Triethylamine → phenyl N-[4-(4-benzyloxycarbonylamino-3-fluorophenoxy)pyridin-2-yl]-N-phenoxycarbonylcarbamate

Participants

Reaction Steps

To a solution of benzyl [4-(2-aminopyridin-4-yloxy)-2-fluorophenyl]carbamate (1.25 g) in tetrahydrofuran (100 ml) were added triethylamine (1.48 ml) and phenyl chloroformate (1.11 ml), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was partitioned between ethyl acetate and a 1N aqueous solution of sodium hydroxide. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The solvent was distilled away to give a crude product of phenyl N-[4-(4-benzyloxycarbonylamino-3-fluorophenoxy)pyridin-2-yl]-N-phenoxycarbonylcarbamate as a brown oil (ESI-MS (m/z): 616 [M+Na]+). This was dissolved in tetrahydrofuran (200 ml), 20% palladium hydroxide (497 mg) was added, and the mixture was stirred at room temperature for 4 hours under a hydrogen atmosphere. The catalyst was removed by filtration. It was subsequently washed with tetrahydrofuran. The filtrate was concentrated to 20 ml to give a solution of phenyl N-[4-(4-amino-3-fluorophenoxy)pyridin-2-yl]-N-phenoxycarbonylcarbamate (ESI-MS (m/z): 482 [M+Na]+, 941 [2M+Na]+) in tetrahydrofuran. This was dissolved in N,N-dimethylformamide (50 ml). After then adding 1-(4-fluorophenylcarbamoyl)cyclopropanecarboxylic acid (1.58 g), benzotriazol -1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (3.13 g) and triethylamine (0.987 ml), the mixture was stirred at room temperature for 13.5 hours. The reaction mixture was partitioned between ethyl acetate and brine. The organic layer was washed with a 1N aqueous solution of sodium hydroxide and brine in that order and dried over anhydrous sodium sulfate. It was then concentrated and the residue was purified by silica gel column chromatography (heptane:ethyl acetate=3:2, 1:1 and 1:2) to give the title compound as a colorless foam (940 mg, 40.0%).

Provenance & Evidence