Sodium hydride → 2-[1-(2-amino-5-chloropyrimidin-4-yl)-6-iodo-1H-indazol-3-yl]propan-2-ol

HRID 1398629Notes

Reaction equation

HRID 1398629 reaction equation
[I:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([OH:14])([CH3:13])[CH3:12])=[N:7][NH:8]2)=[CH:4][CH:3]=1.[H-].[Na+].Cl[C:18]1[C:23]([Cl:24])=[CH:22][N:21]=[C:20]([NH2:25])[N:19]=1>CN(C=O)C>[NH2:25][C:20]1[N:21]=[C:22]([N:8]2[C:9]3[C:5](=[CH:4][CH:3]=[C:2]([I:1])[CH:10]=3)[C:6]([C:11]([OH:14])([CH3:12])[CH3:13])=[N:7]2)[C:23]([Cl:24])=[CH:18][N:19]=1

Participants

5

Reactant 3

HCID 24758Sodium hydride2×HCID 211860654,5-Dichloropyrimidin-2-amineHCID 178458961HCID 178458961, compound

Product 1

HCID 681818792-[1-(2-amino-5-chloropyrimidin-4-yl)-6-iodo-1H-indazol-3-yl]propan-2-ol

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

To a solution of 2-(6-iodo-1H-indazol-3-yl)propan-2-ol (300 mg, 0.99 mmol) in dry DMF (10 mL) at 0° C. under an atmosphere of nitrogen was introduced sodium hydride (63 mg of a 60% dispersion in mineral oil, 1.59 mmol). After 20 minutes at this temperature, 4,5-dichloropyrimidin-2-amine (326 mg, 1.99 mmol) was added and the solution warmed to RT for 10 minutes, then to 65° C. for 18 hr. Following cooling to RT, the reaction mixture was re-treated with additional sodium hydride (24 mg of a 60% dispersion in mineral oil) then warmed to 75° C. under nitrogen for 6 hr. The reaction mixture was cooled to RT, quenched carefully with water (20 mL) and extracted with EtOAc (2×20 mL extractions). The organic extracts were combined, dried (MgSO4), filtered and concentrated in vacuo. Purification of the residue by silica gel flash column chromatography (4:1 to 1:1 heptane/EtOAc gradient) furnished the title compound as an off-white solid: 1H NMR (500 MHz, CDCl3) delta 1.79 (6H, s), 5.19 (2H, br. s.), 7.61 (1H, dd, J=8.35, 1.42 Hz), 7.76 (1H, d, J=8.51 Hz), 8.42 (1H, s), 8.64 (1H, d, J=0.95 Hz); LC-MS: m/z=+429.90/431.65 (M+H)+.

Workup

  1. temperatureFollowing cooling to RT
  2. temperaturethen warmed to 75° C. under nitrogen for 6 hr
  3. temperatureThe reaction mixture was cooled to RT
  4. customquenched carefully with water (20 mL)
  5. extractionextracted with EtOAc (2×20 mL extractions)
  6. dry with materialdried (MgSO4)
  7. filtrationfiltered
  8. concentrationconcentrated in vacuo
  9. customPurification of the residue by silica gel flash column chromatography (4:1 to 1:1 heptane/EtOAc gradient)

Sources & evidence

ORD record
ord-90bb8d6762de4bac800cf85ef28a7ce7
Source dataset
uspto-grants-2014_12
Patent number
US08901313B2

Reaction notes

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