Acetic Acid → Carbamic acid, N-(9-fluoro-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-, phenylmethyl ester

Temperature

0 °C

To a solution of 2-(1H-benzo[d][1,2,3]triazol-1-yl)-2-(benzyloxycarbonylamino)acetic acid (6.06 g, 18.59 mmol) in THF (40 mL) cooled at 0° C. was added oxalyl chloride (1.627 mL, 18.59 mmol), followed by DMF (0.05 mL). The mixture was stirred at 0° C. for 1.5 h. A solution of Intermediate A11 (2 g, 9.29 mmol) and 4-methylmorpholine (3.06 mL, 27.9 mmol) in THF (15 mL) was added slowly. After the addition, the reaction mixture was warmed to room temperature and stirred overnight. The reaction mixture was filtered through CELITE® and washed with 40 ml THF. The filtrate was treated with 7N NH3/MeOH (40 mL). The mixture was stirred at room temperature for 3 h. The reaction mixture was concentrated, the residue was taken into EtOAc (150 mL), washed with 1N NaOH (150 mL), the aqueous layer was extracted with EtOAc (2×125 mL). The combined extracts were washed with brine, dried (MgSO4), filtered and concentrated. The residue was dissolved in acetic acid (13 mL, 227 mmol) and treated with ammonium acetate (3.58 g, 46.5 mmol). The mixture was stirred at room temperature overnight. The reaction mixture was concentrated, and suspended in saturated NaHCO3, extracted thrice with DCM. The combined extracts were washed with brine, dried and concentrated. The residue was purified by silica gel chromatography (hexane/EtOAc) to give Intermediate B1A (3.0 g, 79%): HPLC: RT=2.780 min (H2O/MeOH with TFA, CHROMOLITH® SpeedROD, 4.6×50 mm, gradient=4 min, wavelength=220 nm); MS(ES): m/z=404 [M+H+]; 1H NMR (400 MHz, CDCl3) δ 7.92 (1H, br. s.), 7.57 (2H, d, J=7.04 Hz), 7.46-7.53 (1H, m), 7.30-7.46 (8H, m), 7.15-7.23 (2H, m), 6.61 (1H, d, J=8.14 Hz), 5.42 (1H, d, J=8.36 Hz), 5.20 (2H, s).

1. additionAfter the addition
2. temperaturethe reaction mixture was warmed to room temperature
3. stirringstirred overnight
4. filtrationThe reaction mixture was filtered through CELITE®
5. washwashed with 40 ml THF
6. additionThe filtrate was treated with 7N NH3/MeOH (40 mL)
7. stirringThe mixture was stirred at room temperature for 3 h
8. concentrationThe reaction mixture was concentrated
9. washwashed with 1N NaOH (150 mL)
10. extractionthe aqueous layer was extracted with EtOAc (2×125 mL)
11. washThe combined extracts were washed with brine
12. dry with materialdried (MgSO4)
13. filtrationfiltered
14. concentrationconcentrated
15. stirringThe mixture was stirred at room temperature overnight
16. concentrationThe reaction mixture was concentrated
17. extractionextracted thrice with DCM
18. washThe combined extracts were washed with brine
19. customdried
20. concentrationconcentrated
21. customThe residue was purified by silica gel chromatography (hexane/EtOAc)
22. customto give Intermediate B1A (3.0 g, 79%)

ORD record

ord-3b5e375f31ea4ce398c4273a59676cb8

Source dataset

uspto-grants-2016_01

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09242941B2