Acetyl chloride → N-(4-((4-(3-(3-(tert-Butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)ureido)naphthalen-1-yl) oxy)pyridin-2-yl)acetamide

HRID 1774368Notes

Reaction equation

HRID 1774368 reaction equation
[NH2:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]([NH:19][C:20]([NH:22][C:23]3[N:27]([C:28]4[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=4)[N:26]=[C:25]([C:35]([CH3:38])([CH3:37])[CH3:36])[CH:24]=3)=[O:21])=[CH:11][CH:10]=2)[CH:5]=[CH:4][N:3]=1.CCN(C(C)C)C(C)C.[C:48](Cl)(=[O:50])[CH3:49]>C1COCC1>[C:35]([C:25]1[CH:24]=[C:23]([NH:22][C:20](=[O:21])[NH:19][C:12]2[C:13]3[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:9]([O:8][C:6]3[CH:5]=[CH:4][N:3]=[C:2]([NH:1][C:48](=[O:50])[CH3:49])[CH:7]=3)=[CH:10][CH:11]=2)[N:27]([C:28]2[CH:29]=[CH:30][C:31]([CH3:34])=[CH:32][CH:33]=2)[N:26]=1)([CH3:38])([CH3:37])[CH3:36]

Participants

5

Reactant 3

HCID 6367Acetyl chlorideHCID 81531DiisopropylethylamineHCID 585325691-(4-(2-aminopyridin-4-yloxy)naphthalen-1-yl)-3-(3-tert-butyl-1-p-tolyl-1H-pyrazol-5-yl)urea

Product 1

HCID 53476277N-(4-((4-(3-(3-(tert-Butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)ureido)naphthalen-1-yl) oxy)pyridin-2-yl)acetamide

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Conditions

Temperature
0 °C

Procedure

To a mixture of 1-(4-(2-aminopyridin-4-yloxy)naphthalen-1-yl)-3-(3-tert-butyl-1-p-tolyl-1H-pyrazol-5-yl)urea (40 mg, 0.08 mmol) and DIPEA (69 μL, 0.40 mmol) in THF (5.0 mL) at 0° C. under N2 was added acetyl chloride (22 μL, 0.08 mmol) and the mixture maintained at 0° C. for 30 min and then warmed to RT for 16 hr. The reaction was quenched by the addition of a solution of NH3 in MeOH (1% w/v, 2.0 mL) and after 45 min at RT the volatiles were evaporated in vacuo. The residue was subjected to purification by SCX capture and release and then by flash column chromatography (SiO2, 12 g, [5% MeOH in EtOAc] in isohexane, 0-70%, gradient elution). The impure material so obtained was subjected to re-purification by SCX capture and release and by flash column chromatography (SiO2, 12 g, [5% MeOH in EtOAc] in isohexane, 0-65%, gradient elution) to afford the title compound, Example 3, as a white solid (12 mg, 27%); Rt 2.26 min (Method 2); m/z 549 (M+H)+ (ES+). 1H NMR (400 MHz, DMSO-d6) δ: 1.29 (9H, s), 2.01 (3H, s), 2.38 (3H, s), 6.39 (1H, s), 6.63 (1H, dd), 7.31 (1H, d), 7.36 (2H, d), 7.48 (2H, d), 7.56 (1H, m), 7.61-7.66 (2H, overlapping m), 7.83 (1H, d), 7.96 (1H, d), 8.16 (1H, d), 8.19 (1H, d), 9.02 (1H, s), 9.30 (1H, s), 10.52 (1H, s).

Workup

  1. temperaturewarmed to RT for 16 hr
  2. customThe reaction was quenched by the addition of a solution of NH3 in MeOH (1% w/v, 2.0 mL) and after 45 min at RT the volatiles
  3. customwere evaporated in vacuo
  4. customThe residue was subjected to purification by SCX capture and release
  5. washby flash column chromatography (SiO2, 12 g, [5% MeOH in EtOAc] in isohexane, 0-70%, gradient elution)
  6. customThe impure material so obtained
  7. customwas subjected to re-purification by SCX capture and release and by flash column chromatography (SiO2, 12 g, [5% MeOH in EtOAc] in isohexane, 0-65%, gradient elution)

Sources & evidence

ORD record
ord-90f91f780bf44672a8cf4722e32d5128
Source dataset
uspto-grants-2016_02
Patent number
US09260410B2

Reaction notes

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