Water → 2-(2-methyl-1-phenyl-1H-imidazol-4-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-cyclopropyl-2-oxo-ethyl]-amide

HRID 1898631Notes

Reaction equation

HRID 1898631 reaction equation
[C:1]([CH:3]1[CH2:6][N:5]([C:7](=[O:33])[C@H:8]([NH:12][C:13]([C:15]2[C:23]3[C:18](=[N:19][CH:20]=[C:21](Br)[N:22]=3)[N:17]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[CH:16]=2)=[O:14])[CH:9]2[CH2:11][CH2:10]2)[CH2:4]1)#[N:2].[CH3:34][C:35]1[N:36]([C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=2)[CH:37]=[C:38]([Sn](CCCC)(CCCC)CCCC)[N:39]=1.O.C(=O)(O)[O-].[Na+]>CN(C=O)C.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.[Cu]I.ClCCl>[C:1]([CH:3]1[CH2:6][N:5]([C:7](=[O:33])[C@H:8]([NH:12][C:13]([C:15]2[C:23]3[C:18](=[N:19][CH:20]=[C:21]([C:38]4[N:39]=[C:35]([CH3:34])[N:36]([C:53]5[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=5)[CH:37]=4)[N:22]=3)[N:17]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[CH:16]=2)=[O:14])[CH:9]2[CH2:11][CH2:10]2)[CH2:4]1)#[N:2]

Participants

9

Reactant 4

HCID 962WaterHCID 516892Sodium BicarbonateHCID 575166502-methyl-1-phenyl-4-tributylstannanyl-1H-imidazoleHCID 58438590HCID 58438590, compound

Product 1

HCID 673862212-(2-methyl-1-phenyl-1H-imidazol-4-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-cyclopropyl-2-oxo-ethyl]-amideYield 59.2%

Reagents, catalysts & solvents 4

HCID 24350Copper(1+) iodide; Copper(I) iodide; Cuprous iodide; Cuprous iodide (CuI)CatalystHCID 178418397HCID 178418397, compoundCatalystHCID 6228DimethylformamideSolventHCID 6344DichloromethaneSolvent

Conditions

Temperature
80 °C

Procedure

2-Bromo-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-cyclopropyl-2-oxo-ethyl]-amide (115 mg, 0.188 mmol) and 2-methyl-1-phenyl-4-tributylstannanyl-1H-imidazole (101 mg, 0.225 mmol) were dissolved in 1.9 mL of DMF and the mixture was purged with Ar gas. Tetrakis(triphenylphosphine)palladium (10.8 mg, 0.0094 mmol) and then copper (I) iodide (7.1 mg, 0.038 mmol) were added and the reaction was sealed and stirred in an 80° C. oil bath for 18 h. The reaction was cooled and water, dichloromethane, and sodium bicarbonate solution were added. The layers were separated, and the aqueous layer was extracted twice more with dichloromethane. The combined organic layers were washed with water and then brine, and dried over sodium sulfate. After evaporation, the residue was purified by silica gel chromatography (methanol/dichloromethane) to provide 68 mg (59%) of 2-(2-methyl-1-phenyl-1H-imidazol-4-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-cyclopropyl-2-oxo-ethyl]-amide. (M+H)+=611.

Workup

  1. customthe mixture was purged with Ar gas
  2. customthe reaction was sealed
  3. temperatureThe reaction was cooled
  4. customThe layers were separated
  5. extractionthe aqueous layer was extracted twice more with dichloromethane
  6. washThe combined organic layers were washed with water
  7. dry with materialbrine, and dried over sodium sulfate
  8. customAfter evaporation
  9. customthe residue was purified by silica gel chromatography (methanol/dichloromethane)

Sources & evidence

ORD record
ord-770e8e8dc3484a589679bfee88d5e69a
Source dataset
uspto-grants-2013_08
Patent number
US08518945B2

Reaction notes

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