Lithium diisopropylamide → 1-(2-aminopyrimidin-4-yl)-6-[3-hydroxy-3-(pyrimidin-2-yl)but-1-yn-1-yl]-N,N-dimethyl-1H-indazole-3-carboxamide

HRID 1398598Notes

Reaction equation

HRID 1398598 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:21]([CH3:23])[CH3:22])=[O:20])=[N:9]2)[CH:5]=[CH:4][N:3]=1.[Li+].CC([N-]C(C)C)C.[N:32]1[CH:37]=[CH:36][CH:35]=[N:34][C:33]=1[C:38](=[O:40])[CH3:39]>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:38]([OH:40])([C:33]4[N:34]=[CH:35][CH:36]=[CH:37][N:32]=4)[CH3:39])[CH:15]=3)[C:10]([C:19]([N:21]([CH3:23])[CH3:22])=[O:20])=[N:9]2)[CH:5]=[CH:4][N:3]=1

Participants

5

Reactant 3

HCID 2724682Lithium diisopropylamideHCID 116079091-(Pyrimidin-2-yl)ethan-1-oneHCID 866695911-(2-aminopyrimidin-4-yl)-6-ethynyl-N,N-dimethylindazole-3-carboxamide

Product 1

HCID 681819481-(2-aminopyrimidin-4-yl)-6-[3-hydroxy-3-(pyrimidin-2-yl)but-1-yn-1-yl]-N,N-dimethyl-1H-indazole-3-carboxamide

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent3×

Procedure

To a solution of 1-(2-aminopyrimidin-4-yl)-6-ethynyl-N,N-dimethylindazole-3-carboxamide (80 mg, 0.217 mmol) in THF (1.0 mL) at −78° C. under nitrogen was added 2M LDA in THF (0.27 mL, 0.54 mmol). After 5 minutes 1-pyrimidin-2-yl-ethanone (79 mg, 0.65 mmol) in THF (0.5 mL) was added and the reaction was allowed to warm to RT after 20 minutes. After 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, 0-2% methanol in DCM). Trituration of the partially purified product from EtOAc-heptane gave the title compound: 1H NMR (250 MHz, MeOD) delta 1.93-2.02 (3H, m), 3.22 (3H, s), 3.41 (3H, s), 7.24 (1H, d, J=5.79 Hz), 7.40-7.55 (2H, m), 7.97 (1H, d, J=8.38 Hz), 8.29 (1H, d, J=5.79 Hz), 8.88 (2H, d, J=5.03 Hz), 9.12 (1H, s); LC-MS: m/z=+429.45 (M+H)+.

Workup

  1. customAfter a further 30 minutes the reaction mixture was quenched by addition of saturated aqueous NH4Cl (0.5 mL)
  2. customThe volatiles were removed in vacuo
  3. additionthe mixture was diluted with DCM (10 ml)
  4. washwashed with water (2 mL)
  5. dry with materialdried (Na2SO4)
  6. filtrationfiltered
  7. concentrationconcentrated in vacuo
  8. customThe crude product was purified by flash chromatography (Biotage, 0-2% methanol in DCM)

Sources & evidence

ORD record
ord-1d210997dfa548cb966e335ce9d54442
Source dataset
uspto-grants-2014_12
Patent number
US08901313B2

Reaction notes

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