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EXAMPLE 4 Method D Methyl 4'-[(1R)-1-({4-chloro-3-[(cyanoacetyl)amino]pyridin-2-yl}amino)ethyl]-1,1'-biphenyl-2-carboxylate [0201] [CHEMMOL-00018] [0202] A solution of <strong>[629655-23-8]2-chloro-3-nitro-4-hydroxypyridine</strong> (4.99 g, 28.59 mmol) and (1R)-1-(4-bromophenyl)ethanamine (5.20 g, 25.99 mmol) and 3.61 mL (25.99 mmol) of triethylamine (TEA) in 50 mL of n-butanol was heated to 110 C. for 48 hours. The solvent was removed in vacuo and the crude mixture filtered through silica gel using CH2Cl2. The solvent was removed in vacuo and the crude material (4.2 g) diluted with 50 mL of acetonitrile and treated with 4 mL of phosphorous oxychloride (POCl3) and the reaction mixture was heated to 80 C. for three hours. Additional POCl3 was added during this time to drive the reaction to completion. The solvent was concentrated in vacuo, diluted with EtOAc, washed with aqueous sodium bicarbonate and brine, dried over MgSO4, filtered and concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluted with 10-30% ethyl acetate in hexanes to afford N-[(1R)-1-(4-bromophenyl)ethyl]-4-chloro-3-nitropyridin-2-amine with a mass ion (ES+) of 338.0 for M+H+ (Br79). [0203] To a solution of the above material (4.31 g, 12.09 mmol) in methanol (60 mL), tin(II) chloride dihydrate (13.64 g, 60.47 mmol) was added and heated at 55 C. for 4 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 purified using silica gel chromatography on silica gel eluted with 0-1% MeOH in CH2Cl2 to provide N-2-[(1R)-1-(4-bromophenyl)ethyl]-4-chloropyridine-2,3-diamine with a mass ion (ES+) of 328.0 for M+H+(Br79). [0204] To a solution of the above product (2.77 g, 8.48 mmol) in DMSO (5 mL), bis(pinacolato)diboron (3.23 g, 12.72 mmol), dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium (II) dichloromethane adduct (0.62 g, 0.85 mmol), and potassium acetate (2.50 g, 25.4 mmol) were added at room temperature. The resulting mixture was heated at 90 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, saturated NaCl, dried over MgSO4, filtered and concentrated under vacuum. The residue was eluted on silica gel eluted with 0-1% MeOH in CH2Cl2 to provide 4-chloro-N-2-{(1R)-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ethyl}-pyridine-2,3-diamine as a pink semi-solid with a mass ion (ES+) of 374.2 for M+H+. [0205] A mixture of the above product (0.29 g, 0.77 mmol), methyl 2-iodobenzoate (0.41 g, 1.55 mmol), potassium carbonate (0.322 g, 2.33 mmol), tri-orthotolylphosphine (0.095 g, 0.31 mmol), and palladium acetate (17.4 mg, 0.08 mmol) in 10 mL of THF and 2 mL of water was heated in a sealed flask at 90 C. for 2 hours. 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 30-60% ethyl acetate and hexane to methyl 4'-{(1R)-1-[(3-amino-4-chloropyridin-2-yl)amino]ethyl}-1,1'-biphenyl-2-carboxylate with a mass ion (ES+) of 382.1 for M+H+(35Cl). [0206] To a solution of the above product (0.065 g, 0.17 mmol) in DMF (1 mL), cyanoacetic acid (0.043 g, 0.34 mmol), 1-ethyl-(3-dimethylaminopropyl)-carbodiimide hydrochloride (0.065 g 0.34 mmol), 1-hydroxy-7-azabenzotriazole (0.023 g, 0.34 mmol) was added triethylamine (0.051 g, 0.51 mmol). The resulting solution was stirred at room temperature overnight, and partitioned between ethyl acetate and water. The organic extract was washed with brine, dried over MgSO4, filtered and concentrated. The residue was subjected to silica gel chromatography eluted with 40-60% ethyl acetate in hexanes to provide the title compound that gave proton NMR spectra consistent with theory and a mass ion (ES+) of 449.1 for M+H+(35Cl): 1H NMR (400 MHz, MeOH-d4) delta 7.80 (d, J=6.1 Hz, 1H), 7.30 (d, J=7.4 Hz, 1H), 7.54 (bt, J=7.6 Hz, 1H), 7.34-7.43 (m, 4H), 7.25 (d, J=8.1 Hz, 2H), 6.80 (d, J=5.8 Hz, 1H), 5.23 (q, J=6.8 Hz, 1H), 3.90 (s, 2H), 3.59 (s, 3H), 1.63 (d, J=6.8 Hz, 3H). |
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