Potassium Carbonate → N-tert-butyl-2-(5-(difluoromethoxy)-1-(2-oxo-2-(4-(2,2,2-trifluoroethyl)piperazin-1-yl)ethyl)-1H-indazol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide

HRID 246534Notes

Reaction equation

HRID 246534 reaction equation
Cl[CH2:2][C:3]([N:5]1[CH2:10][CH2:9][N:8]([CH2:11][C:12]([F:15])([F:14])[F:13])[CH2:7][CH2:6]1)=[O:4].C(=O)([O-])[O-].[K+].[K+].[C:22]([NH:26][C:27]([C:29]1[C:37]2[C:32](=[N:33][CH:34]=[C:35]([C:38]3[C:46]4[C:41](=[CH:42][CH:43]=[C:44]([O:47][CH:48]([F:50])[F:49])[CH:45]=4)[NH:40][N:39]=3)[N:36]=2)[N:31]([CH2:51][O:52][CH2:53][CH2:54][Si:55]([CH3:58])([CH3:57])[CH3:56])[CH:30]=1)=[O:28])([CH3:25])([CH3:24])[CH3:23]>CN(C=O)C>[C:22]([NH:26][C:27]([C:29]1[C:37]2[C:32](=[N:33][CH:34]=[C:35]([C:38]3[C:46]4[C:41](=[CH:42][CH:43]=[C:44]([O:47][CH:48]([F:49])[F:50])[CH:45]=4)[N:40]([CH2:2][C:3](=[O:4])[N:5]4[CH2:10][CH2:9][N:8]([CH2:11][C:12]([F:15])([F:14])[F:13])[CH2:7][CH2:6]4)[N:39]=3)[N:36]=2)[N:31]([CH2:51][O:52][CH2:53][CH2:54][Si:55]([CH3:58])([CH3:57])[CH3:56])[CH:30]=1)=[O:28])([CH3:25])([CH3:24])[CH3:23]

Participants

5

Reactant 3

HCID 11430Potassium CarbonateHCID 433627082-Chloro-1-(4-(2,2,2-trifluoroethyl)piperazin-1-yl)ethanoneHCID 712795662-(5-difluoromethoxy-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid tert-butylamide

Product 1

HCID 71280545N-tert-butyl-2-(5-(difluoromethoxy)-1-(2-oxo-2-(4-(2,2,2-trifluoroethyl)piperazin-1-yl)ethyl)-1H-indazol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamideYield 99,044.602%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent2×

Conditions

Temperature
60 °C

Procedure

To a stirred solution of 2-chloro-1-(4-(2,2,2-trifluoroethyl)piperazin-1-yl)ethanone (115 mg, 471 μmol) in DMF (16 mL) under Ar, potassium carbonate (200 mg, 1.45 mmol) was added in a single portion at 25° C. After 1 h, a solution of N-tert-butyl-2-(5-(difluoromethoxy)-1H-indazol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (50 mg, 94.2 μmol) in DMF (4.00 mL) was added in a single portion and the reaction was stirred at 60° C. After 18 h, the reaction was cooled to 25° C. and quenched with water (400 mL). The product was extracted with ethyl acetate (3×150 mL) and the organics were washed with brine (200 mL). The organics were dried over sodium sulfate and concentrated to give a yellow oil. The oil was dried in vacuo (300 mTorr, 25° C.) and purified by chromatography (silica, 12 g Analogix column, 5-80% ethyl acetate in hexanes, gradient over 1 h) to give N-tert-butyl-2-(5-(difluoromethoxy)-1-(2-oxo-2-(4-(2,2,2-trifluoroethyl)piperazin-1-yl)ethyl)-1H-indazol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (69.0 mg, 93.3 mmol, 99%) as a yellow solid. MS (M)'=739; 1H NMR (DMSO-d6) δ: 9.09 (s, 1H), 8.60 (s, 1H), 8.22 (d, J=2.0 Hz, 1H), 7.88 (s, 1H), 7.78 (d, J=9.3 Hz, 1H), 7.40 (dd, J=2.0, 8.8 Hz, 1H), 7.21 (t, J=74.3 Hz, 1H), 5.74 (s, 2H), 5.67 (s, 2H), 3.64 (br. s, 2H), 3.58 (t, J=8.0 Hz, 2H), 3.46 (d, J=4.5 Hz, 2H), 2.77 (br. s, 2H), 2.61 (d, J=18.8 Hz, 4H), 1.52 (s, 9H), 0.86 (t, J=8.0 Hz, 2H), −0.08 (s, 9H).

Workup

  1. waitAfter 18 h
  2. temperaturethe reaction was cooled to 25° C.
  3. customquenched with water (400 mL)
  4. extractionThe product was extracted with ethyl acetate (3×150 mL)
  5. washthe organics were washed with brine (200 mL)
  6. dry with materialThe organics were dried over sodium sulfate
  7. concentrationconcentrated
  8. customto give a yellow oil
  9. customThe oil was dried in vacuo (300 mTorr, 25° C.)
  10. custompurified by chromatography (silica, 12 g Analogix column, 5-80% ethyl acetate in hexanes, gradient over 1 h)

Sources & evidence

ORD record
ord-f9977a8df3de47e0bcc85d77fd2af600
Source dataset
uspto-grants-2014_02
Patent number
US08658646B2

Reaction notes

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