Ammonia → HCID 90082981, compound

Temperature

0 °C

To a stirred suspension of 2-(1H-benzo[d][1,2,3]triazol-1-yl)-2-(benzyloxycarbonylamino)acetic acid (1.08 g, 3.31 mmol) in CH2Cl2 (Ratio: 4.00, Volume: 20 mL) and DMF (5 drops) at room temperature was added oxalyl chloride (0.31 mL, 3.54 mmol). The reaction mixture was stirred at 0° C. for 20 min. The above solution was transferred to an addition funnel, then was added dropwise over 25 min to a cool (0° C.), stirred solution of (2-amino-3-methoxyphenyl)(phenyl)methanone, Intermediate A-1B (379.3 mg, 1.669 mmol) and triethyl amine (0.52 mL, 3.73 mmol) in CH2Cl2 (5 mL). The reaction mixture was removed from the ice bath after 30 min and stirred at room temperature for 1 h. The mixture was washed with saturated NaHCO3 and brine, then dried (MgSO4), filtered and partially concentrated to ˜10 mL. To this was added MeOH (40 mL) and the mixture was partially concentrated to 20 mL. Ammonia (2.0M in MeOH) (5.0 mL, 10.00 mmol) was added to the stirring methanolic solution. The mixture was stirred for 16 h. AcOH (20 mL) was added and the mixture was stirred at room temperature for 5 h. The reaction mixture was then concentrated, the residue was dissolved in CH2Cl2 and water, brought to pH ˜9-10 with 1M NaOH. The organic phase was separated, washed with brine, dried (MgSO4), filtered and concentrated. The residue was purified by flash chromatography (Teledyne ISCO CombiFlash Rf, 0% to 100% solvent A/B=1:1 heptane:DCM/EtOAc, REDISEP® SiO2 80 g, loaded as DCM solution). Fractions containing product were collected and concentrated to afford (benzyl 9-methoxy-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-ylcarbamate, Intermediate A-1C (529.6 mg, 1.275 mmol, 76% yield)) as a pale yellow solid: 1H NMR (400 MHz, chloroform-d) δ ppm 7.98 (1H, s), 7.55 (2H, d, J=7.0 Hz), 7.29-7.50 (8H, m), 7.10-7.19 (1H, m), 7.03-7.09 (1H, m), 6.94 (1H, dd, J=7.9, 1.1 Hz), 6.60 (1H, d, J=8.4 Hz), 5.34 (1H, d, J=8.4 Hz), 5.18 (2H, s), 3.97 (3H, s).

1. customThe above solution was transferred to an addition funnel
2. additionwas added dropwise over 25 min to
3. temperaturea cool (0° C.)
4. customThe reaction mixture was removed from the ice bath after 30 min
5. stirringstirred at room temperature for 1 h
6. washThe mixture was washed with saturated NaHCO3 and brine
7. dry with materialdried (MgSO4)
8. filtrationfiltered
9. concentrationpartially concentrated to ˜10 mL
10. additionTo this was added MeOH (40 mL)
11. concentrationthe mixture was partially concentrated to 20 mL
12. stirringThe mixture was stirred for 16 h
13. stirringthe mixture was stirred at room temperature for 5 h
14. concentrationThe reaction mixture was then concentrated
15. dissolutionthe residue was dissolved in CH2Cl2
16. customThe organic phase was separated
17. washwashed with brine
18. dry with materialdried (MgSO4)
19. filtrationfiltered
20. concentrationconcentrated
21. customThe residue was purified by flash chromatography (Teledyne ISCO CombiFlash Rf, 0% to 100% solvent A/B=1:1 heptane
22. additionFractions containing product
23. customwere collected
24. concentrationconcentrated

ORD record

ord-d571dbc679084d07bfdd8571c3de06ac

Source dataset

uspto-grants-2016_02

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09249157B2