Hydrochloric Acid → 4-(4-Chloro-2-fluorobenzyloxy)-1-(10-methyl-5,6,7,8,9,10-hexahydropyrido[3',2':4,5]pyrrolo[3,2-c]azepin-2-yl)pyridin-2(1H)-one hydrochloride

Temperature

135 °C

A suspension of 4-(4-chloro-2-fluorobenzyloxy)pyridin-2(1H)-one (46 mg, 0.18 mmol), tert-butyl 2-bromo-10-methyl-7,8,9,10-tetrahydropyrido[3′,2′:4,5]pyrrolo[3,2-c]azepine-6(5H)-carboxylate (76 mg, 0.20 mmol), CuI (41 mg, 0.22 mmol), 8-hydroxyquinoline (5 mg, 0.04 mmol) and Cs2CO3 (65 mg, 0.20 mmol) in DMSO (10 mL) was degassed under reduced pressure for 45 min. The suspension was put under N2 and stirred at 135° C. for 21 h. The suspension was cooled, 9:0.9:0.1 CH2Cl2/MeOH/NH4OH (10 mL) was added, and the resulting suspension was stirred at 25° C. for 30 min. The suspension was passed through a plug of silica gel, and the filtrate was washed with brine. Activated carbon was added to the resulting solution, and the resulting suspension was filtered. The filtrate was dried over Na2SO4 and concentrated under reduced pressure. Flash chromatography on silica gel (Et2O/(8:1.9:0.1 Et2O/MeOH/NH4OH) afforded a clear solid. 2 N HCl in Et2O (100 mL) was added to a solution of the clear solid in CH2Cl2 (5 mL) under N2, and the resulting suspension was stirred at 25° C. for 22 h. The suspension was concentrated, and the resulting residue was dissolved in MeOH (1 mL). Et2O was added, and the resulting suspension was filtered. The solid was washed with Et2O and put in a vacuum oven at 40° C. for 1 h to afford 39 mg (44%) of the title compound as a white powder: 1H NMR (500 MHz, DMSO-d6) δ 8.92 (br s, 2H), 8.16 (d, J=8.0 Hz, 1H), 7.81 (d, J=8.0 Hz, 1H), 7.64 (dd, J=8.0, 8.0 Hz, 1H), 7.55 (dd, J=10.0, 2.0 Hz, 1H), 7.41-7.35 (m, 2H), 6.15 (dd, J=8.0, 2.5 Hz, 1H), 6.05 (d, J=2.5 Hz, 1H), 5.19 (s, 2H), 4.52-4.45 (m, 2H), 3.76 (s, 3H), 3.60-3.31 (m, 2H), 3.17-3.11 (m, 2H), 2.13-2.04 (m, 2H); ESI MS m/z 453 [M+H]+.

1. customwas degassed under reduced pressure for 45 min
2. temperatureThe suspension was cooled
3. addition9:0.9:0.1 CH2Cl2/MeOH/NH4OH (10 mL) was added
4. stirringthe resulting suspension was stirred at 25° C. for 30 min
5. washthe filtrate was washed with brine
6. additionActivated carbon was added to the resulting solution
7. filtrationthe resulting suspension was filtered
8. dry with materialThe filtrate was dried over Na2SO4
9. concentrationconcentrated under reduced pressure
10. customFlash chromatography on silica gel (Et2O/(8:1.9:0.1 Et2O/MeOH/NH4OH) afforded a clear solid
11. stirringthe resulting suspension was stirred at 25° C. for 22 h
12. concentrationThe suspension was concentrated
13. dissolutionthe resulting residue was dissolved in MeOH (1 mL)
14. additionEt2O was added
15. filtrationthe resulting suspension was filtered
16. washThe solid was washed with Et2O
17. waitput in a vacuum oven at 40° C. for 1 h

ORD record

ord-605a29702a7f4069aeb6c4dd9929d96b

Source dataset

uspto-grants-2014_01

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08637501B2