合成路线1

The intermediate 4-amino-N-benzyl-2,2-difluoro-5-phenylpentanamide (IX) has been obtained as follows. The esterification of N-(benzyloxycarbonyl)-DL-phenylalanine (I) with methyl iodide and KHCO3 in DMF gives the corresponding methyl ester (II), which is reduced with LiCl and NaBH4 in THF to yield protected DL-phenylalaninol (III). The oxidation of (III) by means of 2,2,6,6-tetramethylpiperdine-1-oxyl free radical (TEMPO), NaBr and NaClO in ethyl acetate/toluene affords protected DL-phenylalaninal (IV), which is condensed with ethyl 2-bromo-2,2-difluoroacetate (V) by means of Zn in THF to provide the 2,2-difluoropentanoic ester (VI). The reaction of ester (VI) with benzylamine (VII) in THF gives the corresponding amide (VIII), which is finally deprotected by means of H2 over Pd/C in methanol/dioxane to yield the target 4-amino-N-benzyl-2,2-difluoro-5-phenylpentanamide (IX) intermediate.