Reaction Steps
3-amino-N-cyclopropyl-4-methylbenzamide (5.50 g) was added to a stirred solution of 5-chloro-2-nitrobenzoic acid (7.59 g), N,N-diisopropylethylamine (12.2 ml) and HATU (14.3 g) in DMF (50 ml). The mixture was stirred at room temperature for 16 hours. The reaction mixture was poured into a saturated NaHCO3 solution (1000 ml) and the resulting solid was filtered and dried (magnesium sulphate) under vacuum at 40° C. There was thus obtained 5-chloro-N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-2-nitrobenzamide (10.02 g); NMR Spectrum: (DMSOd6) 0.56 (m, 2H), 0.67 (m, 2H), 2.30 (s, 3H), 2.83 (m, 1H), 7.31 (d, 1H), 7.61 (d, 1H), 7.85 (d, 1H), 7.93 (d, 2M), 8.18 (d, 1H), 8.37 (d, 1H); Mass Spectrum: M+Na+ 396. B) 1-Methylhomopiperazine (1.25 ml) was added to a stirred solution of 5-chloro-N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-2-nitrobenzamide (0.6 g) in DMSO (5.0 ml). The mixture was heated to 80° C. and stirred for 16 hours. The cooled mixture was poured into a saturated NaHCO3 solution (100 ml) and extracted with ethyl acetate (100 ml) and methylene chloride (100 ml). The organic extracts were combined, dried (magnesium sulphate), concentrated under reduced pressure and the residue was triturated with ethyl acetate/iso-hexane. The resultant solid was filtered and dried under vacuum at 40° C. There was thus obtained N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-5-(4-methyl-1,4-diazepan-1-yl)-2-nitrobenzamide (0.34 g); NMR Spectrum: (DMSOd6) 0.57 (m, 2H), 0.67 (m, 2H), 1.90 (m, 2H), 2.26 (s, 3H), 2.26 (s, 3H), 2.51 (m, 2H), 2.64 (m, 2H), 2.82 (m, 1H), 3.61 (t, 2H), 3.68 (t, 2H), 6.80 (d, 1H), 6.88 (d, 1H), 7.28 (d, 1H), 7.56 (d, 1H), 7.97 (s, 1H), 8.03 (d, 1H), 8.35 (d, 1H), 9.87 (s, 1H); Mass Spectrum: M+H+ 452. C) 10% Palladium-on-carbon (0.05 g) was added to a stirred suspension of N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-5-(4-methyl-1,4-diazepan-1-yl)-2-nitrobenzamide (0.304 g) in methanol (5 ml) and the mixture was stirred under an atmosphere of hydrogen gas at a pressure of 10 bar. After cessation of hydrogen uptake, the catalyst was removed by filtration through diatomaceous earth (Celite®). The filtrate was concentrated under reduced pressure, which provided the crude 2-amino-N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-5-(4-methyl-1,4-diazepan-1-yl)benzamide (0.27 g) which was used without further purification; Mass Spectrum: M+H+ 422.
