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With potassium carbonate; triphenylphosphine;palladium diacetate; In tetrahydrofuran; water; at 100℃; |
EXAMPLE 3 Method C Methyl 4'-[({3-[(cyanoacetyl)amino]pyridin-2-yl}amino)methyl]-6-methyl-1,1'-biphenyl-2-carboxylate [0196] [CHEMMOL-00017] [0197] To a stirred solution of 2-amino-3-nitropyridine (10.0 g, 71.8 mmol) in DMF (75 mL) at 0 C., sodium hydride (60% dispersion in mineral oil, 3.01 g, 79.1 mmol) was added, and stirred at 0 C. for 30 minutes. To the resulting mixture 4-iodo-benzylbromide (22.4 g, 75.5 mmol) was added, and stirring continued at 0 C. for another 60 minutes. The reaction was quenched by the addition of saturated ammonium chloride, and partitioned between ethyl acetate and water. The organic extract was washed with brine, dried over MgSO4, filtered and concentrated under vacuum. The residue was subjected to silica gel chromatography eluted with 20-50% ethyl acetate in hexanes to provide N-(4-iodobenzyl)-3-nitropyridin-2-amine. This material (24.82 g, 69.89 mmol) was then dissolved in methanol (300 mL), tin(II) chloride dihydrate (78.84 g, 349.4 mmol) was added and heated to reflux for three hours. The resulting solution was concentrated under vacuum. The residue was dissolved in ethyl acetate, and 10% aq. sodium carbonate solution was added with vigorous stirring until pH=10. The white suspension was filtered through a pad of Celite, and the filtrate was partitioned between ethyl acetate and water. The organic extract was washed with brine, dried over MgSO4, filtered and concentrated under vacuum to provide N-2-(4-iodobenzyl)pyridine-2,3-diamine which gave an N consistent with theory. [0198] To a stirred solution of N-2-(4-iodobenzyl)pyridine-2,3-diamine (2.0 g, 6.2 mmol) in DMSO (6 mL), bis(pinacolato)diboron (2.3 g, 9.2 mmol), dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium (II) dichloromethane adduct (0.45 g, 0.62 mmol), and potassium acetate (1.8 g, 18.5 mmol) were added at room temperature. The resulting mixture was heated at 80 C. for 1 hour. The reaction was quenched by addition of EtOAc and filtered through celite. The organic extract was washed with water three times, followed by saturated NaCl, and dried over MgSO4, filtered and concentrated under vacuum. The residue was eluted on silica gel with 10-50% ethyl acetate in hexanes to provide N-2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-benzyl]pyridine-2,3-diamine as a brown solid with a mass ion (ES+) of 364.0 for M+H+. [0199] A mixture of the above product (0.10 g, 0.31 mmol), <strong>[131001-86-0]methyl 2-bromo-3-methylbenzoate</strong> (0.084 g, 0.37 mmol), potassium carbonate (0.11 g, 0.77 mmol), triphenylphosphine (4 mg, 0.04 mmol), and palladium acetate (7 mg, 0.01 mmol) in 2 mL of THF and 0.5 mL of water was heated in a sealed vial at 100 C. overnight. The mixture was then cooled and partitioned between ethyl acetate and water. The organic extract was washed with brine, dried over MgSO4, filtered and concentrated under vacuum. The residue was subjected to silica gel chromatography eluted with 0-3% methanol in CH2Cl2 to provide methyl 4'-[(3-aminopyridin-2-yl)amino]methyl}-6-methyl-1,1'-biphenyl-2-carboxylate that gave proton NMR spectra consistent with theory and a mass ion (ES+) of 348.3 for M+H+. [0200] To a stirred solution of the above product (0.100 g, 0.29 mmol), cyanoacetic acid (49 mg, 0.58 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.220 g, 1.15 mmol), 1-hydroxybenzotriazole (10 mg, 0.07 mmol), and triethylamine (0.28 mL, 2.0 mmol) were added, and stirred at room temperature overnight. The mixture was then partitioned between ethyl acetate and water. The organic extract was washed with brine, dried over Na2SO4, filtered, and concentrated under vacuum. The residue was subjected to silica gel chromatography eluted with 0-3% methanol in CH2Cl2 to provide the title compound that gave proton NMR spectra consistent with theory and a mass ion (ES+) of 415.3 for M+H+: 1H NMR(CDCl3, 300 MHz) delta 7.93 (dd, 1H J=1.7, 7.6 Hz), 7.82 (dd, 1H, J=1.5, 6.3 Hz), 7.63 (d, 1H, J=7.6 Hz), 7.47-7.28 (m, 3H), 7.34 (t, 1H, J=7.7 Hz), 7.17 (bd, 2H, J=8.3 Hz), 7.00-6.95 (m, 1H), 4.78 (s, 2H), 3.86 (s, 2H), 3.53 (s, 3H), 2.07 (s, 3H). |
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