2-Pyrrolidone → 4-(6,7-Dimethoxy-quinazolin-4-yl)-piperidine-1-carboxylic acid [4-(2-oxo-pyrrolidin-1-yl)-phenyl]-amide

HRID 657234Notes

Reaction equation

HRID 657234 reaction equation
I[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[C:26]4[C:21](=[CH:22][C:23]([O:29][CH3:30])=[C:24]([O:27][CH3:28])[CH:25]=4)[N:20]=[CH:19][N:18]=3)[CH2:13][CH2:12]2)=[O:10])=[CH:4][CH:3]=1.[NH:31]1[CH2:35][CH2:34][CH2:33][C:32]1=[O:36].CN(C)CCN.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.[Cu]I>[O:36]=[C:32]1[CH2:33][CH2:34][CH2:35][N:31]1[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[C:26]4[C:21](=[CH:22][C:23]([O:29][CH3:30])=[C:24]([O:27][CH3:28])[CH:25]=4)[N:20]=[CH:19][N:18]=3)[CH2:13][CH2:12]2)=[O:10])=[CH:4][CH:3]=1

Participants

7

Reactant 4

HCID 120252-PyrrolidoneHCID 62657Potassium Phosphate, TribasicHCID 66053N,N-DimethylethylenediamineHCID 587707304-(6,7-Dimethoxy-quinazolin-4-yl)-piperidine-1-carboxylic acid (4-iodo-phenyl)-amide

Product 1

HCID 587707334-(6,7-Dimethoxy-quinazolin-4-yl)-piperidine-1-carboxylic acid [4-(2-oxo-pyrrolidin-1-yl)-phenyl]-amideYield 16.4%

Reagents, catalysts & solvents 2

HCID 24350Copper(1+) iodide; Copper(I) iodide; Cuprous iodide; Cuprous iodide (CuI)CatalystHCID 1140TolueneSolvent

Conditions

Temperature
105 °C

Procedure

To a mixture of 4-(6,7-dimethoxy-quinazolin-4-yl)-piperidine-1-carboxylic acid (4-iodo-phenyl)-amide (57.9 mg, 0.11 mmol), as prepared in Example 2b, and pyrrolidin-2-one (13.3 mg, 0.16 mmol) in toluene (3 mL) was added CuI (1.5 mg), followed by N,N-dimethylethylenediamine (1.4 mg) and K3PO4 (56.7 mg). The reaction mixture was heated at 105° C. overnight. It was concentrated under reduced pressure and the crude residue was purified by flash column chromatography on silica gel (10% MeOH/EtOAc as eluent) to afford the desired product (8.6 mg, 16.4% yield). 1H NMR (300 MHz, CD3OD) δ 8.95 (s, 1H), 7.58 (s, 1H), 7.50 (d, J=9.26 Hz, 2H), 7.41 (d, J=9.27 Hz, 2H), 7.32 (s, 1H), 4.36 (m, 2H), 4.06 (s, 3H), 4.04 (s, 3H), 3.91 (t, J=6.93 Hz, 2H), 3.39 (m, 1H), 3.19 (m, 2H), 2.59 (t, J=8.46 Hz, 2H), 1.94-2.30 (m, 6H). LC-MS (ESI) calcd mass 475.2, found 476.4 (MH+).

Workup

  1. concentrationIt was concentrated under reduced pressure
  2. customthe crude residue was purified by flash column chromatography on silica gel (10% MeOH/EtOAc as eluent)

Sources & evidence

ORD record
ord-5f2de5baacd846188328bcade3778238
Source dataset
uspto-grants-2011_12
Patent number
US08071768B2

Reaction notes

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