Phosphorus oxychloride → 5-(4-Chlorobut-1-yn-1-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole

HRID 1057115Notes

Reaction equation

HRID 1057115 reaction equation
[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[N:7]1[C:15]2[C:10](=[CH:11][C:12]([C:16]#[C:17][CH2:18][CH2:19]O)=[CH:13][CH:14]=2)[CH:9]=[N:8]1.O=P(Cl)(Cl)[Cl:23]>N1C=CC=CC=1>[Cl:23][CH2:19][CH2:18][C:17]#[C:16][C:12]1[CH:11]=[C:10]2[C:15](=[CH:14][CH:13]=1)[N:7]([CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][O:1]1)[N:8]=[CH:9]2

Participants

4

Reactant 2

HCID 24813Phosphorus oxychlorideHCID 66793408HCID 66793408, compound2×

Product 1

HCID 667933945-(4-Chlorobut-1-yn-1-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazoleYield 37.4%

Reagents, catalysts & solvents 1

HCID 1049PyridineSolvent

Procedure

To a solution of 4-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)but-3-yn-1-ol (1.0 g, 3.7 mmol; Intermediate 20) in dry pyridine (10 mL) was added dropwise POCl3 (2.4 g, 14.7 mmol) under N2 atmosphere. The resulting solution was stirred at room temperature for 16 hours. Upon completion, the reaction mixture was concentrated in vacuo. The residue was poured into ice-water and extracted with EtOAc (2×10 mL). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was further purified on silica gel column (0˜20% EtOAc in petroleum ether) affording the title compound (400 mg). 1H NMR (400 MHz, DMSO-d6): δ 8.11 (s, 1H), 7.86 (s, 1H), 7.72 (d, 1H), 7.42 (dd, 1H), 5.86 (dd, 1H), 3.90-3.86 (m, 1H), 3.81 (t, 2H), 3.77-3.70 (m, 1H), 2.93 (t, 2H), 2.41-2.34 (m, 1H), 2.05-1.94 (m, 2H), 1.75-1.71 (m, 1H), 1.60-1.55 (m, 2H); LCMS: 289 (M+H)+.

Workup

  1. concentrationUpon completion, the reaction mixture was concentrated in vacuo
  2. additionThe residue was poured into ice-water
  3. extractionextracted with EtOAc (2×10 mL)
  4. washThe combined organic layers were washed with brine
  5. dry with materialdried over Na2SO4
  6. concentrationconcentrated in vacuo
  7. customThe residue was further purified on silica gel column (0˜20% EtOAc in petroleum ether)

Sources & evidence

ORD record
ord-db93660076074a3e9cab65b23ac82050
Source dataset
uspto-grants-2016_07
Patent number
US09399646B2

Reaction notes

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