Tetrabutylammonium Fluoride → 4-[1-(2-aminopyrimidin-4-yl)-3-(2-hydroxypropan-2-yl)-1H-indazol-6-yl]-2-(1-methyl-1H-pyrazol-3-yl)but-3-yn-2-ol

HRID 1398607Notes

Reaction equation

HRID 1398607 reaction equation
[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14](I)[CH:15]=3)[C:10]([C:18]([OH:21])([CH3:20])[CH3:19])=[N:9]2)[CH:5]=[CH:4][N:3]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-].[CH3:40][N:41]1[CH:45]=[CH:44][C:43]([C:46]([OH:54])([C:48]#[C:49][Si](C)(C)C)[CH3:47])=[N:42]1>C1COCC1.C(=O)(O)[O-].[Na+].Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:49]#[C:48][C:46]([C:43]4[CH:44]=[CH:45][N:41]([CH3:40])[N:42]=4)([OH:54])[CH3:47])[CH:15]=3)[C:10]([C:18]([OH:21])([CH3:20])[CH3:19])=[N:9]2)[CH:5]=[CH:4][N:3]=1

Participants

7

Reactant 3

HCID 2724141Tetrabutylammonium FluorideHCID 681818982-[1-(2-aminopyrimidin-4-yl)-6-iodo-1H-indazol-3-yl]propan-2-olHCID 681819652-(1-methyl-1H-pyrazol-3-yl)-4-(trimethylsilyl)but-3-yn-2-ol

Product 1

HCID 601636604-[1-(2-aminopyrimidin-4-yl)-3-(2-hydroxypropan-2-yl)-1H-indazol-6-yl]-2-(1-methyl-1H-pyrazol-3-yl)but-3-yn-2-ol

Reagents, catalysts & solvents 3

HCID 178418476HCID 178418476, compoundCatalystHCID 8028TetrahydrofuranSolvent2×HCID 516892Sodium BicarbonateSolvent

Conditions

Temperature
50 °C

Procedure

To a solution of 2-[1-(2-aminopyrimidin-4-yl)-6-iodo-1H-indazol-3-yl]propan-2-ol (135 mg, 0.31 mmol) in dry THF (4 mL) under an atmosphere of nitrogen was introduced bis(triphenylphosphine)palladium(II) chloride (21.6 mg, 0.03 mmol), TBAF (0.37 mL of a 1M solution in THF, 0.37 mmol) and 2-(1-methyl-1H-pyrazol-3-yl)-4-(trimethylsilyl)but-3-yn-2-ol (137 mg, 0.62 mmol). The reaction mixture was warmed to 50° C. for 1.5 hr. After cooling to RT, the reaction mixture was diluted with saturated aqueous sodium bicarbonate solution (4 ml) and extracted with EtOAc (2×10 mL extractions). The combined extracts were washed with water (5×5 mL), brine (5 mL), dried (Na2SO4) and filtered. After concentration of the filtrate in vacuo, the residue was purified by silica gel flash column chromatography (DCM containing a 1-10% methanol gradient) to furnish the title compound as an off-white solid: 1H NMR (DMSO, 500 MHz) delta 1.63 (6H, s), 1.83 (3H, s), 3.82 (3H, s), 5.57 (1H, s), 6.02 (1H, s), 6.36 (1H, d, J=2.1 Hz), 6.99 (2H, s), 7.05 (1H, d, J=5.5 Hz), 7.31 (1H, d, J=8.4 Hz), 7.61 (1H, d, J=2.0 Hz), 8.11 (1H, d, J=8.3 Hz), 8.27 (1H, d, J=5.5 Hz), 8.84 (1H, s); LC-MS: m/z=+418.10 (M+H)+.

Workup

  1. temperatureAfter cooling to RT
  2. extractionextracted with EtOAc (2×10 mL extractions)
  3. washThe combined extracts were washed with water (5×5 mL), brine (5 mL)
  4. dry with materialdried (Na2SO4)
  5. filtrationfiltered
  6. customAfter concentration of the filtrate in vacuo, the residue was purified by silica gel flash column chromatography (DCM containing a 1-10% methanol gradient)

Sources & evidence

ORD record
ord-f9203a25e07a45fdb7d86f9b3cd6acd1
Source dataset
uspto-grants-2014_12
Patent number
US08901313B2

Reaction notes

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