Lithium diisopropylamide → 4-[1-(2-Aminopyrimidin-4-yl)-3-methylindazol-6-yl]-2-[1-(oxan-2-yl)-1,2,4-triazol-3-yl]but-3-yn-2-ol

HRID 1398557Notes

Reaction equation

HRID 1398557 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.[O:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH:29]1[N:34]1[CH:38]=[N:37][C:36]([C:39](=[O:41])[CH3:40])=[N:35]1>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:39]([C:36]4[N:37]=[CH:38][N:34]([CH:29]5[CH2:30][CH2:31][CH2:32][CH2:33][O:28]5)[N:35]=4)([OH:41])[CH3:40])[CH:11]=3)[C:7]([CH3:19])=[N:8]2)[CH:17]=[CH:16][N:15]=1

Participants

5

Reactant 3

HCID 2724682Lithium diisopropylamideHCID 681819201-[1-(Oxan-2-yl)-1,2,4-triazol-3-yl]ethanoneHCID 866695904-(6-Ethynyl-3-methylindazol-1-yl)pyrimidin-2-amine

Product 1

HCID 681817964-[1-(2-Aminopyrimidin-4-yl)-3-methylindazol-6-yl]-2-[1-(oxan-2-yl)-1,2,4-triazol-3-yl]but-3-yn-2-ol

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Procedure

To a solution of 4-(6-ethynyl-3-methylindazol-1-yl)pyrimidin-2-amine (90 mg, 0.36 mmol) in dry THF (1.5 mL) at −78° C. under an atmosphere of nitrogen was added 2M LDA in THF (0.45 mL, 0.903 mmol). After 5 minutes, 1-[1-(oxan-2-yl)-1,2,4-triazol-3-yl]ethanone (211.45 mg in 1.5 mL dry THF, 1.08 mmol) was added. After 20 minutes the mixture was allowed to warm up to RT, then stirred for a further 30 minutes. The reaction mixture was quenched by addition of saturated aqueous NH4Cl (0.5 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, 2-11% methanol gradient in DCM) to give the title intermediate as a pale yellow oil: 1H NMR (500 MHz, DMSO) delta 1.76-1.56 (3H, m), 1.90 (3H, s), 2.18-1.94 (3H, m), 2.58 (3H, s), 3.74-3.60 (1H, m), 4.03-3.87 (1H, m), 5.60-5.43 (1H, m), 6.27 (1H, s), 6.96 (2H, s), 7.04 (1H, d, J=5.5 Hz), 7.34 (1H, d, J=8.1 Hz), 7.84 (1H, d, J=8.4 Hz), 8.26 (1H, d, J=5.5 Hz), 8.68 (1H, s), 8.84 (1H, s); LC-MS: m/z=+445.05 (M+H)+.

Workup

  1. waitAfter 20 minutes the mixture was allowed
  2. customThe reaction mixture was quenched by addition of saturated aqueous NH4Cl (0.5 mL)
  3. customThe volatiles were removed in vacuo
  4. additionthe 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, 2-11% methanol gradient in DCM)

Sources & evidence

ORD record
ord-5b072980515c47d3837add6f578ad67a
Source dataset
uspto-grants-2014_12
Patent number
US08901313B2

Reaction notes

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