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

HRID 1398563Notes

Reaction equation

HRID 1398563 reaction equation
[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]#[CH:18])[CH:15]=3)[C:10]([C:19](N(C)C)=O)=[N:9]2)[CH:5]=[CH:4][N:3]=1.[Li+].CC([N-]C(C)C)C.[CH3:32][Si:33]([CH3:47])([CH3:46])[CH2:34][CH2:35][O:36][CH2:37][N:38]1[CH:42]=[CH:41][N:40]=[C:39]1[C:43](=[O:45])[CH3:44]>C1COCC1>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]#[C:18][C:43]([C:39]4[N:38]([CH2:37][O:36][CH2:35][CH2:34][Si:33]([CH3:32])([CH3:47])[CH3:46])[CH:42]=[CH:41][N:40]=4)([OH:45])[CH3:44])[CH:15]=3)[C:10]([CH3:19])=[N:9]2)[CH:5]=[CH:4][N:3]=1

Participants

5

Reactant 3

HCID 2724682Lithium diisopropylamideHCID 598646231-(1-{[2-(Trimethylsilyl)ethoxy]methyl}imidazol-2-yl)ethanoneHCID 866695911-(2-aminopyrimidin-4-yl)-6-ethynyl-N,N-dimethylindazole-3-carboxamide

Product 1

HCID 681816514-[1-(2-aminopyrimidin-4-yl)-3-methyl-1H-indazol-6-yl]-2-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl)but-3-yn-2-ol

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent3×

Procedure

To a solution of 1-(2-aminopyrimidin-4-yl)-6-ethynyl-N,N-dimethylindazole-3-carboxamide (200 mg, 0.8 mmol) in THF (2 mL) at −78° C. under nitrogen was added 2M LDA in THF (1.40 mL, 2.81 mmol). After 1 hour, 1-(1-{[2-(trimethylsilyl)ethoxy]methyl}imidazol-2-yl)ethanone (771.45 mg, 3.21 mmol) in THF (1.0 mL) was added. After stirring for 15 minutes, the reaction mixture was allowed to warm to RT and stirred for 2 hr. The reaction mixture was quenched by addition of saturated aqueous ammonium chloride (3 mL) and the volatiles were removed in vacuo. The reaction 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, 1-12% methanol gradient in DCM) to surrender the title compound as a yellow solid: 1H NMR (500 MHz, DMSO) delta −0.19 (9H, s), 0.83-0.77 (2H, m), 2.01 (3H, s), 2.57 (3H, s), 3.59-3.49 (2H, m), 5.62 (1H, d, J=10.3 Hz), 5.78 (1H, d, J=10.2 Hz), 6.42 (1H, s), 6.86 (1H, d, J=1.1 Hz), 6.96 (2H, s), 7.03 (1 H, d, J=5.5 Hz), 7.27 (1H, d, J=1.0 Hz), 7.36 (1H, dd, J=8.1, 1.1 Hz), 7.84 (1H, d, J=8.2 Hz), 8.25 (1H, d, J=5.5 Hz), 8.85 (1H, s); LC-MS: m/z=+490.10 (M+H)+

Workup

  1. stirringstirred for 2 hr
  2. customThe reaction mixture was quenched by addition of saturated aqueous ammonium chloride (3 mL)
  3. customthe volatiles were removed in vacuo
  4. additionThe reaction mixture was diluted with DCM (10 ml)
  5. washwashed with water (2 mL)
  6. dry with materialdried (Na2SO4)
  7. filtrationfiltered
  8. concentrationconcentrated in vacuo
  9. customThe crude product was purified by flash chromatography (Biotage, 1-12% methanol gradient in DCM)

Sources & evidence

ORD record
ord-16a139b0e0c54bcfba963729fc2e89b1
Source dataset
uspto-grants-2014_12
Patent number
US08901313B2

Reaction notes

Loading…