Sodium Iodide → 2-(5-Chloro-1H-indazol-1-yl)-N-(1-hydroxy-2-methylpropan-2-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide

HRID 246463Notes

Reaction equation

HRID 246463 reaction equation
Br[C:2]1[N:3]=[C:4]2[C:10]([C:11]([NH:13][C:14]([CH3:18])([CH3:17])[CH2:15][OH:16])=[O:12])=[CH:9][N:8]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])[C:5]2=[N:6][CH:7]=1.[I-].[Na+].CN[C@@H]1CCCC[C@H]1NC.[Cl:39][C:40]1[CH:41]=[C:42]2[C:46](=[CH:47][CH:48]=1)[NH:45][N:44]=[CH:43]2.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.[Cu]I>[OH:16][CH2:15][C:14]([NH:13][C:11]([C:10]1[C:4]2[C:5](=[N:6][CH:7]=[C:2]([N:45]3[C:46]4[C:42](=[CH:41][C:40]([Cl:39])=[CH:48][CH:47]=4)[CH:43]=[N:44]3)[N:3]=2)[N:8]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])[CH:9]=1)=[O:12])([CH3:18])[CH3:17]

Participants

8

Reactant 5

HCID 5238Sodium IodideHCID 62657Potassium Phosphate, TribasicHCID 696811H-Indazole, 5-chloro-HCID 2733821trans-N,N'-dimethyl-1,2-cyclohexanediamineHCID 715756472-Bromo-N-(1-hydroxy-2-methylpropan-2-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide

Product 1

HCID 712799172-(5-Chloro-1H-indazol-1-yl)-N-(1-hydroxy-2-methylpropan-2-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamideYield 74%

Reagents, catalysts & solvents 2

HCID 24350Copper(1+) iodide; Copper(I) iodide; Cuprous iodide; Cuprous iodide (CuI)CatalystHCID 1140TolueneSolvent

Conditions

Temperature
110 °C

Procedure

2-Bromo-N-(1-hydroxy-2-methylpropan-2-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (145 mg, 328 μmol) was dissolved in toluene (3 mL) and copper (I) iodide (3.29 mg, 36.7 μmol), sodium iodide (98.2 mg, 655 μmol) and trans-N,N′-dimethylcyclohexane-1,2-diamine (11.9 mg, 83.6 μmol) added. The mixture was degassed with bubbling nitrogen, then sealed and the mixture heated at to 110° C. After 15 h, 5-chloro-1H-indazole (50 mg, 328 μmol) and potassium phosphate tribasic (146 mg, 688 μmol) were added, the mixture degassed again, and the mixture sealed and the mixture heated at for an additional 24 h. The mixture was cooled, filtered the filtrates concentrated and purified by chromatography (silica, 24 g Analogix column, 0-40% ethyl Acetate in hexanes to give 2-(5-chloro-indazol-1-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (2-hydroxy-1,1-dimethyl-ethyl)-amide (124 mg, 74%) as a solid. MS (M+H)+=515; 1H NMR (CDCl3) d: 9.19 (s, 1H), 8.52 (d, J=8.9 Hz, 1H), 8.37 (s, 1H), 8.24 (s, 1H), 7.89 (s, 1H), 7.81-7.85 (m, 1H), 7.47 (dd, J=8.9, 1.9 Hz, 1H), 5.73 (s, 2H), 3.81 (s, 2H), 3.60 (dd, J=8.8, 7.6 Hz, 2H), 1.54 (s, 6H), 0.91-1.01 (m, 2H), −0.02 (s, 9H)

Workup

  1. customThe mixture was degassed with bubbling nitrogen
  2. customsealed
  3. customthe mixture degassed again
  4. customthe mixture sealed
  5. temperaturethe mixture heated at for an additional 24 h
  6. temperatureThe mixture was cooled
  7. filtrationfiltered the filtrates
  8. concentrationconcentrated
  9. custompurified by chromatography (silica, 24 g Analogix column, 0-40% ethyl Acetate in hexanes

Sources & evidence

ORD record
ord-2bce9850329a4cc0ba46f695a4b01ec1
Source dataset
uspto-grants-2014_02
Patent number
US08658646B2

Reaction notes

Loading…