Water → 4-(6,6-dimethyl-5,6,7,8-tetrahydroquinazolin-4-yl)-7-[2-methyl-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazo[4,5-b]pyridin-6-yl]-2,3,4,5-tetrahydro-1,4-benzoxazepine

HRID 241104Notes

Reaction equation

HRID 241104 reaction equation
Br[C:2]1[CH:3]=[C:4]2[N:10]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[C:9]([CH3:19])=[N:8][C:5]2=[N:6][CH:7]=1.[CH3:20][C:21]1([CH3:45])[CH2:30][CH2:29][C:28]2[N:27]=[CH:26][N:25]=[C:24]([N:31]3[CH2:37][C:36]4[CH:38]=[C:39](B(O)O)[CH:40]=[CH:41][C:35]=4[O:34][CH2:33][CH2:32]3)[C:23]=2[CH2:22]1.C(N(CC)C(C)C)(C)C.O>CN(C)C=O.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]>[CH3:20][C:21]1([CH3:45])[CH2:30][CH2:29][C:28]2[N:27]=[CH:26][N:25]=[C:24]([N:31]3[CH2:37][C:36]4[CH:38]=[C:39]([C:2]5[CH:3]=[C:4]6[N:10]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[C:9]([CH3:19])=[N:8][C:5]6=[N:6][CH:7]=5)[CH:40]=[CH:41][C:35]=4[O:34][CH2:33][CH2:32]3)[C:23]=2[CH2:22]1

Participants

8

Reactant 4

HCID 962WaterHCID 81531DiisopropylethylamineHCID 595928396-bromo-2-methyl-1-(2-trimethylsilanylethoxymethyl)-1H-imidazo[4,5-b]pyridineHCID 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 668205234-(6,6-dimethyl-5,6,7,8-tetrahydroquinazolin-4-yl)-7-[2-methyl-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazo[4,5-b]pyridin-6-yl]-2,3,4,5-tetrahydro-1,4-benzoxazepineYield 73%

Reagents, catalysts & solvents 3

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)CatalystHCID 6228DimethylformamideSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
95 °C

Procedure

A solution of 6-bromo-2-methyl-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazo[4,5-b]pyridine (reagent preparation 35) (0.43 g, 1.30 mmol), [4-(6,6-dimethyl-5,6,7,8-tetrahydroquinazolin-4-yl)-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl]boronic acid (reagent preparation 23) (0.45 g, 1.30 mmol) and N,N-diisopropylethylamine (1.10 mL, 6.50 mmol) in N,N-dimethylformamide (4 mL), and water (1 mL) was degassed by bubbling nitrogen gas for five minutes followed by the addition of [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (52 mg, 0.065 mmol), then stirred at 95° C. for 16 hours. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (100 mL), and filtered through a pad of Celite. The filtrate was washed with 1M aqueous lithium chloride (50 mL) and brine, dried over sodium sulfate, filtered and concentrated. Column chromatography on silica (gradient 1-2% 7N ammonia in methanol in chloroform) gave 4-(6,6-dimethyl-5,6,7,8-tetrahydroquinazolin-4-yl)-7-[2-methyl-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazo[4,5-b]pyridin-6-yl]-2,3,4,5-tetrahydro-1,4-benzoxazepine (0.54 g, 73% yield). MS (EI) for C32H42N6O2Si: 571 (MH+).

Workup

  1. customby bubbling nitrogen gas for five minutes
  2. temperatureThe reaction mixture was cooled to room temperature
  3. filtrationfiltered through a pad of Celite
  4. washThe filtrate was washed with 1M aqueous lithium chloride (50 mL) and brine
  5. dry with materialdried over sodium sulfate
  6. filtrationfiltered
  7. concentrationconcentrated

Sources & evidence

ORD record
ord-e1d0937323f043879a82910c52e9f308
Source dataset
uspto-grants-2014_02
Patent number
US08648066B2

Reaction notes

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