反应详情

Glycolic acid (50 mg) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU, 250 mg) were added sequentially, each in one portion, to a stirred solution of 4-[3-chloro-4-fluoro-anilino]-5-[(2R)-pyrrolidin-2-ylmethoxy]quinazolin-7-ol (197 mg) and N,N-diisopropylethylamine (177 μl) in DCM (4 ml) at room temperature. The reaction mixture was stirred for 60 hours and then an additional portion of glycolic acid (20 mg) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU, 100 mg) were added and the mixture was stirred for a further 5 hours. The reaction mixture was then diluted with DCM (10 ml) and washed with saturated aqueous sodium hydrogen carbonate. The organic layer was dried (MgSO4) and concentrated in vacuo to leave a yellow oil, which was purified by column chromatography using 5% methanol in DCM as eluent to give the 4-[3-chloro-4-fluoro-anilino]-5-{[(2R)-1-glycoloylpyrrolidin-2-yl]-methoxy}-quinazolin-7-ol as a grey solid (96 mg, 42%); NMR Spectrum (DMSO-d6 at 373 K) 10.10 (brs, 1H), 9.60 (brs, 1H), 8.40 (s, 1H), 8.15 (m, 1H), 7.65 (m, 1H), 7.40 (m, 1H), 6.70 (s, 2H), 4.60 (m, 1H), 4.40 (m, 1H), 4.20 (m, 1H), 4.05 (m, 2H), 3.55-3.40 (m, 2H), 2.15-1.85 (m, 4H); Mass spectrum MH+ 449.

1. customat room temperature
2. stirringthe mixture was stirred for a further 5 hours
3. washwashed with saturated aqueous sodium hydrogen carbonate
4. dry with materialThe organic layer was dried (MgSO4)
5. concentrationconcentrated in vacuo
6. customto leave a yellow oil, which
7. customwas purified by column chromatography