Diisopropylethylamine → US8933228, Ref 2

HRID 593418Notes

Reaction equation

HRID 593418 reaction equation
[CH3:1][O:2][CH2:3][C:4](Cl)=[O:5].[NH2:7][C:8]1[CH:13]=[C:12]([O:14][C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18]([NH:25][C:26]([NH:28][C:29]3[N:33]([C:34]4[CH:39]=[CH:38][C:37]([CH3:40])=[CH:36][CH:35]=4)[N:32]=[C:31]([C:41]([CH3:44])([CH3:43])[CH3:42])[CH:30]=3)=[O:27])=[CH:17][CH:16]=2)[CH:11]=[CH:10][N:9]=1.CCN(C(C)C)C(C)C>C1COCC1>[C:41]([C:31]1[CH:30]=[C:29]([NH:28][C:26](=[O:27])[NH:25][C:18]2[C:19]3[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:15]([O:14][C:12]3[CH:11]=[CH:10][N:9]=[C:8]([NH:7][C:4](=[O:5])[CH2:3][O:2][CH3:1])[CH:13]=3)=[CH:16][CH:17]=2)[N:33]([C:34]2[CH:39]=[CH:38][C:37]([CH3:40])=[CH:36][CH:35]=2)[N:32]=1)([CH3:44])([CH3:43])[CH3:42]

Participants

5

Reactant 3

HCID 81531DiisopropylethylamineHCID 96623Methoxyacetyl chlorideHCID 585325691-(4-(2-aminopyridin-4-yloxy)naphthalen-1-yl)-3-(3-tert-butyl-1-p-tolyl-1H-pyrazol-5-yl)urea

Product 1

HCID 46218331US8933228, Ref 2Yield 61%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Conditions

Temperature
0 °C

Procedure

Methoxyacetyl chloride (64.2 μl, 0.703 mmol) was added slowly 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 (8) (89 mg, 0.176 mmol) and DIPEA (153 μl, 0.878 mmol) in THF (5 mL). The reaction mixture was stirred at 0° C. for a further 20 min and then warmed to RT. After 2.5 hr, the reaction was quenched by the addition of a solution of 1% NH3 in MeOH (3 mL), and the resulting mixture stirred for a further 45 min. The volatiles were removed in vacuo and the residue was dissolved in a mixture of MeOH (5 mL) and AcOH (2 mL) and subjected to SCX capture and release eluting with 1% NH3 in MeOH solution. The crude material was purified by flash column chromatography (SiO2; 12 g) eluting with 0 to 60% [5% MeOH in EtOAc] in iso-hexane to give N-(4-(4-(3-(3-tert-butyl-1-p-tolyl-1H-pyrazol-5-yl)ureido)naphthalen-1-yloxy)pyridin-2-yl)-2-methoxyacetamide (1) (62 mg, 61%) as a white solid: m/z 579 (M+H)+ (ES+). 1H NMR (400 MHz, DMSO-d6) δ: 1.29 (9H, s), 2.40 (3H, s), 3.31 (3H, s), 3.99 (2H, s), 6.41 (1H, s), 6.70 (1H, dd), 7.32-7.40 (3H, m), 7.44-7.48 (2H, m), 7.55-7.61 (1H, m), 7.63-7.67 (2H, m), 7.84 (1H, dd), 7.97 (1H, d), 8.09 (1H, d), 8.19 (1H, d), 8.79 (1H, s), 9.13 (1H, s), 10.02 (1H, s).

Workup

  1. temperaturewarmed to RT
  2. waitAfter 2.5 hr
  3. customthe reaction was quenched by the addition of a solution of 1% NH3 in MeOH (3 mL)
  4. stirringthe resulting mixture stirred for a further 45 min
  5. customThe volatiles were removed in vacuo
  6. dissolutionthe residue was dissolved in a mixture of MeOH (5 mL) and AcOH (2 mL)
  7. washeluting with 1% NH3 in MeOH solution
  8. customThe crude material was purified by flash column chromatography (SiO2; 12 g)
  9. washeluting with 0 to 60% [5% MeOH in EtOAc] in iso-hexane

Sources & evidence

ORD record
ord-50580cf8c3ce418699be6b4f2aa42d2b
Source dataset
uspto-grants-2016_01
Patent number
US09242960B2

Reaction notes

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