Dipropylamine → tert-Butyl (8-bromo-4-(dipropylcarbamoyl)-3H-benzo[b]azepin-2-yl)carbamate

Temperature

-15 °C

To a solution of dipropylamine (2.16 ml, 15.7 mmol) in CH2Cl2 (50 mL) at −10° C. was added EDCI (3.02 g, 15.7 mmol) followed by diisopropylethylamine (2.97 ml, 17.1 mmol) over 5 min. The resulting mixture was stirred for 40 min at −15° C. To the reaction mixture was added (1E,4E)-8-bromo-2-(tert-butoxycarbonylamino)-3H-benzo[b]azepine-4-carboxylic acid (5.00 g, 13.1 mmol) followed by HOBt (2.13 g, 15.7 mmol) over 5 min maintaining the reaction temperature between −15 to −12° C. The resulting mixture was warmed to room temperature and stirred for 19 h. The reaction mixture was poured onto water (50 mL). The organic layer was separated and the aqueous layer was extracted with CH2Cl2 (50 mL). The combined organic layers were washed with sat'd aq NH4Cl (75 mL). The organic layer was separated. The sat'd aq NH4Cl solution was extracted with CH2Cl2 (50 mL) again. The combined organic layers were washed with sat'd aq NaHCO3 (2×75 mL) followed by brine (2×100 mL). The organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure to give the crude material that was taken into ether (50 mL) and kept in the freezer for 16 h. The precipitates were filtered off and the filtrate was concentrated under reduced pressure to afford 4.64 g (76%) of tert-butyl (1E,4E)-8-bromo-4-(dipropylcarbamoyl)-3H-benzo[b]azepin-2-ylcarbamate. MS APCI(+) m/z 464, 466 (M+1, Br pattern) detected.

1. temperaturemaintaining the reaction temperature between −15 to −12° C
2. temperatureThe resulting mixture was warmed to room temperature
3. stirringstirred for 19 h
4. additionThe reaction mixture was poured onto water (50 mL)
5. customThe organic layer was separated
6. extractionthe aqueous layer was extracted with CH2Cl2 (50 mL)
7. washThe combined organic layers were washed with sat'd aq NH4Cl (75 mL)
8. customThe organic layer was separated
9. extractionThe sat'd aq NH4Cl solution was extracted with CH2Cl2 (50 mL) again
10. washThe combined organic layers were washed with sat'd aq NaHCO3 (2×75 mL)
11. dry with materialThe organic layer was dried over MgSO4
12. filtrationfiltered
13. concentrationconcentrated under reduced pressure
14. customto give the crude material that
15. waitkept in the freezer for 16 h
16. filtrationThe precipitates were filtered off
17. concentrationthe filtrate was concentrated under reduced pressure

ORD record

ord-c152d40986fc46c0aaf8ae5c23ad3108

Source dataset

uspto-grants-2016_01

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09242964B2