| 92% |
With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; water; at 120℃; for 2h; |
Example 16. Synthesis of N-[3'-(aminomethyl)-2-methylbiphenyl-3-yl]methyl}-5- nitro-4-(4,5,7,8-tetrahydroimidazo[4,5-d]azepin-6(lH)-yl)pyrimidin-2-amine; A solution of 3-bromo-2-methyl-benzamide (500 mg, 2.340 mmol) and pyridine (0.60 mL, 7.42 mmol) in dichloromethane (10 mL) was cooled to 0 0C and treated with trifluoroacctic anhydride (1.0 mL, 7.08 mmol). The reaction mixture was warmed to room temperature and stirred for 15 h, then partitioned between ethyl acetate (100 mL) and 1 M HCl solution (25 mL). The organic phase was washed with satd NaHCOs solution (25 mL) and brine (25 mL), dried over Na2SO4, filtered and concentrated to afford 423 mg (92%) of 3-bromo-2-methyl-benzonitrile as a pale yellow oil that was carried on without further purification.To a mixture of 3-bromo-2-mcthyl-bcnzonitrilc (400 mg, 2.04 mmol), [3-N-boc- aminomethyl)phenyl]boronic acid (768 mg, 3.06 mmol), tetrakis(triphenylphosphine)palladium (236 mg, 0.204 mmol), and sodium carbonate (649 mg, 6.12 mmol) was added dimethoxyethane (16 mL) and water (1.6 mL). The reaction mixture was sealed under N2 and heated at 120 C for 2 h. The reaction mixture was partitioned between ethyl acetate (125 mL) and 5% NaCl solution (40 mL). The organic <n="48"/>phase was washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel chromatography eluting with 5-15% ethyl acetate in hexanes to furnish 604 mg (92%) of (3'-cyano-2'-methyl-biphenyl-3-ylmethyl)-carbamic acid tert- butyl ester, m/z 323.5 (M + H)+.A solution of (3'-cyano~2'-methyl-biphenyl-3-ylmethyl)-carbamic acid te/Y-butyl ester (100 mg, 0.31 mmol) and cobaltous chloride hexahydrate (111 mg, 0.47 mmol) in 2:1 THF/H2O (3 mL) was cooled to 0 C and treated with sodium borohydride (59 mg, 1.55 mmol), portionwise over several minutes. The reaction mixture was warmed to room temperature and stirred for 1 h. After the addition of 1 mL of cone NH4OH, the mixture was stirred for 5 min and then filtered, washing the collected solids with 2:1 THF/H2O (20 mL). The filtrates were concentrated, and the residue was partitioned between dichloromethane (15 mL) and water (5 mL). The aqueous phase was extracted with dichloromethane (2x15 mL), and the combined organic phases were washed with brine, dried over Na2SO4, filtered and concentrated to furnish 74 mg (73%) of (3'-aminomcthyl-2'-mcthyl-biphcnyl-3- yhnethyl)-carbamic acid tert-bvyl ester as an off-white solid, m/z 327.6 (M + H)+. (Osby, J. O.; Heinzman, S. W.; Ganem, B. J. Am. Chem. Soc. 1986, 108, 67-72).To a solution of (3'-aminomethyl-2'-methyl-biphenyl-3-ylmethyl)-carbamic acid tert-butyl ester (76 mg, 0.23 mmol) and diisopropylethylamine (0.045 mL, 0.26 mmol) in dichloromethane (2.0 mL) was added 2-chloro-5-nitro-4-thiocyanato-pyrimidine (50 mg, 0.23 mmol). The rxn mixture was stirred at room temperature for 72 h, then diluted with 5% MeOH in CH2Cl2 (30 mL) and washed with 1 M HCl solution (8 mL). The organic phase was washed with satd NaHCO3 solution and brine, dried over Na2SO4, filtered and concentrated. The crude product was purified by silica gel chromatography eluting with 15-30% ethyl acetate in hexanes to afford 74 mg (63%) of {2'-methyl-3'-[(5-nitro-4- thiocyanato-pyrimidin-2-ylamino)-methyl]-biphenyl-3-ylmethyl}-carbamic acid tert-buty ester, m/z 507.5 (M + H)+.To a solution of 1 ,4,5,6,7,8-hexahydro-iτnidazo[4,5-<i]azepine, di-HCl salt (37 mg, 0.18 mmol) and diisopropylethylamine (0.102 mL, 0.58 mmol) in 3:1 dichloromethane/JV,N- dimethylformamide (2.0 mL) was added {2'-methyl-3'-[(5-nitro-4-thiocyanato-pyrimidin- 2-ylamino)-methyl]-biphenyl-3-ylmethyl} -carbamic acid tert-butyl ester (74 mg, 0.15 <n="49"/>mmol). The rxn mixture was stirred at room temperature for 7.5 h, then diluted with ethyl acetate (35 mL) and washed with 5% NaCl solution (3*12 mL) and brine (15 mL), dried over Na2SO4, filtered and concentrated. The crude product was purified by silica gel chromatography eluting with 0-5% MeOH in CH2Cl2 to give 63 mg (74%) of (2'-methyl- 3'-[5-nitro-4-(4,5,7,8-tetrahydro-lH-imidazo[4,5-r|azepm-6-yl)-pyrimidin-2-ylamino]- methyl}-biphenyl-3-ylmethyl)-carbamic acid tert-butyl ester, m/z 585.8 (M + H)+.A solution of (2I-methyl-3'-[5-nitro-4-(4,5J7,8-tetrahydro-lH-imidazo[4,5-
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