反应详情

温度

0 °C

A solution of diethyl (4-{[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino}-3-methoxybenzyl)phosphonate (Compound 1E, 897 mg, 1.98 mmol) and 7-amino-4-[1-(3-hydroxypropyl)-1H-pyrazol-4-yl]-2-methyl-2,3-dihydro-1H-isoindol-1-one (Compound 1C, 634 mg, 2.21 mmol) in TFE (12 mL) was charged with TFA (654 mg, 5.74 mmol) and irradiated in a microwave reactor for 1 h at 105° C. The reaction mixture was transferred to a round bottom flask and concentrated in vacuo. The residue, dissolved in MeOH and cooled to 0° C., was charged with 7.0 M of NH3 in MeOH (5 mL) and then warmed to rt over 2 h. The suspension was concentrated in vacuo and purified using a Teledyne ISCO CombiFlash® Rf system (eluting with 0-10% MeOH:CH2Cl2) to isolate the desired compound as 1.10 g of a white solid. 1H NMR (400 MHz, DMSO-d6) δ 10.72 (s, 1H), 9.12 (s, 1H), 8.38 (s, 1H), 8.27 (s, 1H), 8.06-8.63 (m, 1H), 7.96 (s, 1H), 7.70 (d, J=8.8 Hz, 1H), 7.41 (d, J=7.1 Hz, 1H), 7.10 (br. t, J=2.0 Hz, 1H), 6.96 (br td, J=2.3, 8.0 Hz, 1H), 4.53-4.67 (m, 3H), 4.21 (t, J=7.20 Hz, 2H), 4.00 (qd, J=7.1, 8.1 Hz, 4H), 3.74 (s, 3H), 3.43 (q, J=6.1 Hz, 2H), 3.36 (d, J=20 Hz, 2H), 3.11 (s, 3H), 1.97 (quin, J=6.6 Hz, 2H), 1.17 (t, J=7 Hz, 6H). MS (ESI): m/z 704.23 (100) [M+H]+. HPLC: tR=3.73 min (ZQ3: polar—5 min).

1. customirradiated in a microwave reactor for 1 h at 105° C
2. customThe reaction mixture was transferred to a round bottom flask
3. concentrationconcentrated in vacuo
4. dissolutionThe residue, dissolved in MeOH
5. additionwas charged with 7.0 M of NH3 in MeOH (5 mL)
6. temperaturewarmed to rt over 2 h
7. concentrationThe suspension was concentrated in vacuo
8. custompurified
9. washa Teledyne ISCO CombiFlash® Rf system (eluting with 0-10% MeOH:CH2Cl2)