合成路线1

Condensation of the ortho-metalated derivative of 3-fluoroanisole (I) –generated in situ by treatment of anisole (I) with BuLi in THF at –78 °C– with 6-chloro-2-phenyl-3,1-benzoxazin-4-one (II) gives the diaryl ketone (III), which is N-deprotected by means of KOH in refluxing MeOH/H2O, yielding the aniline derivative (IV). Diazotization of amine (IV) with NaNO2 and HCl in AcOH/H2O, followed by treatment with I2 in the presence of KI in cold EtOAc/H2O affords the aryl iodide (V). Iodobenzophenone (V) is then subjected to Heck coupling with N-Boc-propargylamine (VI) in the presence of PdCl2(PPh3)2, CuI and Et2NH in CH2Cl2 to provide adduct (VII), which is submitted sequentially to triple bond hydration, N-Boc deprotection and cyclization by sequential treatment with HgSO4 and formic acid in CH2Cl2 at 0 °C, and then DIEA in CH2Cl2 or by treatment with HCl in dioxane/H2O and then Na2CO3 in CH2Cl2 to give the 3,4-dihydro[2]benzoazepinone (VIII). Condensation of benzazepinone (VIII) with N,Ndimethylformamide dimethylacetal (IX) in toluene at 80 °C yields the 4-(dimethylaminomethylene)[2]benzoazepinone derivative (X) , which is finally condensed with methyl 4-guanidino-2-methoxybenzoate hydrochloride (XI) in the presence of K2CO3 in refluxing MeOH .
Intermediate (XI) is prepared by condensation of methyl 4-amino-2-methoxybenzoate (XII) with chloroformamidine hydrochloride (XIII) in Me2SO2 at 120 °C, followed by acidification with TFA to yield methyl 4-guanidino-2-methoxybenzoate trifluoroacetate salt (XIV). Subsequent treatment of the trifluoroacetate salt with HCl at 80 °C provides the corresponding hydrochloride (XIV) .