反应详情

To a solution of N-((1R,2S,5R)-2-((S)-3-amino-2-oxopyrrolidin-1-yl)-5-(methylamino)cyclohexyl)acetamide (12.5 g, 46.6 mmol) in dichloromethane was added triethylamine (12.98 mL, 93 mmol) and 4-chloro-6-(trifluoromethyl)quinazoline (10.83 g, 46.6 mmol). The mixture was stirred at room temperature overnight and then concentrated under reduced pressure to dryness. The residue was dissolved in dichloromethane (350 mL) and extracted with a solution of aqueous acetic acid (1×200 mL, 1×100 mL; made from 300 mL of H2O and 16 mL of acetic acid. The acidic aqueous layer (pH 4-5) was extracted with dichloromethane (2×300 mL), basified with Na2CO3 to pH 10-11, and then extracted with dichloromethane (2×350 mL; maintained pH of aqueous layer at 10-11 with Na2CO3 as necessary). The organic phase was washed with saturated NaCl solution (1×200 mL); the NaCl layer was back-extracted with dichloromethane (1×100 mL). The organic extracts were combined, dried (Na2SO4), filtered, and concentrated in vacuo to give the title compound (19.4 g, 90%). LC/MS found [M+H]+=465. HPLC shows the purity as 99.4%, with the largest single impurity as 0.5%. 1H-NMR (500 MHz, CD3OD), δ ppm: 8.77 (1H, s), 8.56 (1H, s), 8.02 (1H, dd, J=8.80, 1.37 Hz), 7.87 (1H, d, J=8.52 Hz), 5.25 (1H, t, J=8.52 Hz), 4.53 (1H, q, J=3.94 Hz), 4.01 (1H, dt, J=11.96, 3.85, 3.71 Hz), 3.46-3.64 (2H, m), 2.77-2.86 (1H, m), 2.47-2.57 (1H, m), 2.41 (3H, s), 2.22 (1H, dq, J=12.51, 12.44, 3.57 Hz), 1.98 (3H, s), 1.95-1.98 (1H, m), 1.92-1.98 (1H, m), 1.84-1.91 (1H, m), 1.78 (1H, t, J=3.44 Hz), 1.71-1.76 (1H, m), 1.62-1.69 (1H, m).

1. concentrationconcentrated under reduced pressure to dryness
2. dissolutionThe residue was dissolved in dichloromethane (350 mL)
3. extractionextracted with a solution of aqueous acetic acid (1×200 mL, 1×100 mL
4. extractionThe acidic aqueous layer (pH 4-5) was extracted with dichloromethane (2×300 mL)
5. extractionextracted with dichloromethane (2×350 mL; maintained pH of aqueous layer at 10-11 with Na2CO3 as necessary)
6. washThe organic phase was washed with saturated NaCl solution (1×200 mL)
7. extractionthe NaCl layer was back-extracted with dichloromethane (1×100 mL)
8. dry with materialdried (Na2SO4)
9. filtrationfiltered
10. concentrationconcentrated in vacuo