反应详情

温度

110 °C

A mixture of 3-(7-bromo-4-methyl-3-oxo-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-ylamino)-azetidine-1-carboxylic acid tert-butyl ester (1 g, 2.1 mmol), phenylboronic acid (0.79 g, 6.4 mmol), 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (0.351 g, 0.43 mmol) and K2CO3 (0.890 g, 6.4 mmol) in dioxane (24 mL) and water (4 mL) was heated at 110° C. overnight. The reaction mixture was cooled to ambient temperature and the solvent was removed in vacuo to give the crude product, which was purified by column chromatography (eluting with 10-40% EtOAc in petroleum ether) to give 3-(4-methyl-3-oxo-7-phenyl-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-ylamino)-azetidine-1-carboxylic acid tert-butyl ester (0.710 g racemate, 1.5 mmol, 71%) as an off-white powder. The racemic material was further separated by chiral SFC (Table 2, Method 1) to give two isomers: 3-(4(R)-methyl-3-oxo-7-phenyl-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-ylamino)-azetidine-1-carboxylic acid tert-butyl ester (Enantiomer 1, SFC (Table 1, Method 1), Rt=3.374 min., 0.281 g, 0.61 mmol, 29%) and 3-(4(S)-methyl-3-oxo-7-phenyl-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-ylamino)-azetidine-1-carboxylic acid tert-butyl ester (Enantiomer 2, SFC (Table 1, Method 1), Rt=4.333 min., 0.252 g, 26%). LC/MS (Table 1, Method 2) Rt=1.25 min.; MS m/z: 464 [M+H]+.

1. temperatureThe reaction mixture was cooled to ambient temperature
2. customthe solvent was removed in vacuo
3. customto give the crude product, which
4. customwas purified by column chromatography (eluting with 10-40% EtOAc in petroleum ether)