Cesium carbonate → 1-(5-Tert-butyl-isoxazol-3-yl)-3-{3-[7-(3-chloro-propoxy)-6-methoxy-quinazolin-4-yloxy]-phenyl}-urea

HRID 871299Notes

Reaction equation

HRID 871299 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]([OH:20])[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl[C:22]1[C:31]2[C:26](=[CH:27][C:28]([O:34][CH2:35][CH2:36][CH2:37][Cl:38])=[C:29]([O:32][CH3:33])[CH:30]=2)[N:25]=[CH:24][N:23]=1.C([O-])([O-])=O.[Cs+].[Cs+]>C1COCC1.C(OCC)(=O)C>[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:22]3[C:31]4[C:26](=[CH:27][C:28]([O:34][CH2:35][CH2:36][CH2:37][Cl:38])=[C:29]([O:32][CH3:33])[CH:30]=4)[N:25]=[CH:24][N:23]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]

Participants

6

Reactant 3

HCID 10796Cesium carbonateHCID 574472274-Chloro-7-(3-chloropropoxy)-6-methoxyquinazolineHCID 668765951-(5-Tert-butylisoxazol-3-yl)-3-(3-hydroxyphenyl)urea

Product 1

HCID 668760291-(5-Tert-butyl-isoxazol-3-yl)-3-{3-[7-(3-chloro-propoxy)-6-methoxy-quinazolin-4-yloxy]-phenyl}-ureaYield 61%

Reagents, catalysts & solvents 2

HCID 8028TetrahydrofuranSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
50 °C

Procedure

To a solution of (1-(5-tert-butyl-isoxazol-3-yl)-3-(3-hydroxy-phenyl)-urea, 300 mg, 1.089 mmol) from Example 1A and (4-chloro-7-(3-chloro-propoxy)-6-methoxy-quinazoline (343.96 mg, 1.119 mmol), from the previous step in THF, was added Cs2CO3 (532.2 mg, 1.63 mmol) and the mixture was heated at 50° C. for 12 hours. Completion of the reaction was monitored by LCMS. The reaction mixture was diluted with ethyl acetate and the ethyl acetate layer was washed with water and brine successively. The organic layer was dried (Na2SO4) and concentrated to dryness. The crude compound was purified by column chromatography to afford the pure compound 1-(5-tert-butyl-isoxazol-3-yl)-3-{3-[7-(3-chloro-propoxy)-6-methoxy-quinazolin-4-yloxy]-phenyl}-urea, (310 mg, 61%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 9.55 (s, 1H), 9.00 (s, 1H), 8.55 (s, 1H), 7.55 (m, 2H), 7.40 (m, 2H), 7.25 (d, 1H), 6.95 (d, 1H), 6.45 (s, 1H), 4.35 (t, 2H), 4.00 (s, 3H), 3.85 (2, 2H), 1.30 (s, 9H); LC-MS (ESI)m/z 526 (M+H)+.

Workup

  1. washthe ethyl acetate layer was washed with water and brine successively
  2. dry with materialThe organic layer was dried (Na2SO4)
  3. concentrationconcentrated to dryness
  4. customThe crude compound was purified by column chromatography

Sources & evidence

ORD record
ord-d6f8eca45d44466d8817e04ca88abbb8
Source dataset
uspto-grants-2015_03
Patent number
US08969587B2

Reaction notes

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