl in the presence of Et3N in CH2Cl2 at 0 °C, followed by reduction with LiAlH4 in Et2O gives tert-butyl 2-(6-chloro-5-fluoroindol-3-yl)-1(S)-methylethylcarbamate (X). Hydrolysis of carbamate (X) with HCl in MeOH yields the corresponding amine (XI), which is finally submitted to Pictet-Spengler cyclization with 5-chloroisatin (XII) in the presence of p-TsOH in EtOH at 110 °C .