2,4-Dichloro-6,7-dimethoxyquinazoline → HCID 58267815, compound

HRID 871695Notes

Reaction equation

HRID 871695 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].CC(C)([O-])C.[K+].[Cl:27][C:28]1[N:37]=[C:36](Cl)[C:35]2[C:30](=[CH:31][C:32]([O:41][CH3:42])=[C:33]([O:39][CH3:40])[CH:34]=2)[N:29]=1>CN(C=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:36]3[C:35]4[C:30](=[CH:31][C:32]([O:41][CH3:42])=[C:33]([O:39][CH3:40])[CH:34]=4)[N:29]=[C:28]([Cl:27])[N:37]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]

Participants

5

Reactant 3

HCID 5203272,4-Dichloro-6,7-dimethoxyquinazolineHCID 23665647Potassium tert-butoxideHCID 668765951-(5-Tert-butylisoxazol-3-yl)-3-(3-hydroxyphenyl)urea

Product 1

HCID 58267815HCID 58267815, compoundYield 32%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent2×

Procedure

To a stirred solution of 1-(5-tert-butylisoxazol-3-yl)-3-(3-hydroxyphenyl)urea (prepared as described in Example 1A) (80 mg, 0.291 mmol) in anhydrous degassed DMF (2 mL) at rt and under an argon atmosphere, was added potassium tert-butoxide (65 mg, 0.581 mmol). The reaction mixture was stirred at rt for a further 2 h. A solution of 2,4-dichloro-6,7-dimethoxyquinazoline (75 mg, 0.291 mmol) in anhydrous DMF (1 mL) was added and the reaction mixture was stirred at rt for a further 15 h. The reaction mixture was partitioned between a mixture of ethyl acetate (20 mL) and brine solution (20 mL), and the organic layer separated. The aqueous layer was extracted further with ethyl acetate (1×20 mL) and the combined organic layers dried over magnesium sulfate. Concentration under reduced pressure gave the crude product which was purified via silica gel flash chromatography (eluting with a gradient of 25% ethyl acetate in hexanes to 100% ethyl acetate) to afford 1-(5-tert-butylisoxazol-3-yl)-3-(3-(2-chloro-6,7-dimethoxyquinazolin-4-yloxy)phenyl)urea (46 mg, 32%) as a solid. 1H NMR (300 MHz, CDCl3) δ 9.60 (brs, 1H), 9.03 (brs, 1H), 7.61 (m, 1H), 7.57 (m, 1H), 7.39-7.46 (m, 2H), 7.31 (m, 1H), 7.01 (m, 1H), 6.48 (s, 1H), 4.00 (s, 3H), 3.98 (s, 3H), 1.28 (s, 9H); LC-MS (ESI) m/z 498 (M+H)+.

Workup

  1. stirringthe reaction mixture was stirred at rt for a further 15 h
  2. customThe reaction mixture was partitioned between a mixture of ethyl acetate (20 mL) and brine solution (20 mL)
  3. customthe organic layer separated
  4. extractionThe aqueous layer was extracted further with ethyl acetate (1×20 mL)
  5. dry with materialthe combined organic layers dried over magnesium sulfate
  6. concentrationConcentration under reduced pressure
  7. customgave the crude product which
  8. customwas purified via silica gel flash chromatography (
  9. washeluting with a gradient of 25% ethyl acetate in hexanes to 100% ethyl acetate)

Sources & evidence

ORD record
ord-8f23b955c2654d8688a1c65ee6ced817
Source dataset
uspto-grants-2015_03
Patent number
US08969587B2

Reaction notes

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