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

HRID 1918142Notes

Reaction equation

HRID 1918142 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[S: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]([S: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 569536273-(6,7-Dimethoxyquinazolin-4-ylthio)anilineHCID 66876741phenyl 3-tert-butyl-1-isobutyl-1H-pyrazol-5-ylcarbamate

Product 1

HCID 582678611-(3-tert-butyl-1-isobutyl-1H-pyrazol-5-yl)-3-(3-(6,7-dimethoxyquinazolin-4-ylthio)phenyl)ureaYield 32%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Conditions

Temperature
60 °C

Procedure

A stirred solution of phenyl 3-tert-butyl-1-isobutyl-1H-pyrazol-5-ylcarbamate described in Example 332A (150 mg, 0.47 mmol), N,N-diisopropylethylamine (80 mg, 0.62 mmol) and 3-(6,7-dimethoxyquinazolin-4-ylthio)aniline (prepared as described in Example 115B) (100 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-ylthio)phenyl)urea (52 mg, 32%) as a pale yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 9.07 (s, 1H), 8.70 (s, 1H), 8.48 (s, 1H), 7.85 (s, 1H), 7.24-7.53 (m, 5H), 6.07 (s, 1H), 4.00 (s, 6H), 3.72 (d, J=7.2 Hz, 2H), 2.07 (m, 1H), 1.20 (s, 9H), 0.83 (d, J=6.8 Hz, 6H); LC-MS (ESI) m/z 535 (M+H)+.

Workup

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

Sources & evidence

ORD record
ord-ff9d68d0760f4a08956a7d06c250a9f2
Source dataset
uspto-grants-2013_12
Patent number
US08618289B2

Reaction notes

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