Sodium hydride → 1-(5-Tert-butylisoxazol-3-yl)-3-(3-(7-methoxy-6-(3-(methylsulfonyl)propoxy)quinazolin-4-ylthio)phenyl)urea

HRID 871335Notes

Reaction equation

HRID 871335 reaction equation
[H-].[Na+].[C:3]([C:7]1[O:11][N:10]=[C:9]([NH:12][C:13]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([SH:22])[CH:17]=2)=[O:14])[CH:8]=1)([CH3:6])([CH3:5])[CH3:4].Cl[C:24]1[C:33]2[C:28](=[CH:29][C:30]([O:42][CH3:43])=[C:31]([O:34][CH2:35][CH2:36][CH2:37][S:38]([CH3:41])(=[O:40])=[O:39])[CH:32]=2)[N:27]=[CH:26][N:25]=1>O1CCCC1.C(OCC)(=O)C.O>[C:3]([C:7]1[O:11][N:10]=[C:9]([NH:12][C:13]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([S:22][C:24]3[C:33]4[C:28](=[CH:29][C:30]([O:42][CH3:43])=[C:31]([O:34][CH2:35][CH2:36][CH2:37][S:38]([CH3:41])(=[O:39])=[O:40])[CH:32]=4)[N:27]=[CH:26][N:25]=3)[CH:17]=2)=[O:14])[CH:8]=1)([CH3:6])([CH3:4])[CH3:5]

Participants

6

Reactant 3

HCID 24758Sodium hydrideHCID 668758091-(5-Tert-butylisoxazol-3-yl)-3-(3-mercaptophenyl)ureaHCID 866535064-Chloro-7-methoxy-6-(3-(methylsulfonyl)propoxy)quinazoline

Product 1

HCID 442168711-(5-Tert-butylisoxazol-3-yl)-3-(3-(7-methoxy-6-(3-(methylsulfonyl)propoxy)quinazolin-4-ylthio)phenyl)ureaYield 4%

Reagents, catalysts & solvents 2

HCID 8028TetrahydrofuranSolvent2×HCID 22728543Water ethylacetateSolvent

Conditions

Temperature
0 °C

Procedure

To a suspension of sodium hydride (11 mg, 0.44 mmol) in anhydrous tetrahydrofuran (2 mL) cooled to 0° C., was added 1-(5-tert-butylisoxazol-3-yl)-3-(3-mercaptophenyl)urea from the previous step (117 mg, 0.40 mmol) as a solution in tetrahydrofuran (1 mL) and the mixture stirred at 0° C. for 30 minutes. To this suspension 4-chloro-7-methoxy-6-(3-(methylsulfonyl)propoxy)quinazoline from Example 41B Step 1 (133 mg, 0.40 mmol) was added and the resulting mixture was stirred at 0° C. and slowly allowed to reach room temperature. After stirring for additional 1 h, the mixture was taken up in ethyl acetate/water and extracted. The combined organic layers were dried (MgSO4) and concentrated under reduced pressure. The residue was purified by preparative HPLC (Phenomenex phenylhexyl reverse phase column) to afford 1-(5-tert-butylisoxazol-3-yl)-3-(3-(7-methoxy-6-(3-(methylsulfonyl)propoxy)quinazolin-4-ylthio)phenyl)urea (10.30 mg, 4%) as a solid. 1H NMR (300 MHz, DMSO-d6) δ 9.73 (bs, 1H), 9.19 (bs, 1H), 8.70 (s, 1H), 7.85 (s, 1H), 7.53-7.27 (m, 5H), 6.49 (s, 1H), 4.32 (bs, 2H), 4.01 (s, 3H), 3.35 (2H), 3.07 (s, 3H), 2.28 (bs, 2H), 1.28 (s, 9H); LC-MS (ESI) m/z 586 (M+H)+.

Workup

  1. stirringthe resulting mixture was stirred at 0° C.
  2. customto reach room temperature
  3. stirringAfter stirring for additional 1 h
  4. extractionextracted
  5. dry with materialThe combined organic layers were dried (MgSO4)
  6. concentrationconcentrated under reduced pressure
  7. customThe residue was purified by preparative HPLC (Phenomenex phenylhexyl reverse phase column)

Sources & evidence

ORD record
ord-c28bef6cab224166ac5fdd3f74ffec7a
Source dataset
uspto-grants-2015_03
Patent number
US08969587B2

Reaction notes

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