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

HRID 246449Notes

Reaction equation

HRID 246449 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+].[CH:36]1([CH2:39]Br)[CH2:38][CH2:37]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[CH2:39][CH:36]2[CH2:38][CH2:37]2)=[CH:4][CH:3]=1

Participants

6

Reactant 3

HCID 24758Sodium hydrideHCID 81503BromomethylcyclopropaneHCID 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 712806052-(6-chloro-1-(cyclopropylmethyl)-1H-indazol-3-yl)-N-isopropyl-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamideYield 74.5%

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 (120 mg, 247 μmol) was dissolved in DMF (1 mL) and cooled to 0° C. Sodium hydride (12.9 mg, 322 μmol) was added. After 30 min cyclopropylmethyl bromide (50.1 mg, 0.0360 mL, 371 μmol) was added and the mixture 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 gradient) to give 2-(6-chloro-1-(cyclopropylmethyl)-1H-indazol-3-yl)-N-isopropyl-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (99 mg, 184 μmol, 74.2%) as a yellow powder. 1H NMR (CDCl3) δ: 9.27 (s, 1H), 8.43-8.50 (m, 2H), 8.31 (d, J=8.3 Hz, 1H), 7.54 (s, 1H), 7.23 (s, 1H), 5.73 (s, 2H), 4.40-4.56 (m, 1H), 4.35 (d, J=6.8 Hz, 2H), 3.54-3.64 (m, 2H), 1.42 (d, J=6.4 Hz, 7H), 0.89-1.00 (m, 2H), 0.62-0.71 (m, 2H), 0.51 (q, J=4.9 Hz, 2H), −0.07-−0.01 (m, 9H)

Workup

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

Sources & evidence

ORD record
ord-1755f83800fd4c14978888f076cf5f19
Source dataset
uspto-grants-2014_02
Patent number
US08658646B2

Reaction notes

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