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

HRID 246084Notes

Reaction equation

HRID 246084 reaction equation
[CH3:1][S:2]([CH2:5][C@H:6]([NH:8][C:9]([C:11]1[C:19]2[C:14](=[N:15][CH:16]=[C:17]([C:20]3[C:28]4[C:23](=[CH:24][C:25]([Cl:29])=[CH:26][CH:27]=4)[N:22]([CH3:30])[N:21]=3)[N:18]=2)[N:13](COCC[Si](C)(C)C)[CH:12]=1)=[O:10])[CH3:7])(=[O:4])=[O:3].FC(F)(F)C(O)=O.C([O-])(=O)C.[Na+].O>ClCCl.C(OCC)(=O)C>[CH3:1][S:2]([CH2:5][C@H:6]([NH:8][C:9]([C:11]1[C:19]2[C:14](=[N:15][CH:16]=[C:17]([C:20]3[C:28]4[C:23](=[CH:24][C:25]([Cl:29])=[CH:26][CH:27]=4)[N:22]([CH3:30])[N:21]=3)[N:18]=2)[NH:13][CH:12]=1)=[O:10])[CH3:7])(=[O:3])=[O:4]

Participants

7

Reactant 4

HCID 962WaterHCID 6422Trifluoroacetic acidHCID 517045Sodium AcetateHCID 712860622-(6-chloro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((R)-2-methanesulfonyl-1-methyl-ethyl)-amide

Product 1

HCID 712883052-(6-chloro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((R)-2-methanesulfonyl-1-methyl-ethyl)-amideYield 37%

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-methanesulfonyl-1-methyl-ethyl)-amide (65 mg, 0.113 mmol) was dissolved in dichloromethane (0.8 ml) and then stirred in an ice bath. Trifluoroacetic acid (0.4 ml) was slowly added and the ice bath was removed. The reaction was stirred at room temperature for 3 h then cooled in ice bath. Sodium bicarbonate solution was added and the mixture was extracted three times with ethyl acetate. The combined organic layers were washed with sodium chloride solution and dried over sodium sulfate. After evaporation, the residue was dissolved in absolute ethanol (7 ml) and sodium acetate (185 mg, 2.25 mmol) was added. The mixture was stirred for 20 h at 60° C. The reaction was cooled, and water and ethyl acetate were added. The aqueous layer was extracted twice more with ethyl acetate. The combined organic layers were washed with sodium chloride solution, dried over sodium sulfate and evaporated to a residue. After purification by silica gel chromatography (methanol/dichloromethane), 18.6 mg (37%) of 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((R)-2-methanesulfonyl-1-methyl-ethyl)-amide was obtained. MS: (M+H)+=447; mp=287-290° C. 1H NMR (300 MHz, DMSO-d6) δ ppm 12.91 (s, 1H) 9.10 (s, 1H) 8.54 (d, J=8.7 Hz, 1H) 8.47 (s, 1H) 8.26 (d, J=7.9 Hz, 1H) 7.97-8.02 (m, 1H) 7.35 (dd, J=8.7, 1.5 Hz, 1H) 4.60-4.72 (m, 1H) 4.18 (s, 3H) 3.45-3.63 (m, 2H) 3.06 (s, 3H) 1.52 (d, J=6.8 Hz, 3H).

Workup

  1. customthe ice bath was removed
  2. stirringThe reaction was stirred at room temperature for 3 h
  3. temperaturethen cooled in ice bath
  4. additionSodium bicarbonate solution was added
  5. extractionthe mixture was extracted three times 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. dissolutionthe residue was dissolved in absolute ethanol (7 ml)
  10. stirringThe mixture was stirred for 20 h at 60° C
  11. temperatureThe reaction was cooled
  12. extractionThe aqueous layer was extracted twice more with ethyl acetate
  13. washThe combined organic layers were washed with sodium chloride solution
  14. dry with materialdried over sodium sulfate
  15. customevaporated to a residue
  16. customAfter purification by silica gel chromatography (methanol/dichloromethane)

Sources & evidence

ORD record
ord-12c9c5f35b084612acee9b731630c546
Source dataset
uspto-grants-2014_02
Patent number
US08658646B2

Reaction notes

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