Sodium hydride → 2-(6-chloro-1-((5-methylisoxazol-3-yl)methyl)-1H-indazol-3-yl)-N-isopropyl-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide

HRID 246455Notes

Reaction equation

HRID 246455 reaction equation
[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]3[N:12]=[C:13]4[C:19]([C:20]([NH:22][CH:23]([CH3:25])[CH3:24])=[O:21])=[CH:18][N:17]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[C:14]4=[N:15][CH:16]=3)=[N:7][NH:8]2)=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:37][C:38]1[CH:42]=[C:41]([CH3:43])[O:40][N:39]=1>CN(C=O)C.O>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]3[N:12]=[C:13]4[C:19]([C:20]([NH:22][CH:23]([CH3:25])[CH3:24])=[O:21])=[CH:18][N:17]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:31])([CH3:33])[CH3:32])[C:14]4=[N:15][CH:16]=3)=[N:7][N:8]2[CH2:37][C:38]2[CH:42]=[C:41]([CH3:43])[O:40][N:39]=2)=[CH:4][CH:3]=1

Participants

6

Reactant 3

HCID 24758Sodium hydrideHCID 27763043-(Bromomethyl)-5-methylisoxazoleHCID 712803652-(6-chloro-1H-indazol-3-yl)-N-isopropyl-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide

Product 1

HCID 712799782-(6-chloro-1-((5-methylisoxazol-3-yl)methyl)-1H-indazol-3-yl)-N-isopropyl-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamideYield 93%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 6228DimethylformamideSolvent

Conditions

Temperature
0 °C

Procedure

2-(6-Chloro-1H-indazol-3-yl)-N-isopropyl-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (80 mg, 165 μmol) was dissolved in DMF (1 mL) and cooled to 0° C. Sodium hydride (10.6 mg, 264 μmol) was added and the mixture was allowed to stir for 30 min. 3-(Bromomethyl)-5-methylisoxazole (31.9 mg, 181 μmol) was added and the mixture was warmed to room temperature. After 15 h, the mixture was diluted with water and extracted with ethyl acetate. The organic extracts were washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by chromatography (silica, 40 g Analogix column, 20%-50% ethyl acetate in hexanes 15 min) to give 2-(6-chloro-1-((5-methylisoxazol-3-yl)methyl)-1H-indazol-3-yl)-N-isopropyl-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (89 mg, 153 μmol, 93.0%) as a yellow powder. MS (M+Na)+=602; 1H NMR (CDCl3) δ: 9.23-9.32 (m, 1H), 8.48 (s, 2H), 8.18-8.30 (m, 1H), 7.54-7.61 (m, 1H), 7.27 (m, 2H), 5.70-5.76 (m, 2H), 5.65-5.69 (m, 2H), 4.38-4.56 (m, 1H), 3.52-3.65 (m, 2H), 2.31-2.41 (m, 3H), 1.35-1.47 (m, 6H), 0.89-1.00 (m, 2H), −0.03 (s, 9H).

Workup

  1. temperaturethe mixture was warmed to room temperature
  2. waitAfter 15 h
  3. extractionextracted with ethyl acetate
  4. washThe organic extracts were washed with brine
  5. dry with materialdried over anhydrous sodium sulfate
  6. concentrationconcentrated in vacuo
  7. customThe residue was purified by chromatography (silica, 40 g Analogix column, 20%-50% ethyl acetate in hexanes 15 min)

Sources & evidence

ORD record
ord-351acb33c1b9431a9f6c192ee37685eb
Source dataset
uspto-grants-2014_02
Patent number
US08658646B2

Reaction notes

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