Hydrochloric Acid → 4-(Benzyloxy)-1-(2,9-dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-7-yl)pyridin-2(1H)-one hydrochloride

HRID 930637Notes

Reaction equation

HRID 930637 reaction equation
Br[C:2]1[CH:10]=[C:9]2[C:5]([C:6]3[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][C:7]=3[N:8]2[CH3:11])=[CH:4][CH:3]=1.[CH2:17]([O:24][C:25]1[CH:30]=[CH:29][NH:28][C:27](=[O:31])[CH:26]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.OC1C=CC=C2C=1N=CC=C2.C([O-])([O-])=O.[K+].[K+].[ClH:49].CCOCC>CS(C)=O.C(Cl)Cl.[Cu]I>[ClH:49].[CH2:17]([O:24][C:25]1[CH:30]=[CH:29][N:28]([C:2]2[CH:10]=[C:9]3[C:5]([C:6]4[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][C:7]=4[N:8]3[CH3:11])=[CH:4][CH:3]=2)[C:27](=[O:31])[CH:26]=1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1

Participants

10

Reactant 6

HCID 313Hydrochloric AcidHCID 19238-HydroxyquinolineHCID 3283Diethyl EtherHCID 11430Potassium CarbonateHCID 36077244-Benzyloxy-2(1H)-pyridoneHCID 579503597-Bromo-2,9-dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole

Product 1

HCID 686575684-(Benzyloxy)-1-(2,9-dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-7-yl)pyridin-2(1H)-one hydrochlorideYield 33%

Reagents, catalysts & solvents 3

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

Conditions

Temperature
130 °C

Procedure

A stirred solution of 7-bromo-2,9-dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (250 mg, 0.895 mmol) in DMSO (4 mL) under nitrogen was treated sequentially with 4-(benzyloxy)pyridin-2(1H)-one (180 mg, 0.895 mmol), 8-hydroxyquinoline (20 mg, 0.14 mmol), CuI (196 mg, 1.04 mmol) and K2CO3 (142 mg, 1.04 mmol). The mixture was placed under vacuum for 30 minutes and then flushed with nitrogen. After stirring overnight at 130° C., the mixture was allowed to cool to room temperature, diluted with CH2Cl2, washed with brine, dried over Na2SO4 and concentrated. Purification by flash column chromatography (12 g ISCO column eluting with methylene chloride and a methanol/ammonia mixture (10:1); gradient 100% methylene chloride to 80% methylene chloride over 30 min at 25 mL/min) provided the free-base. This was dissolved in methylene chloride (2 mL) and treated with 2 N HCl in Et2O (1 equivalent) and the mixture was concentrated to provide the title compound (131 mg, 33%) as a yellow solid: mp 270-274° C.; 1H NMR (500 MHz, CD3OD) δ 7.67-7.63 (m, 2H), 7.50-7.40 (m, 3H), 7.43-7.35 (m, 3H), 7.08 (dd, J=8.3, 1.6 Hz, 1H), 6.40 (dd, J=7.5, 2.6 Hz, 1H), 6.21 (d, J=2.6 Hz, 1H), 5.22 (s, 2H), 4.81-4.80 (m, 1H), 4.58 (d, J=15.3 Hz, 1H), 3.88-3.84 (m, 1H), 3.72 (s, 3H), 3.55-3.49 (m, 1H), 3.21-3.16 (m, 5H); ESI MS m/z 400 [M+H]+; HPLC (Method B)>98.9% (AUC), tR=13.0 min.

Workup

  1. customflushed with nitrogen
  2. temperatureto cool to room temperature
  3. additiondiluted with CH2Cl2
  4. washwashed with brine
  5. dry with materialdried over Na2SO4
  6. concentrationconcentrated
  7. customPurification by flash column chromatography (12 g ISCO column
  8. washeluting with methylene chloride
  9. customgradient 100% methylene chloride to 80% methylene chloride over 30 min at 25 mL/min) provided the free-base
  10. concentrationthe mixture was concentrated

Sources & evidence

ORD record
ord-c12c718d60314d44a04db89ae0cddae2
Source dataset
uspto-grants-2016_03
Patent number
US09296743B2

Reaction notes

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