Diisopropylethylamine → 1-(3-tert-butyl-1-isobutyl-1H-pyrazol-5-yl)-3-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)urea

HRID 871736Notes

Reaction equation

HRID 871736 reaction equation
[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11](=[O:19])OC2C=CC=CC=2)[N:7]([CH2:20][CH:21]([CH3:23])[CH3:22])[N:6]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)C(C)C)(C)C.[CH3:33][O:34][C:35]1[CH:36]=[C:37]2[C:42](=[CH:43][C:44]=1[O:45][CH3:46])[N:41]=[CH:40][N:39]=[C:38]2[O:47][C:48]1[CH:49]=[C:50]([CH:52]=[CH:53][CH:54]=1)[NH2:51]>C1COCC1>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:51][C:50]2[CH:52]=[CH:53][CH:54]=[C:48]([O:47][C:38]3[C:37]4[C:42](=[CH:43][C:44]([O:45][CH3:46])=[C:35]([O:34][CH3:33])[CH:36]=4)[N:41]=[CH:40][N:39]=3)[CH:49]=2)=[O:19])[N:7]([CH2:20][CH:21]([CH3:22])[CH3:23])[N:6]=1)([CH3:2])([CH3:3])[CH3:4]

Participants

5

Reactant 3

HCID 81531DiisopropylethylamineHCID 498410023-[(6,7-Dimethoxy-4-quinazolinyl)oxy]anilineHCID 66876741phenyl 3-tert-butyl-1-isobutyl-1H-pyrazol-5-ylcarbamate

Product 1

HCID 569542221-(3-tert-butyl-1-isobutyl-1H-pyrazol-5-yl)-3-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)ureaYield 38%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

A stirred solution of phenyl 3-tert-butyl-1-isobutyl-1H-pyrazol-5-ylcarbamate (150 mg, 0.47 mmol), N,N-Diisopropylethylamine (80 mg, 0.62 mmol) and 3-(6,7-dimethoxyquinazolin-4-yloxy)aniline (prepared as described in Example 113A) (92 mg, 0.31 mmol) in THF (1.0 mL) was heated at 60° C. for 15 h. After cooling to rt, the reaction solution was partitioned between dichloromethane and a saturated aqueous solution of sodium carbonate. The organic phase was separated and concentrated under reduced pressure. The crude product was purified via silica gel column chromatography (eluting with a gradient of 40:1 to 20:1 dichloromethane:methanol) then reverse-phase preparative HPLC to afford 1-(3-tert-butyl-1-isobutyl-1H-pyrazol-5-yl)-3-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)urea (60 mg, 38%) as a pale yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 9.09 (s, 1H), 8.57 (s, 1H), 8.49 (s, 1H), 7.61 (m, 1H), 7.57 (m, 1H), 7.37-7.41 (m, 2H), 7.24 (m, 1H), 6.94 (m, 1H), 6.01 (s, 1H), 4.00 (s, 3H), 3.99 (s, 3H), 3.71 (d, J=7.6 Hz, 2H), 2.07 (m, 1H), 1.20 (s, 9H), 0.83 (d, J=6.4 Hz, 6H); LC-MS (ESI) m/z 519 (M+H)+.

Workup

  1. customthe reaction solution was partitioned between dichloromethane
  2. customThe organic phase was separated
  3. concentrationconcentrated under reduced pressure
  4. customThe crude product was purified via silica gel column chromatography (
  5. washeluting with a gradient of 40:1 to 20:1 dichloromethane

Sources & evidence

ORD record
ord-b9d04edbf633407199616dc4e3ded61f
Source dataset
uspto-grants-2015_03
Patent number
US08969587B2

Reaction notes

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