1,4-Dioxane → 5-[4-(6,6-Dimethyl-5,6,7,8-tetrahydroquinazolin-4-yl)-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl]-3-nitropyridin-2-amine

HRID 241098Notes

Reaction equation

HRID 241098 reaction equation
[NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5](Br)=[CH:4][N:3]=1.[CH3:12][C:13]1([CH3:37])[CH2:22][CH2:21][C:20]2[N:19]=[CH:18][N:17]=[C:16]([N:23]3[CH2:29][C:28]4[CH:30]=[C:31](B(O)O)[CH:32]=[CH:33][C:27]=4[O:26][CH2:25][CH2:24]3)[C:15]=2[CH2:14]1.C(N(C(C)C)CC)(C)C.O1CCOCC1>C(OCC)(=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O>[CH3:12][C:13]1([CH3:37])[CH2:22][CH2:21][C:20]2[N:19]=[CH:18][N:17]=[C:16]([N:23]3[CH2:29][C:28]4[CH:30]=[C:31]([C:5]5[CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]([NH2:1])=[N:3][CH:4]=5)[CH:32]=[CH:33][C:27]=4[O:26][CH2:25][CH2:24]3)[C:15]=2[CH2:14]1

Participants

8

Reactant 4

HCID 312751,4-DioxaneHCID 81531DiisopropylethylamineHCID 1388782-Amino-5-bromo-3-nitropyridineHCID 66820411[4-(6,6-Dimethyl-5,6,7,8-tetrahydroquinazolin-4-yl)-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl]boronic acid

Product 1

HCID 668203605-[4-(6,6-Dimethyl-5,6,7,8-tetrahydroquinazolin-4-yl)-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl]-3-nitropyridin-2-amineYield 97%

Reagents, catalysts & solvents 3

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)CatalystHCID 962WaterSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
90 °C

Procedure

A mixture of 2-amino-5-bromo-3-nitropyridine (0.31 g, 1.4 mmol [4-(6,6-dimethyl-5,6,7,8-tetrahydroquinazolin-4-yl)-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl]boronic acid (0.50 g, 1.4 mmol), [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (103 mg, 0.1 mmol), diisopropylethylamine (0.94 g, 7.1 mmol), 1,4-dioxane (20 mL), and water (2 mL) was stirred at 90° C. for 4 hours. The reaction mixture was cooled, diluted with ethyl acetate (100 mL) then filtered through celite. The filtrate was washed with 50 mL portion each of 5% aqueous citric acid, water, then brine solution, dried over sodium sulfate, filtered and concentrated to give a brown solid residue. It was washed with 35% ethyl acetate-hexane to give 5-[4-(6,6-dimethyl-5,6,7,8-tetrahydroquinazolin-4-yl)-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl]-3-nitropyridin-2-amine (0.63 g, 97% yield). MS (EI) for C24H26N6O3: 447 (MH+).

Workup

  1. temperatureThe reaction mixture was cooled
  2. filtrationthen filtered through celite
  3. washThe filtrate was washed with 50 mL portion each of 5% aqueous citric acid, water
  4. dry with materialbrine solution, dried over sodium sulfate
  5. filtrationfiltered
  6. concentrationconcentrated
  7. customto give a brown solid residue
  8. washIt was washed with 35% ethyl acetate-hexane

Sources & evidence

ORD record
ord-c5378c5ce037439ea1b63fe12420f0be
Source dataset
uspto-grants-2014_02
Patent number
US08648066B2

Reaction notes

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