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

HRID 631688Notes

Reaction equation

HRID 631688 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) δ9.09 (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-d5b985ce3a3e48009093111a5a1aeb99
Source dataset
uspto-grants-2016_04
Patent number
US09320739B2

Reaction notes

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