Triethylamine → 5-(Cyclopropylethynyl)-4-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole

HRID 1057114Notes

Reaction equation

HRID 1057114 reaction equation
Br[C:2]1[C:3]([F:17])=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1)[N:6]=[CH:5]2.C(N(CC)CC)C.[C:25]([CH:27]1[CH2:29][CH2:28]1)#[CH:26]>C(OCC)(=O)C.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.[Cu]I>[CH:27]1([C:25]#[C:26][C:2]2[C:3]([F:17])=[C:4]3[C:8](=[CH:9][CH:10]=2)[N:7]([CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)[N:6]=[CH:5]3)[CH2:29][CH2:28]1

Participants

7

Reactant 3

HCID 8471TriethylamineHCID 138823CyclopropylacetyleneHCID 667933085-Bromo-4-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole2×

Product 1

HCID 667934355-(Cyclopropylethynyl)-4-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazoleYield 56.4%

Reagents, catalysts & solvents 3

HCID 24350Copper(1+) iodide; Copper(I) iodide; Cuprous iodide; Cuprous iodide (CuI)CatalystHCID 178418476HCID 178418476, compoundCatalystHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
120 °C

Procedure

In a high pressure tube, a mixture of 5-bromo-4-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (8.0 g, 26.8 mmol; Intermediate 21), PdCl2(PPh3)2 (3.7 g, 5.35 mmol), CuI (1.0 g, 5.35 mmol), and triethylamine (30 mL) was deoxygenated with three cycles of vacuum/nitrogen. Ethynylcyclopropane (8.9 g, 134 mmol) was added under N2 atmosphere. The tube was sealed and the reaction mixture was heated at 120° C. for 63 hours. Upon completion, the reaction mixture was diluted with ethyl acetate and filtered through Celite. The filtrate was concentrated in vacuo and the residue was purified by column chromatography on silica gel (0˜10% ethyl acetate in petroleum ether) affording the title compound (4.3 g). 1H NMR (400 MHz, DMSO-d6): δ 8.25 (s, 1H), 7.55 (d, 1H), 7.40 (dd, 1H), 5.88 (dd, 1H), 3.88-3.85 (m, 1H), 3.76-3.73 (m, 2H), 2.43-2.33 (m, 1H), 2.05-1.95 (m, 2H), 1.76-1.72 (m, 1H), 1.62-1.56 (m, 3H), 0.93-0.89 (m, 2H), 0.79-0.74 (m, 2H); LCMS: 285 (M+H)+.

Workup

  1. customwas deoxygenated with three cycles of vacuum/nitrogen
  2. customThe tube was sealed
  3. filtrationfiltered through Celite
  4. concentrationThe filtrate was concentrated in vacuo
  5. customthe residue was purified by column chromatography on silica gel (0˜10% ethyl acetate in petroleum ether)

Sources & evidence

ORD record
ord-f1795e3b5d934c1fa769daa1651760e6
Source dataset
uspto-grants-2016_07
Patent number
US09399646B2

Reaction notes

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