Dimethylformamide → 2-(6-fluoro-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((S)-2-methoxy-1-methyl-ethyl)-amide

HRID 246252

Reaction equation

HRID 246252 reaction equation
[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([Sn](CCCC)(CCCC)CCCC)=[N:7][NH:8]2)=[CH:4][CH:3]=1.[CH3:24][O:25][CH2:26][C@@H:27]([NH:29][C:30]([C:32]1[C:40]2[C:35](=[N:36][CH:37]=[C:38](Br)[N:39]=2)[N:34]([CH2:42][O:43][CH2:44][CH2:45][Si:46]([CH3:49])([CH3:48])[CH3:47])[CH:33]=1)=[O:31])[CH3:28].CN(C=O)C>C(OCC)C.[Cu]I.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:24][O:25][CH2:26][C@@H:27]([NH:29][C:30]([C:32]1[C:40]2[C:35](=[N:36][CH:37]=[C:38]([C:6]3[C:5]4[C:9](=[CH:10][C:2]([F:1])=[CH:3][CH:4]=4)[NH:8][N:7]=3)[N:39]=2)[N:34]([CH2:42][O:43][CH2:44][CH2:45][Si:46]([CH3:48])([CH3:47])[CH3:49])[CH:33]=1)=[O:31])[CH3:28]

Participants

7

Reactant 3

HCID 6228DimethylformamideHCID 866779092-bromo-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((S)-2-methoxy-1-methyl-ethyl)-amideHCID 1784482326-fluoro-3-(tributylstannyl)-1H-indazole

Product 1

HCID 712883712-(6-fluoro-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((S)-2-methoxy-1-methyl-ethyl)-amideYield 92.3%

Reagents, catalysts & solvents 3

HCID 24350Copper(1+) iodide; Copper(I) iodide; Cuprous iodide; Cuprous iodide (CuI)CatalystHCID 178418397HCID 178418397, compoundCatalystHCID 3283Diethyl EtherSolvent

Conditions

Temperature
80 °C

Procedure

6-Fluoro-3-tributylstannyl-1H-indazole (1.10 g, 2.59 mmol), copper(I) iodide (24 mg, 0.13 mmol,) and 2-bromo-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((S)-2-methoxy-1-methyl-ethyl)-amide (560 mg, 1.26 mmol) were combined with DMF (6 mL) to give a yellow solution. The mixture was degassed with bubbling nitrogen for 10 min, then tetrakis(triphenylphosphine)palladium (0) (73 mg, 0.06 mmol) was added and the reaction was stirred under nitrogen at 80° C. for 2 h. The reaction mixture was cooled, diluted with diethyl ether (60 mL) and washed with water and brine. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by silica gel chromatography (0-10% methanol in dichloromethane with 0.5% ammonium hydroxide) to obtain 580 mg (92%) of 2-(6-fluoro-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((S)-2-methoxy-1-methyl-ethyl)-amide as an off-white solid. MS: (M+H)+=499.

Workup

  1. customto give a yellow solution
  2. customThe mixture was degassed with bubbling nitrogen for 10 min
  3. temperatureThe reaction mixture was cooled
  4. washwashed with water and brine
  5. dry with materialThe organic layer was dried over sodium sulfate
  6. filtrationfiltered
  7. concentrationconcentrated in vacuo
  8. customThe crude material was purified by silica gel chromatography (0-10% methanol in dichloromethane with 0.5% ammonium hydroxide)

Sources & evidence

ORD record
ord-ee81e7b32da74480a5529153b0176b0a
Source dataset
uspto-grants-2014_02
Patent number
US08658646B2

Linked notes

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