Dichloromethane → 1-(4-(2-(1-isopropyl-3-(methoxymethyl)-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol

HRID 1629344Notes

Reaction equation

HRID 1629344 reaction equation
Br[C:2]1[CH:26]=[CH:25][C:5]2[C:6]3[N:10]([CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1)[CH:9]=[C:8]([C:14]1[N:15]([CH:22]([CH3:24])[CH3:23])[N:16]=[C:17]([CH2:19][O:20][CH3:21])[N:18]=1)[N:7]=3.[CH3:27][C:28]([OH:45])([CH3:44])[CH2:29][N:30]1[CH:34]=[C:33](B2OC(C)(C)C(C)(C)O2)[CH:32]=[N:31]1.C(Cl)Cl.C(=O)([O-])[O-].[Cs+].[Cs+]>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.COCCOC>[CH:22]([N:15]1[C:14]([C:8]2[N:7]=[C:6]3[C:5]4[CH:25]=[CH:26][C:2]([C:33]5[CH:32]=[N:31][N:30]([CH2:29][C:28]([CH3:44])([OH:45])[CH3:27])[CH:34]=5)=[CH:3][C:4]=4[O:13][CH2:12][CH2:11][N:10]3[CH:9]=2)=[N:18][C:17]([CH2:19][O:20][CH3:21])=[N:16]1)([CH3:24])[CH3:23]

Participants

8

Reactant 4

HCID 6344DichloromethaneHCID 10796Cesium carbonateHCID 582041312-methyl-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]propan-2-olHCID 582043878-Bromo-2-(2-isopropyl-5-methoxymethyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene

Product 1

HCID 582043771-(4-(2-(1-isopropyl-3-(methoxymethyl)-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-olYield 35%

Reagents, catalysts & solvents 3

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)CatalystHCID 962WaterSolventHCID 80711,2-DimethoxyethaneSolvent

Conditions

Temperature
140 °C

Procedure

A mixture of 8-bromo-2-(2-isopropyl-5-methoxymethyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene (100 mg, 0.24 mmol), 2-methyl-1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrazol-1-yl]-propan-2-ol (127 mg, 0.48 mmol), PdCl2(dppf).DCM (9.8 mg, 0.012 mmol), cesium carbonate (234 mg, 0.72 mmol), DME (1.6 mL), water (0.27 mL) and IMS (0.5 mL) was degassed and then heated at 140° C. for 20 min using microwave irradiation. The reaction mixture was partitioned between DCM and water, the aqueous extracted twice with DCM and the combined organic extracts washed with brine then dried (Na2SO4), filtered and concentrated in vacuo. The resultant residue was subjected to RPHPLC (C18 column, gradient 5 to 95% methanol in water+0.1% HCO2H) to give 302 as a white solid (40 mg, 35%). LCMS: RT=3.77 min, [M+H]+478. 1H NMR 400 MHz (DMSO-d) δ: 8.37 (1 H, d, J=8.38 Hz), 8.17 (1 H, s), 7.94 (2 H, d, J=7.28 Hz), 7.40 (1 H, dd, J=8.37, 1.80 Hz), 7.28 (1 H, d, J=1.77 Hz), 5.89-5.88 (1 H, m), 4.74 (1 H, s), 4.53 (4 H, m), 4.38 (2 H, s), 4.04 (2 H, s), 3.32 (3 H, s), 1.49 (6 H, d, J=6.60 Hz), 1.10 (6 H, s).

Workup

  1. custommicrowave irradiation
  2. customThe reaction mixture was partitioned between DCM and water
  3. extractionthe aqueous extracted twice with DCM
  4. washthe combined organic extracts washed with brine
  5. dry with materialthen dried (Na2SO4)
  6. filtrationfiltered
  7. concentrationconcentrated in vacuo

Sources & evidence

ORD record
ord-d4db336ab97342898e29d5dbd0172cee
Source dataset
uspto-grants-2014_07
Patent number
US08785626B2

Reaction notes

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