合成路线1

The reaction of isatoic anhydride (I) with 1-(3-aminopropyl)-4-phenylpiperazine (II) in DMF at 40-60 C gives the o-aminobenzamide derivative (III), which is then cyclized by the action of phosgene in refluxing chlorobenzene.

合成路线2

By condensation of trans-4-aminocyclohexanol (I) with isatoic anhydride (II) in hot (100 C) xylene to give 2-amino-N-(trans-4-hydroxycyclohexyl)benzamide (III) , m.p. 219.5-220 C, which is reduced with LiAlH4 in THF to (trans-4-hydroxycyclohexyl)(2-aminobenzyl)amine (IV) (oxalate, m.p. 185-6 C); this product is finally brominated with Br2 in acetic acid.

合成路线3

The reaction of isatoic anhydride (I) with glycine ethyl ester (II) gives N-(2-aminobenzoyl)glycine ethyl ester (III), which is cyclized with carbonyldiimidazole (CDI) to yield 2-(2,4-dioxo-1,2,3,4-tetrahydroquinazolin-3-yl)acetic acid ethyl ester (IV). The alkylation of (IV) with 3,4-dichlorobenzyl bromide (V) affords 2-[1-(3,4-dichlorobenzyl)-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-3-yl]acetic acid ethyl ester (VI), which is finally hydrolyzed in basic medium.

合成路线4

The reaction of 2-nitrobenzoic acid with SOCl2 gives the acyl chloride (II), which is condensed with D-proline (III) by means of TEA in dichloromethane yielding the acyl proline (IV). The reductive cyclization of (IV) with H2 over Pd/C in methanol affords the pyrrolobenzodiazepinedione (V). The selective reduction of the C-11 lactam group of (V) with NaBH4 and TFA in glyme gave the pyrrolobenzodiazepinone (VI), which is finally coupled with 4-[(2-phenylbenzoyl)amino]benzoyl chloride (VII) furnishing the title compound.

合成路线5

The reaction of 2-nitrobenzoic acid with SOCl2 gives the acyl chloride (II), which is condensed with D-proline (III) by means of TEA in dichloromethane yielding the acyl proline (IV). The reductive cyclization of (IV) with H2 over Pd/C in methanol affords the pyrrolobenzodiazepinedione (V). The reduction of both lactam groups of (V) with LiAlH4 gave the pyrrolobenzodiazepine (VI), which is finally coupled with 4-[(2-phenylbenzoyl)amino]-benzoyl chloride (VII) furnishing the title compound.

合成路线6

Condensation of isatoic anhydride (I) with DL-phenylalanine ethyl ester (II) affords anthranilamide (III). Subsequent acylation of amino amide (III) with indole-2-carbonyl chloride (IV) provides diamide (V). The ethyl ester group of (V) is finally hydrolyzed to the target carboxylic acid with methanolic KOH

合成路线7

The intermediate anthranilamide (IV) is prepared by two alternative methods. Acylation of 3-(trifluoromethyl)aniline (I) with 2-nitrobenzoyl chloride (II) yields benzamide (III). The nitro group of (III) is then reduced to the corresponding amine (IV) by catalytic hydrogenation over Pd/C (1). Alternatively, 3-(trifluoromethyl)aniline (I) is condensed with isatoic anhydride (V) to furnish directly anthranilamide (IV) (2). Finally, reductive alkylation of (IV) with pyridine-4-carbaldehyde (VI) employing NaBH3CN gives rise to the target pyridylmethyl amine.

合成路线8