Morpholine → HCID 66876822, compound

HRID 1917788Notes

Reaction equation

HRID 1917788 reaction equation
[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]3[C:30]4[C:25](=[CH:26][CH:27]=[C:28](I)[CH:29]=4)[N:24]=[CH:23][N:22]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1.C([O-])([O-])=O.[Cs+].[Cs+]>COCCOC.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]3[C:30]4[C:25](=[CH:26][CH:27]=[C:28]([N:32]5[CH2:37][CH2:36][O:35][CH2:34][CH2:33]5)[CH:29]=4)[N:24]=[CH:23][N:22]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]

Participants

6

Reactant 3

HCID 8083MorpholineHCID 10796Cesium carbonateHCID 66876492HCID 66876492, compound

Product 1

HCID 66876822HCID 66876822, compoundYield 3.4%

Reagents, catalysts & solvents 2

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 80711,2-DimethoxyethaneSolvent

Conditions

Temperature
70 °C

Procedure

A mixture of 1-(5-tert-butylisoxazol-3-yl)-3-[3-(6-iodoquinazolin-4-yloxy)phenyl]urea from Example 92A (0.225 g, 0.425 mmol), morpholine (0.5 mL), xamtphhos (0.087 g, 0.15 mmol), tris(dibenzylideneacetone)dipalladium (0) (0.046 g, 0.05 mmol), and Cs2CO3 (0.489 g, 1.5 mmol) in 1,2-dimethoxyethane (8 mL) was heated at 70° C. for 4 hours. It was quenched with water and extracted with CH2Cl2. Extracts were dried over MgSO4 and concentrated under reduced pressure. It was purified by silica gel chromatophraphy with 30-100% EtOAc/hexane and 5% MeOH/EtOAc as eluants, and by preparative HPLC(C18) with 60-80% CH3CN/H2O (0.05% AcOH) to afford 1-(5-tert-butylisoxazol-3-yl)-3-[3-(6-morpholinoquinazolin-4-yloxy)phenyl]urea as a solid (0.007 g, 3.4%). 1H NMR (300 MHz, CD3CN) δ 9.48 (br, 1H), 8.39 (s, 1H), 7.78 (m, 4H), 7.67 (dd, 1H), 7.44 (m, 3H), 7.03 (d, 1H), 3.76 (t, 4H), 3.23 (t, 4H), 1.11 (s, 9H); LC-MS (ESI) m/z 489 (M+H)+.

Workup

  1. customIt was quenched with water
  2. extractionextracted with CH2Cl2
  3. dry with materialExtracts were dried over MgSO4
  4. concentrationconcentrated under reduced pressure
  5. customIt was purified by silica gel chromatophraphy with 30-100% EtOAc/hexane and 5% MeOH/EtOAc as eluants

Sources & evidence

ORD record
ord-35595a41654e4c6e8c0d668d7fde5727
Source dataset
uspto-grants-2013_12
Patent number
US08618289B2

Reaction notes

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