N,N,N',N'-Tetramethylethylenediamine → 1-(Tetrahydro-2H-pyran-2-yl)-5-(3,3,3-trifluoroprop-1-yn-1-yl)-1H-indazole

Temperature

80 °C

To a solution of LDA (2 M in THF, 3.2 mL, 6.4 mmol) in anhydrous THF (10 mL) was added dropwise 2-bromo-3,3,3-trifluoroprop-1-ene (0.55 g, 3.1 mmol) at −78° C. The resulting mixture was stirred at that temperature for 15 minutes, followed by the addition of ZnCl2 (1 M in ethyl ether, 6.5 mL, 6.5 mmol) and TMEDA (1 mL, 6.5 mmol). The mixture was stirred at −78° C. for further 30 minutes and then 30 minutes at room temperature. 5-Iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (0.99 g, 3.0 mmol) and Pd(PPh3)4 (0.21 g, 0.18 mmol) were added. The reaction mixture was heated at 80° C. for 6 hours under N2 atmosphere. Upon completion, the reaction mixture was quenched with water (100 mL) and then diluted with ethyl acetate (300 mL). The organic layer was separated, dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography on silica gel (0˜=20% EtOAc in petroleum ether) affording the title compound (299 mg). 1H NMR (300 MHz, DMSO-d6): δ 8.28 (s, 1H), 8.24 (s, 1H), 7.87 (d, 1H), 7.68 (dd, 1H), 5.91 (dd, 1H), 3.90-3.86 (m, 1H), 3.79-3.72 (m, 1H), 2.41-2.36 (m, 1H), 2.05-1.96 (m, 2H), 1.76-1.72 (m, 1H), 1.60-1.56 (m, 2H); LCMS: 295 (M+H)+.

1. stirringThe mixture was stirred at −78° C. for further 30 minutes
2. custom30 minutes
3. customat room temperature
4. customUpon completion, the reaction mixture was quenched with water (100 mL)
5. additiondiluted with ethyl acetate (300 mL)
6. customThe organic layer was separated
7. dry with materialdried over Na2SO4
8. concentrationconcentrated in vacuo
9. customThe residue was purified by column chromatography on silica gel (0˜=20% EtOAc in petroleum ether)

ORD record

ord-b446f8de21b540f8a8eb19d0fe50917a

Source dataset

uspto-grants-2012_10

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08299112B2