Nitrogen → 4-{[2-(benzyloxy)-4,6-dimethylpyridin-3-yl]methyl}-6-methyl-9-[2-(methylamino)pyrimidin-5-yl]-7-(propan-2-yloxy)-3,4-dihydro-1,4-benzoxazepin-5(2H)-one

HRID 577573Notes

Reaction equation

HRID 577573 reaction equation
[CH2:1]([O:8][C:9]1[C:14]([CH2:15][N:16]2[C:22](=[O:23])[C:21]3[C:24]([CH3:33])=[C:25]([O:29][CH:30]([CH3:32])[CH3:31])[CH:26]=[C:27](Br)[C:20]=3[O:19][CH2:18][CH2:17]2)=[C:13]([CH3:34])[CH:12]=[C:11]([CH3:35])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:36][NH:37][C:38]1[N:43]=[CH:42][C:41](B2OC(C)(C)C(C)(C)O2)=[CH:40][N:39]=1.C(=O)([O-])[O-].[Na+].[Na+].N#N>O1CCOCC1.O.CCOC(C)=O.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].C(Cl)Cl>[CH2:1]([O:8][C:9]1[C:14]([CH2:15][N:16]2[C:22](=[O:23])[C:21]3[C:24]([CH3:33])=[C:25]([O:29][CH:30]([CH3:32])[CH3:31])[CH:26]=[C:27]([C:41]4[CH:40]=[N:39][C:38]([NH:37][CH3:36])=[N:43][CH:42]=4)[C:20]=3[O:19][CH2:18][CH2:17]2)=[C:13]([CH3:34])[CH:12]=[C:11]([CH3:35])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1

Participants

9

Reactant 4

HCID 947NitrogenHCID 10340Sodium CarbonateHCID 467396412-Methylaminopyrimidine-5-boronic acid, pinacol esterHCID 867237854-((2-(benzyloxy)-4,6-dimethylpyridin-3-yl)methyl)-9-bromo-7-isopropoxy-6-methyl-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one

Product 1

HCID 867238004-{[2-(benzyloxy)-4,6-dimethylpyridin-3-yl]methyl}-6-methyl-9-[2-(methylamino)pyrimidin-5-yl]-7-(propan-2-yloxy)-3,4-dihydro-1,4-benzoxazepin-5(2H)-oneYield 74%

Reagents, catalysts & solvents 4

HCID 178418807HCID 178418807, compoundCatalystHCID 962WaterSolventHCID 8857Ethyl AcetateSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
100 °C

Procedure

A solution of 4-{[2-(benzyloxy)-4,6-dimethylpyridin-3-yl]methyl}-9-bromo-6-methyl-7-(propan-2-yloxy)-3,4-dihydro-1,4-benzoxazepin-5(2H)-one (116 g, 121 mg, 0.224 mmol), N-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine (52.7 mg, 0.224 mmol) and sodium carbonate (2.0 M, 71.2 mg, 0.672 mmol) in 1,4-dioxane (2.0 mL) was degassed (N2) for 5 min, then PdCl2(dppf)-DCM (50.0 mg, 0.0610 mmol) was added. The reaction was heated at 100° C. for 1 hour. The reaction was diluted with water (25 mL) and EtOAc (25 mL). The layers were separated and the organic phase was dried with magnesium sulfate and concentrated under vacuum. The residue was purified by column chromatography (silica gel, heptanes/EtOAc) to give 4-{[2-(benzyloxy)-4,6-dimethylpyridin-3-yl]methyl}-6-methyl-9-[2-(methylamino)pyrimidin-5-yl]-7-(propan-2-yloxy)-3,4-dihydro-1,4-benzoxazepin-5(2H)-one (128a, 94 mg, 74% yield) as a white solid.

Workup

  1. customThe layers were separated
  2. dry with materialthe organic phase was dried with magnesium sulfate
  3. concentrationconcentrated under vacuum
  4. customThe residue was purified by column chromatography (silica gel, heptanes/EtOAc)

Sources & evidence

ORD record
ord-0efec7f57ff44e7892ecbe5a868e45ea
Source dataset
uspto-grants-2015_05
Patent number
US09040515B2

Reaction notes

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