Water → 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-((R)-3-fluoro-pyrrolidin-1-yl)-1-methyl-ethyl]-amide

HRID 246094Notes

Reaction equation

HRID 246094 reaction equation
[F:1][C@@H:2]1[CH2:6][CH2:5][N:4]([CH2:7][C@H:8]([NH:10][C:11]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[C:19]([C:22]4[C:30]5[C:25](=[CH:26][C:27]([Cl:31])=[CH:28][CH:29]=5)[N:24]([CH3:32])[N:23]=4)[N:20]=3)[N:15](COCC[Si](C)(C)C)[CH:14]=2)=[O:12])[CH3:9])[CH2:3]1.FC(F)(F)C(O)=O.C(N)CN.O>ClCCl.C(OCC)(=O)C>[F:1][C@@H:2]1[CH2:6][CH2:5][N:4]([CH2:7][C@H:8]([NH:10][C:11]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[C:19]([C:22]4[C:30]5[C:25](=[CH:26][C:27]([Cl:31])=[CH:28][CH:29]=5)[N:24]([CH3:32])[N:23]=4)[N:20]=3)[NH:15][CH:14]=2)=[O:12])[CH3:9])[CH2:3]1

Participants

7

Reactant 4

HCID 962WaterHCID 3301EthylenediamineHCID 6422Trifluoroacetic acidHCID 71286055HCID 71286055, compound

Product 1

HCID 712862332-(6-chloro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-((R)-3-fluoro-pyrrolidin-1-yl)-1-methyl-ethyl]-amideYield 65.8%

Reagents, catalysts & solvents 2

HCID 6344DichloromethaneSolventHCID 8857Ethyl AcetateSolvent

Procedure

2-(6-Chloro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-((R)-3-fluoro-pyrrolidin-1-yl)-1-methyl-ethyl]-amide (65 mg, 0.11 mmol) was dissolved in dichloromethane (0.7 ml) and cooled in ice bath. Trifluoroacetic acid (0.4 ml) was slowly added and the reaction was stirred at room temperature for 3 h. The reaction was evaporated and the residue was suspended in dichloromethane (1.1 ml). Ethylenediamine (0.45 ml, 6.65 mmol) was added and the mixture was stirred for 18 h. Water and then ethyl acetate were added to the mixture. The layers were separated and the aqueous layer was extracted twice more with ethyl acetate. The combined organic layers were washed with sodium chloride solution and dried over sodium sulfate. After evaporation, the residue was purified by silica gel chromatography (methanol/dichloromethane) to afford 33 mg (65%) of 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-((R)-3-fluoro-pyrrolidin-1-yl)-1-methyl-ethyl]-amide. MS (M+H)+=456; mp=233-234° C. 1H NMR (300 MHz, DMSO-d6) δ: 12.81-12.93 (m, 1H), 9.10 (s, 1H), 8.44 (s, 1H), 8.38-8.46 (m, 1H), 8.07 (d, J=8.3 Hz, 1H), 7.99-8.03 (m, 1H), 7.28-7.36 (m, 1H), 4.97-5.24 (m, 1H), 4.20-4.33 (m, 1H), 4.17 (s, 3H), 2.54-2.90 (m, 1H), 2.54-2.90 (m, 4H), 2.32-2.44 (m, 1H), 1.66-2.13 (m, 2H), 1.32 (d, J=6.4 Hz, 3H).

Workup

  1. temperaturecooled in ice bath
  2. customThe reaction was evaporated
  3. stirringthe mixture was stirred for 18 h
  4. customThe layers were separated
  5. extractionthe aqueous layer was extracted twice more with ethyl acetate
  6. washThe combined organic layers were washed with sodium chloride solution
  7. dry with materialdried over sodium sulfate
  8. customAfter evaporation
  9. customthe residue was purified by silica gel chromatography (methanol/dichloromethane)

Sources & evidence

ORD record
ord-095ebf4c6a564b48b7f75ac8e072eea3
Source dataset
uspto-grants-2014_02
Patent number
US08658646B2

Reaction notes

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