6-fluoro-1-methyl-3-(tributylstannyl)-1H-indazole → 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((R)-1-benzyl-pyrrolidin-3-yl)-amide

HRID 246229Notes

Reaction equation

HRID 246229 reaction equation
[CH2:1]([N:8]1[CH2:12][CH2:11][C@@H:10]([NH:13][C:14]([C:16]2[C:24]3[C:19](=[N:20][CH:21]=[C:22](Br)[N:23]=3)[N:18]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[CH:17]=2)=[O:15])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:34][C:35]1[CH:43]=[C:42]2[C:38]([C:39]([Sn](CCCC)(CCCC)CCCC)=[N:40][N:41]2[CH3:44])=[CH:37][CH:36]=1>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>[CH2:1]([N:8]1[CH2:12][CH2:11][C@@H:10]([NH:13][C:14]([C:16]2[C:24]3[C:19](=[N:20][CH:21]=[C:22]([C:39]4[C:38]5[C:42](=[CH:43][C:35]([F:34])=[CH:36][CH:37]=5)[N:41]([CH3:44])[N:40]=4)[N:23]=3)[N:18]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[CH:17]=2)=[O:15])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1

Participants

6

Reactant 2

HCID 712803076-fluoro-1-methyl-3-(tributylstannyl)-1H-indazoleHCID 866779622-bromo-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((R)-1-benzyl-pyrrolidin-3-yl)-amide

Product 1

HCID 712860862-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((R)-1-benzyl-pyrrolidin-3-yl)-amideYield 68.3%

Reagents, catalysts & solvents 3

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

Conditions

Temperature
80 °C

Procedure

In a 40 ml vial containing 2-bromo-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((R)-1-benzyl-pyrrolidin-3-yl)-amide (1.32 g, 2.49 mmol) was added a solution of 6-fluoro-1-methyl-3-tributylstannyl-1H-indazole (1.20 g, 2.73 mmol) in DMF (25 ml). The vial was backfilled with nitrogen and tetrakis(triphenylphosphine)palladium (0) (159 mg, 0.14 mmol) and copper (I) iodide (107 mg, 0.56 mmol) were added. Again the vial was backfilled with nitrogen, then sealed and the reaction mixture was stirred in a heating block at 80° C. for 4 h. The reaction mixture was cooled to room temperature diluted with EtOAc/hexanes (100/30 ml) and washed with water (100 ml). The aqueous layer was extracted with EtOAc/hexanes (100/30 ml). The combined organic layers were washed with brine then dried over MgSO4, filtered, and concentrated. The crude was purified by flash chromatography (120 g Analogix) with 20% to 100% EtOAc in hexanes. The approriate fractions were combined and concentrated to yield 1.02 g (62%) of 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((R)-1-benzyl-pyrrolidin-3-yl)-amide as a light yellow solid. LC-MS (M+H)+=600.

Workup

  1. additionwere added
  2. customsealed
  3. temperatureThe reaction mixture was cooled to room temperature
  4. washwashed with water (100 ml)
  5. extractionThe aqueous layer was extracted with EtOAc/hexanes (100/30 ml)
  6. washThe combined organic layers were washed with brine
  7. dry with materialthen dried over MgSO4
  8. filtrationfiltered
  9. concentrationconcentrated
  10. customThe crude was purified by flash chromatography (120 g Analogix) with 20% to 100% EtOAc in hexanes
  11. concentrationconcentrated

Sources & evidence

ORD record
ord-ddc60f172724478199e983661ba23508
Source dataset
uspto-grants-2014_02
Patent number
US08658646B2

Reaction notes

Loading…