反应详情

2-Amino-3-(2-chlorophenyl)propanoic acid hydrochloride (3.0 g, 12.7 mmol) was suspended in acetonitrile (50 mL) and water (5 mL), triethylamine (3.57 mL, 25.4 mmol) was added which caused a precipitate to form and inefficient stirring. Water (10 mL) was added until all solids were dissolved. 5-Chloroisatoic anhydride (2.51 g, 12.7 mmol) was added in portions, waiting until each portion dissolved before adding the next. Successive portions required longer periods of time, up to 15 minutes for the last portions. After the last portion was added, the suspension was sonicated for several minutes then stirred at ambient temperature overnight. The clear solution was concentrated in vacuo then azeotroped twice with acetone. The residue was redissolved in acetic acid (30 mL) and heated to 130° C. for 6 hours. The mixture was concentrated in vacuo to an oil, diluted with ethyl acetate (150 mL), washed with water (3×50 mL) then brine, dried with sodium sulfate, filtered and concentrated to a brown solid. This solid was resuspended in ethyl acetate (20 mL) and hexanes (10 mL) then slurried at ambient temperature for 30 minutes. Filtration provided 7-chloro-3-(2-chlorobenzyl)-3,4-dihydro-1H-benzo[e][1,4]diazepine-2,5-dione (2.4 g, 56%). 1H-NMR (300 MHz, DMSO-d6) δ 2.97 (m, 1H), 3.23 (m, 1H), 4.00 (m, 1H), 7.12 (d, 1H, J=8.79 Hz), 7.27 (m, 2H), 7.40 (m, 2H), 7.58 (dd, 1H, J1=8.79 Hz, J2=2.64 Hz), 7.67 (d, 1H, J=2.64 Hz), 8.73 (d, 1H, J=6.15 Hz), 10.59 (s, 1H); ESI m/z 335.0, 337.0.

1. customto form
2. dissolutionwere dissolved
3. waitwaiting until each portion
4. dissolutiondissolved
5. additionbefore adding the next
6. additionAfter the last portion was added
7. customthe suspension was sonicated for several minutes
8. concentrationThe clear solution was concentrated in vacuo
9. customthen azeotroped twice with acetone
10. dissolutionThe residue was redissolved in acetic acid (30 mL)
11. temperatureheated to 130° C. for 6 hours
12. concentrationThe mixture was concentrated in vacuo to an oil
13. additiondiluted with ethyl acetate (150 mL)
14. washwashed with water (3×50 mL)
15. dry with materialbrine, dried with sodium sulfate
16. filtrationfiltered
17. concentrationconcentrated to a brown solid
18. waithexanes (10 mL) then slurried at ambient temperature for 30 minutes
19. filtrationFiltration