Ammonia → HCID 90087811, compound

Temperature

0 °C

A suspension of 2-(1H-benzo[d][1,2,3]triazol-1-yl)-2-(((benzyloxy)carbonyl)amino)acetic acid (17.30 g, 53.0 mmol) in THF (128 ml) and cooled to 0° C. Oxalyl chloride (4.64 ml, 53.0 mmol) was added, followed by 50 μL DMF. The reaction mixture was stirred for 2 h at 0° C. A solution of (2-amino-3-methylphenyl)(phenyl) methanone (5.09 g, 24.09 mmol) and N-methyl morpholine (7.95 ml, 72.3 mmol) was added, and the reaction mixture was allowed to warm gradually to room temperature. After 2.5 h ammonia (7 M in MeOH) (21.29 ml, 149 mmol) was added and the reaction mixture was stirred overnight. The resulting mixture was diluted with EtOAc (250 mL), and then washed with H2O (250 mL), 1 M NaOH (250 mL), and brine (250 mL). The organic layer was concentrated and then suspended in acetic acid (48.2 ml). Ammonium acetate (9.29 g, 120 mmol) was added. After 2.5 hours, H2O was added to precipitate the product resulting in a sticky solid. The solid was collected by filtration and suspended in a minimal amount of MeOH and cooled to 0° C. The resulting white solid was collected by filtration, washed with cold MeOH and then diethyl ether. The resulting material was dried under vacuum. The mixture of enantiomers was separated using SFC to afford the desired compound: (S)-benzyl (9-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)carbamate (1.6 g, 16.63%). HPLC RT=2.773 min (CHROMOLITH® SpeedROD, 5.0 μm, 4.6 mm×50 mm, 10-90% aqueous methanol containing 0.1% TFA, 4 min gradient, monitored at 220 nm). [M+H+]=400.4. 1H NMR (400 MHz, DMSO-d6) δ 8.35 (d, J=8.6 Hz, 1H), 7.56-7.37 (m, 11H), 7.23-7.17 (m, 1H), 7.16-7.12 (m, 1H), 5.12-4.99 (m, 3H), 2.42 (s, 3H).

1. temperatureto warm gradually to room temperature
2. stirringthe reaction mixture was stirred overnight
3. washwashed with H2O (250 mL), 1 M NaOH (250 mL), and brine (250 mL)
4. concentrationThe organic layer was concentrated
5. waitAfter 2.5 hours
6. customto precipitate the product
7. customresulting in a sticky solid
8. filtrationThe solid was collected by filtration
9. temperaturecooled to 0° C
10. filtrationThe resulting white solid was collected by filtration
11. washwashed with cold MeOH
12. customThe resulting material was dried under vacuum
13. additionThe mixture of enantiomers
14. customwas separated

ORD record

ord-11099682037840759aeef9fd5df5d0cd

Source dataset

uspto-grants-2015_09

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09133139B2