Tetrabutylammonium Fluoride → HCID 46836036, compound

HRID 2069070Notes

Reaction equation

HRID 2069070 reaction equation
[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11](=[O:37])[NH:12][C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][N:28]=[C:27]([NH:31][C:32](=[O:36])[CH2:33][O:34][CH3:35])[CH:26]=3)=[CH:15][CH:14]=2)[N:7]([C:38]2[CH:43]=[CH:42][C:41]([CH2:44][O:45][Si](C(C)(C)C)(C)C)=[CH:40][CH:39]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.CCOC(C)=O>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11](=[O:37])[NH:12][C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][N:28]=[C:27]([NH:31][C:32](=[O:36])[CH2:33][O:34][CH3:35])[CH:26]=3)=[CH:15][CH:14]=2)[N:7]([C:38]2[CH:43]=[CH:42][C:41]([CH2:44][OH:45])=[CH:40][CH:39]=2)[N:6]=1)([CH3:4])([CH3:2])[CH3:3]

Participants

5

Reactant 2

HCID 2724141Tetrabutylammonium Fluoride2×HCID 68314424HCID 68314424, compound

Product 1

HCID 46836036HCID 46836036, compoundYield 65.1%

Reagents, catalysts & solvents 2

HCID 8028TetrahydrofuranSolventHCID 8857Ethyl AcetateSolvent

Procedure

The pyrazole amine Intermediate N (100 mg, 0.278 mmol) was added portionwise to a stirred suspension of CDI (45.1 mg, 0.278 mmol) in DCM (0.5 mL) over 1 hr and the reaction mixture was stirred at RT for 16 hr. A solution of the naphthylamine, Intermediate M, (47 mg, 0.139 mmol) in DCM (0.5 mL) was added dropwise over 2 hr. After a further 2 hr the mixture was evaporated in vacuo and the residue was purified by flash column chromatography (SiO2, 12 g, 30-70% EtOAc in isohexane, gradient elution) to yield N-(4-((4-(3-(3-tert-butyl-1-(4-((tert-butyldimethylsilyloxy)methyl)phenyl)-1H-pyrazol-5-yl)ureido)naphthalen-1-yloxy)methyl)pyridin-2-yl)-2-methoxyacetamide (67) (42 mg, 20%): m/z 723 (M+H)+ (ES+) To a solution of the silyl ether (67) (42 mg, 58 μmol) in THF under nitrogen at −5° C. was added a solution of TBAF (1M in THF, 58 μL, 58 μmol). The mixture was warmed to RT and a second aliquot of TBAF (1M in THF, 58 μL, 58 μmol) was added. After 1 hr the mixture was diluted with EtOAc and washed with saturated aqueous ammonium chloride. The aqueous layer was extracted with EtOAc and the combined organic layers were washed with water and brine and then dried (MgSO4) and evaporated in vacuo. The residue was purified by flash column chromatography (SiO2, 12 g, 2-6% MeOH in DCM, gradient elution) to provide the title compound (Example 49) (23 mg, 63%): m/z 609 (M+H)+ (ES+); 1H NMR (400 MHz, DMSO-d6) δ: 1.28 (9 H, s), 3.37 (3H, s) 4.08 (2H, s), 4.59 (2H, d), 5.32 (1H, t), 5.39 (2H, s), 6.36 (1H, s), 7.02 (1H, d), 7.29 (1H, dd), 7.48 (2H, m), 7.52 (2H, m), 7.54-7.63 (3H, overlapping m), 7.93 (1H, m), 8.30-8.37 (3H, overlapping m), 8.63 (1H, s), 8.81 (1H, s), 10.02 (1H, br s).

Workup

  1. washwashed with saturated aqueous ammonium chloride
  2. extractionThe aqueous layer was extracted with EtOAc
  3. washthe combined organic layers were washed with water and brine
  4. dry with materialdried (MgSO4)
  5. customevaporated in vacuo
  6. customThe residue was purified by flash column chromatography (SiO2, 12 g, 2-6% MeOH in DCM, gradient elution)

Sources & evidence

ORD record
ord-79a37921f32247b79088e47032a24626
Source dataset
uspto-grants-2012_10
Patent number
US08299073B2

Reaction notes

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