Lithium diisopropylamide → 4-[1-(2-aminopyrimidin-4-yl)-3-methyl-1H-indazol-6-yl]-2-(1-methyl-1H-imidazol-2-yl)but-3-yn-2-ol

HRID 1398555Notes

Reaction equation

HRID 1398555 reaction equation
[C:1]([C:3]1[CH:11]=[C:10]2[C:6]([C:7]([CH3:19])=[N:8][N:9]2[C:12]2[CH:17]=[CH:16][N:15]=[C:14]([NH2:18])[N:13]=2)=[CH:5][CH:4]=1)#[CH:2].[Li+].CC([N-]C(C)C)C.[CH3:28][N:29]1[CH:33]=[CH:32][N:31]=[C:30]1[C:34](=[O:36])[CH3:35]>C1COCC1>[NH2:18][C:14]1[N:13]=[C:12]([N:9]2[C:10]3[C:6](=[CH:5][CH:4]=[C:3]([C:1]#[C:2][C:34]([C:30]4[N:29]([CH3:28])[CH:33]=[CH:32][N:31]=4)([OH:36])[CH3:35])[CH:11]=3)[C:7]([CH3:19])=[N:8]2)[CH:17]=[CH:16][N:15]=1

Participants

5

Reactant 3

HCID 2724682Lithium diisopropylamide2×HCID 143396711-(1-Methyl-1H-imidazol-2-yl)ethan-1-one2×HCID 866695904-(6-Ethynyl-3-methylindazol-1-yl)pyrimidin-2-amine

Product 1

HCID 681815584-[1-(2-aminopyrimidin-4-yl)-3-methyl-1H-indazol-6-yl]-2-(1-methyl-1H-imidazol-2-yl)but-3-yn-2-ol

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent4×

Procedure

To a solution of 4-(6-ethynyl-3-methylindazol-1-yl)pyrimidin-2-amine (150 mg, 0.6 mmol) in THF (2 mL) at −78° C. under nitrogen was added 2M LDA in THF (0.75 mL, 1.50 mmol). After 5 minutes, 1-(1-methyl-1H-imidazol-2-yl)ethanone (225 mg, 1.81 mmol) in THF (1.0 mL) was added, and after a further 20 minutes the mixture was allowed to warm to RT and stirred for 1.5 hours. The reaction mixture was then cooled to −78° C. and treated with additional 2M LDA in THF (0.3 mL, 0.6 mmol) and 1-(1-methyl-1H-imidazol-2-yl)ethanone (90 mg, 0.6 mmol). After stirring at RT for 4 hr, the reaction mixture was quenched by addition of saturated aqueous NH4Cl (2 mL). The volatiles were removed in vacuo and the mixture was diluted with DCM (10 ml) and washed with water (2 mL), dried (Na2SO4), filtered and concentrated in vacuo. The crude product was purified by flash chromatography (Biotage, 3-12% methanol gradient in DCM) to give the title compound: 1H NMR (500 MHz, DMSO) delta 2.00 (3H, s), 2.57 (3H, s), 3.92 (3H, s), 6.32 (1H, s), 6.77 (1H, s), 6.98 (2 H, s), 7.03 (1H, d, J=5.5 Hz), 7.15 (1H, s), 7.36 (1H, d, J=8.2), 7.84 (1H, d, J=8.2 Hz), 8.25 (1H, d, J=5.5 Hz), 8.84 (1H, s); LC-MS: m/z=+374.05 (M+H)+.

Workup

  1. waitafter a further 20 minutes the mixture was allowed
  2. temperatureThe reaction mixture was then cooled to −78° C.
  3. stirringAfter stirring at RT for 4 hr
  4. customthe reaction mixture was quenched by addition of saturated aqueous NH4Cl (2 mL)
  5. customThe volatiles were removed in vacuo
  6. additionthe mixture was diluted with DCM (10 ml)
  7. washwashed with water (2 mL)
  8. dry with materialdried (Na2SO4)
  9. filtrationfiltered
  10. concentrationconcentrated in vacuo
  11. customThe crude product was purified by flash chromatography (Biotage, 3-12% methanol gradient in DCM)

Sources & evidence

ORD record
ord-7160f79c534843c7b66f34601089bd95
Source dataset
uspto-grants-2014_12
Patent number
US08901313B2

Reaction notes

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