反应详情

To a solution of N-((1R,2S,5R)-2-((S)-3-amino-2-oxopyrrolidin-1-yl)-5-(tert-butylamino)cyclohexyl)acetamide (30 g, 97 mmol) in IPA (400 ml) was added TEA (27 ml, 195 mmol) and 4-chloro-6-(trifluoromethyl)quinazoline (25 g, 107 mmol; see P. H. Carter, et al. PCT application WO 2005/021500). The mixture was stirred at room temperature overnight and then stirred at 70° C. for 1 h. The resulted solution was concentrated under reduced pressure to dryness. The residue was dissolved in dichloromethane (1 L) and extracted with acetic acid solution I (prepared by combining 700 mL of water and 22.6 mL of glacial acetic acid) twice (500 ml, 200 ml). The acidic aqueous layer (pH 4-5) was extracted with dichloromethane (2×300 ml). The dichloromethane layer was extracted with acetic acid solution II (300 ml; prepared by combining 300 mL water with 4 mL of glacial acetic acid). The combined acetic acid layers were basified with 1 M NaOH to pH>12 and extracted with dichloromethane (3×700 ml). The combined organic layers were dried and concentrated to give the crude product as a solid (45.6 g, 93% yield). The crude product was purified by recrystallization from EtOAc (400 ml)/Hexane (900 ml) to give 42.86 g (88%) N-((1R,2S,5R)-5-(tert-butylamino)-2-((S)-2-oxo-3-(6-(trifluoromethyl)quinazolin-4-ylamino)pyrrolidin-1-yl)cyclohexyl)acetamide with 99.7% purity. 1H-NMR (500 MHz, DMSO-d6) δ ppm 9.71 (1H, br. s.), 9.02 (1H, s), 8.71 (1H, d, J=7.97 Hz), 8.59 (1H, s), 8.04 (1H, dd, J=8.66, 1.79 Hz), 7.88 (1H, d, J=8.52 Hz), 4.91-5.13 (1H, m), 4.30-4.57 (1H, m), 3.86 (1H, dt, J=11.89, 3.71, 3.64 Hz), 3.43-3.57 (1H, m), 3.35-3.45 (1H, m), 3.04 (1H, t, J=3.85 Hz), 2.23-2.40 (1H, m), 2.05-2.22 (1H, m), 1.90-1.98 (1H, m), 1.86-1.93 (3H, m), 1.50-1.78 (5H, m), 0.98-1.15 (9H, m). 13C-NMR (126 MHz, DMSO-d6) δ ppm 171.23, 169.35, 159.54, 156.87, 151.17, 128.97, 128.20, 125.76 (1 C, q, J=30.52 Hz), 121.55 (1 C, br. s.), 124.04 (1 C, q, J=272.11 Hz), 114.31, 53.26, 52.39, 50.81, 47.56, 45.70, 42.77, 34.52, 32.17, 29.14 (3 C, s), 26.49, 23.29, 20.30. 19F-NMR (471 MHz, DMSO-d6) δ ppm −60.34 (s). m/z: 507.0 [M+H]. Anal. Calcd for C25H33N6O2F3: C, 59.27;H, 6.56; N, 16.59; F, 11.25 Found: C, 59.44;H, 6.64; N, 16.74; F, 10.99.

1. stirringstirred at 70° C. for 1 h
2. concentrationThe resulted solution was concentrated under reduced pressure to dryness
3. dissolutionThe residue was dissolved in dichloromethane (1 L)
4. extractionextracted with acetic acid solution I (prepared by combining 700 mL of water and 22.6 mL of glacial acetic acid) twice (500 ml, 200 ml)
5. extractionThe acidic aqueous layer (pH 4-5) was extracted with dichloromethane (2×300 ml)
6. extractionThe dichloromethane layer was extracted with acetic acid solution II (300 ml; prepared by combining 300 mL water with 4 mL of glacial acetic acid)
7. extractionextracted with dichloromethane (3×700 ml)
8. customThe combined organic layers were dried
9. concentrationconcentrated
10. customto give the crude product as a solid (45.6 g, 93% yield)
11. customThe crude product was purified by recrystallization from EtOAc (400 ml)/Hexane (900 ml)