Reaction Steps
N,N-Diisopropylethylamine (101 uL, 0.66 mmol) was added to a mixture of O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (53 mg, 0.14 mmol), and 4-(aminocarbonyl)-3-[(cyclopropylmethyl)amino]-benzoic acid (synthesized according to reagent preparation 39) (31 mg, 0.13 mmol) and the resulting mixture was stirred at room temperature for 30 minutes. A solution of 1-[6-(3-endo-amino-8-azabicyclo[3.2.1]oct-8-yl)pyridin-3-yl]-3-(1-methylpiperidin-4-yl)propan-1-one hydrochloride salt (51 mg, 0.13 mmol) in N,N-dimethylformamide (0.5 mL) was added and stirring was continued for 18 hours. The reaction mixture was diluted with methanol (1.5 mL), and purified by preparatory reverse phase HPLC (ammonium acetate buffered aqueous acetonitrile eluent) to give 2-[(cyclopropylmethyl)amino]-N4-(8-{5-[3-(1-methylpiperidin-4-yl)propanoyl]pyridin-2-yl}-8-azabicyclo[3.2.1]oct-3-endo-yl)benzene-1,4-dicarboxamide as the acetate salt, (54 mg, 66% yield). 1H NMR (400 MHz, d4-Methanol): 8.65 (d, 1H), 7.97 (dd, 1H), 7.54 (d, 1H), 6.96 (d, 1H), 6.82 (dd, 1H), 6.67 (d, 1H), 4.57, (Br, 2H), 3.89 (tr, 1H), 3.04 (m, 2H), 2.95 (d, 2H), 2.87 (tr, 2H), 2.44 (s, 3H), 2.37 (tr, 2H), 2.21-2.01 (m, 6H), 1.91 (br, 1H), 1.88 (br, 1H), 1.80 (s, 3H), 1.78 (m, 1H), 1.58 (q, 4H), 1.38 (br, 1H), 1.22 (m, 2H), 1.02 (m, 1H), 0.47 (m, 2H), 0.20 (m, 2H); MS (EI) for C33H44N6O3: 573 (MH+).
