Ethyl Acetate → 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [1-(4-bromo-phenyl)-cyclopropyl]-amide

HRID 246223Notes

Reaction equation

HRID 246223 reaction equation
[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([NH:11][C:12]([C:14]3[C:22]4[C:17](=[N:18][CH:19]=[C:20]([C:23]5[C:31]6[C:26](=[CH:27][C:28]([F:32])=[CH:29][CH:30]=6)[N:25]([CH3:33])[N:24]=5)[N:21]=4)[N:16](COCC[Si](C)(C)C)[CH:15]=3)=[O:13])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-].CC(=O)OCC.C(=O)(O)[O-].[Na+]>C1COCC1.O.C(#N)C.CC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([NH:11][C:12]([C:14]3[C:22]4[C:17](=[N:18][CH:19]=[C:20]([C:23]5[C:31]6[C:26](=[CH:27][C:28]([F:32])=[CH:29][CH:30]=6)[N:25]([CH3:33])[N:24]=5)[N:21]=4)[NH:16][CH:15]=3)=[O:13])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1

Participants

9

Reactant 4

HCID 8857Ethyl AcetateHCID 516892Sodium BicarbonateHCID 2724141Tetrabutylammonium FluorideHCID 712859912-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanylethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [1-(4-bromo-phenyl)-cyclopropyl]-amide

Product 1

HCID 712883622-(6-fluoro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [1-(4-bromo-phenyl)-cyclopropyl]-amideYield 63.4%

Reagents, catalysts & solvents 4

HCID 180AcetoneSolventHCID 962WaterSolventHCID 6342AcetonitrileSolventHCID 8028TetrahydrofuranSolvent

Conditions

Temperature
85 °C

Procedure

To a stirred solution of 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanylethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [1-(4-bromo-phenyl)-cyclopropyl]-amide (50 mg, 0.078 mmol) in THF (3 mL) was added a solution of TBAF (1.0 M in THF, 1.18 mL, 1.18 mmol) at room temperature. The resulting light brown solution was heated to 85° C. and stirred for 3 h at which time TLC analysis (EA, Rf=0.3) indicated the absence of starting material. Then, the reaction mixture was cooled to room temperature and 3 mL of acetone and 9 mL of saturated sodium bicarbonate solution were added and the resulting suspension was stirred for 1 h. The reaction suspension was diluted with water and the organic compound was extracted into EtOAc (3×25 mL) and the combined extracts were washed with brine solution and dried over MgSO4. Filtration of the drying agent and removal of the solvent under vacuum gave the crude solid which was dissolved in acetonitrile with heating. The resulting greenish solution was stored in the refrigerator for 15 h and the solids were collected by filtration and washed with acetonitrile. After drying in air, 25 mg (63%) of 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [1-(4-bromo-phenyl)-cyclopropyl]-amide was isolated as a off-white solid. LC-MS (M+H)+=507; 1H NMR (300 MHz, DMSO-d6) δ: 12.91 (s, 1H), 9.11 (s, 1H), 8.99 (s, 1H), 8.52 (s, 1H), 8.39-8.51 (m, 1H), 7.68 (dd, J=9.7, 1.9 Hz, 1H), 7.47 (d, J=8.5 Hz, 2H), 7.27 (d, J=8.5 Hz, 2H), 7.14 (td, J=9.0, 2.0 Hz, 1H), 4.14 (s, 3H), 1.44 (s, 4H).

Workup

  1. temperatureThen, the reaction mixture was cooled to room temperature
  2. extractionthe organic compound was extracted into EtOAc (3×25 mL)
  3. washthe combined extracts were washed with brine solution
  4. dry with materialdried over MgSO4
  5. filtrationFiltration of the drying agent and removal of the solvent under vacuum
  6. customgave the crude solid which
  7. temperaturewith heating
  8. waitThe resulting greenish solution was stored in the refrigerator for 15 h
  9. filtrationthe solids were collected by filtration
  10. washwashed with acetonitrile
  11. customAfter drying in air

Sources & evidence

ORD record
ord-976c9e0698fe4d7aa5d1f2fc5e8af049
Source dataset
uspto-grants-2014_02
Patent number
US08658646B2

Reaction notes

Loading…