Lithium diisopropylamide → 3-[1-(2-aminopyrimidin-4-yl)-6-bromo-1H-indazol-3-yl]-1,1-difluoro-2-methylpropan-2-ol

HRID 1398614Notes

Reaction equation

HRID 1398614 reaction equation
[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH3:18])=[N:7][N:8]2[C:11]2[CH:16]=[CH:15][N:14]=[C:13]([NH2:17])[N:12]=2)=[CH:4][CH:3]=1.C([N-]C(C)C)(C)C.[Li+].[F:27][CH:28]([F:32])[C:29](=[O:31])[CH3:30]>C1COCC1>[NH2:17][C:13]1[N:12]=[C:11]([N:8]2[C:9]3[C:5](=[CH:4][CH:3]=[C:2]([Br:1])[CH:10]=3)[C:6]([CH2:18][C:29]([CH3:30])([OH:31])[CH:28]([F:32])[F:27])=[N:7]2)[CH:16]=[CH:15][N:14]=1

Participants

5

Reactant 3

HCID 2724682Lithium diisopropylamideHCID 34947711,1-Difluoropropan-2-oneHCID 681818654-(6-bromo-3-methyl-1H-indazol-1-yl)pyrimidin-2-amine

Product 1

HCID 681817953-[1-(2-aminopyrimidin-4-yl)-6-bromo-1H-indazol-3-yl]-1,1-difluoro-2-methylpropan-2-ol

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent3×

Conditions

Temperature
-78 °C

Procedure

To a solution of 4-(6-bromo-3-methyl-1H-indazol-1-yl)pyrimidin-2-amine (500 mg, 1.64 mmol) in dry THF (5 mL) at −78° C. under an atmosphere of nitrogen, was introduced lithium diisopropylamide (2.1 mL of a 2M solution in THF, 4.11 mmol). After 5 minutes, a solution of 1,1-difluoropropan-2-one (0.4 mL, 4.93 mmol) in dry THF (2 mL) was added. The reaction mixture was warmed to RT after 20 minutes at −78° C. After 30 minutes at RT, the reaction mixture was quenched (5 mL of sat. aq. ammonium chloride) and concentrated in vacuo. The residue was diluted with DCM (10 mL), washed with water (2 mL) and the organic extract dried (Na2SO4), filtered and concentrated in vacuo. Purification of the residue by flash chromatography (Biotage, elution with DCM containing a 1-12% gradient of MeOH) furnished the title compound as a yellow solid: 1H NMR (500 MHz, CDCl3) delta 1.36 (3H, s), 3.19 (1H, d, J=15.1 Hz), 3.34 (1H, d, J=14.9 Hz), 3.40 (1H, s), 5.17 (2H, s), 5.67 (1H, t, J=56.3 Hz), 7.24 (1H, d, J=8.5, 1.5 Hz), 7.45 (1H, dd, J=8.5, 1.5 Hz), 7.61 (1H, d, J=8.5 Hz), 8.32 (1H, d, J=5.6 Hz), 9.00 (1H, d, J=1.4 Hz); LC-MS: m/z=+397.90/399.90 (M+H)+.

Workup

  1. waitAfter 30 minutes at RT
  2. customthe reaction mixture was quenched (5 mL of sat. aq. ammonium chloride)
  3. concentrationconcentrated in vacuo
  4. additionThe residue was diluted with DCM (10 mL)
  5. washwashed with water (2 mL)
  6. extractionthe organic extract
  7. dry with materialdried (Na2SO4)
  8. filtrationfiltered
  9. concentrationconcentrated in vacuo
  10. customPurification of the residue by flash chromatography (
  11. washBiotage, elution with DCM containing a 1-12% gradient of MeOH)

Sources & evidence

ORD record
ord-c75ee3feb9b14385b105fb67efdad171
Source dataset
uspto-grants-2014_12
Patent number
US08901313B2

Reaction notes

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