Aniline → 1-{4-[(Benzyl-methyl-amino)-methyl]-2-methoxy-phenyl}-3-(5-methyl-pyrazin-2-yl)-urea

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Reaction Steps

Benzyl-(3-methoxy-4-nitro-benzyl)-carbamic acid tert-butyl ester was reduced to the corresponding aniline according to the general hydrogenation procedure detailed above for compound 336. The crude aniline was used in the coupling step as follows: A solution of 5-methylpyrazine-2-carboxylic acid (34.5 mg, 0.25 mmol) and added triethylamine (28 mg, 0.275 mmol) in 5 mL of anhydrous toluene was stirred at room temperature until the solid dissolved. Diphenylphosphoryl azide (62 mg, 0.225 mmol) was added and the solution heated to 90° C. for 20 min. The reaction pot was then transferred to a 60° C. oil bath, and the aniline (0.25 mmol) was added as a solution in 2 mL toluene. After stirring for 4.5 hr at 60° C., the mixture was cooled to room temperature, diluted with EtOAc, washed with sat'd NaHCO3, then brine. The organic phase was dried over MgSO4, filtered and concentrated. The resulting residue was purified by preparative TLC, eluting with 5% MeOH in CH2Cl2, to give the desired urea. The Boc group was removed by treatment of the Boc protected amine in 15 mL of CH2Cl2 with 3 mL TFA and stirring at room temperature for 3h. The mixture was diluted with EtOAc (50 mL), washed with 20 mL of sat'd NaHCO3 followed by 20 mL of brine. The organic phase was then dried over MgSO4, filtered and concentrated to give the free amine 1H NMR (400 MHz, d6-DMSO): δ11.35 (s, 1H), 9.68 (s, 1H), 8.41 (s, 1H), 8.28 (d, J=8.21 Hz, 1H), 8.06 (s, 1H, 7.36 (s, 6H), 6.96 (s, 1H), 6.94 (d, J=8.21 Hz, 1H), 3.95 (s, 3H), 3.84 (s, 2H), 3.81 (s, 2H), 2.52 (s, 3H), 2.13 (s, 1H). MS APCI-pos, M+1=377.9

Provenance & Evidence