Hydrochloric Acid → 4-(2,4-Difluorobenzyloxy)-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

HRID 474994Notes

Reaction equation

HRID 474994 reaction equation
[F:1][C:2]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:3]=1[CH2:4][O:5][C:6]1[CH:11]=[CH:10][NH:9][C:8](=[O:12])[CH:7]=1.Br[C:19]1[CH:20]=[CH:21][C:22]2[C:26]3[CH2:27][N:28](C(OC(C)(C)C)=O)[CH2:29][CH2:30][CH2:31][C:25]=3[N:24]([CH3:39])[C:23]=2[N:40]=1.OC1C=CC=C2C=1N=CC=C2.C([O-])([O-])=O.[Cs+].[Cs+].[ClH:58]>CS(C)=O.CCOCC.C(Cl)Cl.[Cu]I>[ClH:58].[F:1][C:2]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:3]=1[CH2:4][O:5][C:6]1[CH:11]=[CH:10][N:9]([C:19]2[CH:20]=[CH:21][C:22]3[C:26]4[CH2:27][NH:28][CH2:29][CH2:30][CH2:31][C:25]=4[N:24]([CH3:39])[C:23]=3[N:40]=2)[C:8](=[O:12])[CH:7]=1

Participants

10

Reactant 5

HCID 313Hydrochloric AcidHCID 19238-HydroxyquinolineHCID 10796Cesium carbonateHCID 220503904-(2,4-difluorobenzyloxy)-1H-pyridin-2-oneHCID 86649551tert-butyl 2-bromo-10-methyl-7,8,9,10-tetrahydropyrido[3',2':4,5]pyrrolo[3,2-c]azepine-6(5H)-carboxylate

Product 1

HCID 668746904-(2,4-Difluorobenzyloxy)-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 hydrochlorideYield 35%

Reagents, catalysts & solvents 4

HCID 24350Copper(1+) iodide; Copper(I) iodide; Cuprous iodide; Cuprous iodide (CuI)CatalystHCID 679Dimethyl SulfoxideSolventHCID 3283Diethyl EtherSolventHCID 6344DichloromethaneSolvent

Conditions

Temperature
135 °C

Procedure

A suspension of 4-(2,4-difluorobenzyloxy)pyridin-2(1H)-one (68 mg, 0.29 mmol), tert-butyl 2-bromo-10-methyl-7,8,9,10-tetrahydropyrido[3′,2′:4,5]pyrrolo[3,2-c]azepine-6(5H)-carboxylate (120 mg, 0.316 mmol), CuI (65 mg, 0.34 mmol), 8-hydroxyquinoline (8 mg, 0.06 mmol) and Cs2CO3 (103 mg, 0.316 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 24 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 tan residue. 2 N HCl in Et2O (100 mL) was added to a solution of the tan residue in CH2Cl2 (5 mL) under N2, and the resulting suspension was stirred at 25° C. for 2 d. The suspension was filtered, and the solid was washed with Et2O and put in a vacuum oven at 40° C. for 1 h to afford 47 mg (35%) of the title compound as a white powder: 1H NMR (500 MHz, DMSO-d6) δ 8.86 (br s, 2H), 8.16 (d, J=8.5 Hz, 1H), 7.81 (d, J=8.0 Hz, 1H), 7.67 (dd, J=15.5, 8.5 Hz, 1H), 7.40-7.34 (m, 2H), 7.18 (ddd, J=8.5, 8.5, 2.5 Hz, 1H), 7.15 (dd, J=8.0, 3.0 Hz, 1H), 6.06 (d, J=2.5 Hz, 1H), 5.17 (s, 2H), 4.51-4.45 (m, 2H), 3.77 (s, 3H), 3.60-3.42 (m, 2H), 3.17-3.13 (m, 2H), 2.12-2.05 (m, 2H); ESI MS m/z 437 [M+H]+.

Workup

  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 tan residue
  11. stirringthe resulting suspension was stirred at 25° C. for 2 d
  12. filtrationThe suspension was filtered
  13. washthe solid was washed with Et2O
  14. waitput in a vacuum oven at 40° C. for 1 h

Sources & evidence

ORD record
ord-c380f88d998d4b849cf70b655e7b9d0b
Source dataset
uspto-grants-2014_01
Patent number
US08637501B2

Reaction notes

Loading…