Triethylamine → (3-{3-[4-(4-Amino-quinazolin-7-ylmethyl)-3-oxo-piperazin-1-yl]-prop-1-ynyl}-pyridin-4-yl)-carbamic acid tert-butyl ester

HRID 1432965Notes

Reaction equation

HRID 1432965 reaction equation
[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH2:12][N:13]3[CH2:18][CH2:17][N:16]([CH2:19][C:20]#[CH:21])[CH2:15][C:14]3=[O:22])=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1.[C:23]([O:27][C:28](=[O:37])[NH:29][C:30]1[CH:35]=[CH:34][N:33]=[CH:32][C:31]=1I)([CH3:26])([CH3:25])[CH3:24].CCN(CC)CC>CN(C=O)C.CCOC(C)=O.O.[Cu]I>[C:23]([O:27][C:28](=[O:37])[NH:29][C:30]1[CH:35]=[CH:34][N:33]=[CH:32][C:31]=1[C:21]#[C:20][CH2:19][N:16]1[CH2:17][CH2:18][N:13]([CH2:12][C:8]2[CH:7]=[C:6]3[C:11]([C:2]([NH2:1])=[N:3][CH:4]=[N:5]3)=[CH:10][CH:9]=2)[C:14](=[O:22])[CH2:15]1)([CH3:26])([CH3:24])[CH3:25]

Participants

8

Reactant 3

HCID 8471TriethylamineHCID 10903275(3-Iodo-pyridin-4-yl)-carbamic acid tert-butyl esterHCID 538421351-(4-Amino-quinazolin-7-ylmethyl)-4-prop-2-ynyl-piperazin-2-one

Product 1

HCID 69026971(3-{3-[4-(4-Amino-quinazolin-7-ylmethyl)-3-oxo-piperazin-1-yl]-prop-1-ynyl}-pyridin-4-yl)-carbamic acid tert-butyl esterYield 36%

Reagents, catalysts & solvents 4

HCID 24350Copper(1+) iodide; Copper(I) iodide; Cuprous iodide; Cuprous iodide (CuI)CatalystHCID 962WaterSolventHCID 6228DimethylformamideSolventHCID 8857Ethyl AcetateSolvent

Procedure

A solution containing 1-(4-amino-quinazolin-7-ylmethyl)-4-prop-2-ynyl-piperazin-2-one (100 mg, 0.34 mmol), EXAMPLE 283, (3-iodo-pyridin-4-yl)-carbamic acid tert-butyl ester, EXAMPLE 69, Part B, (108 mg, 0.34 mmol), Et3N (140 mg, 1.36 mmol), (Ph3P)4PdCl2 (12 mg, 0.017 mmol), and CuI (2 mg, 0.01 mmol) in anhydrous DMF (5 mL) is stirred at ambient temperature. After 5 h, the reaction mixture is diluted with EtOAc (50 mL) and water (50 mL) and the layers are separated. The aqueous layer is extracted twice with EtOAc (25 mL) and the combined organic phase is washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The crude residue is purified by flash silica gel chromatography (CH2Cl2 to 10% MeOH CH2Cl2) to provide 59 mg (36%) of the title compound as a colorless oil. 1H NMR (300 MHz, CDCl3) δ1.49 (s, 9H), 2.84 (m, 2H), 3.35 (m, 2H), 3.44 (s, 2H), 3.71 (s, 2H), 4.75 (s, 2H), 6.19 (br s, 2H), 7.24 (d, J=5.5 Hz, 1H), 7.41 (d, J=8.4 Hz, 1H), 7.66 (s, 1H), 7.79 (d, J=8.4 Hz, 1H), 8.05 (d, J=5.5 Hz, 1H), 8.37 (s, 1H), 8.49 (s, 1H), 8.58 (s, 1H) ppm; MS (ISP loop): m/z 488 (M+H).

Workup

  1. customthe layers are separated
  2. extractionThe aqueous layer is extracted twice with EtOAc (25 mL)
  3. washthe combined organic phase is washed with brine
  4. dry with materialdried over anhydrous Na2SO4
  5. filtrationfiltered
  6. concentrationconcentrated
  7. customThe crude residue is purified by flash silica gel chromatography (CH2Cl2 to 10% MeOH CH2Cl2)

Sources & evidence

ORD record
ord-df10e527203e4c95961d517c8055daa5
Source dataset
uspto-grants-2009_11
Patent number
US07612075B2

Reaction notes

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