Tetrabutylammonium Fluoride → 2-(6-Fluoro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((R)-1-cyanomethyl-pyrrolidin-3-yl)-amide

HRID 246233Notes

Reaction equation

HRID 246233 reaction equation
[C:1]([CH2:3][N:4]1[CH2:8][CH2:7][C@@H:6]([NH:9][C:10]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[C:18]([C:21]4[C:29]5[C:24](=[CH:25][C:26]([F:30])=[CH:27][CH:28]=5)[N:23]([CH3:31])[N:22]=4)[N:19]=3)[N:14](COCC[Si](C)(C)C)[CH:13]=2)=[O:11])[CH2:5]1)#[N:2].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[C:1]([CH2:3][N:4]1[CH2:8][CH2:7][C@@H:6]([NH:9][C:10]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[C:18]([C:21]4[C:29]5[C:24](=[CH:25][C:26]([F:30])=[CH:27][CH:28]=5)[N:23]([CH3:31])[N:22]=4)[N:19]=3)[NH:14][CH:13]=2)=[O:11])[CH2:5]1)#[N:2]

Participants

4

Reactant 2

HCID 2724141Tetrabutylammonium FluorideHCID 866779632-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((R)-1-cyanomethyl-pyrrolidin-3-yl)-amide

Product 1

HCID 866779642-(6-Fluoro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((R)-1-cyanomethyl-pyrrolidin-3-yl)-amideYield 33%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Conditions

Temperature
85 °C

Procedure

To a 100 ml round-bottomed flask containing 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((R)-1-cyanomethyl-pyrrolidin-3-yl)-amide (216 mg, 0.394 mmol) suspended in THF (5 ml) was added TBAF (1.0 M in THF, 5.0 ml, 5.0 mmol). The vial was backfilled with nitrogen then sealed and heated in an oil bath at 85° C. for 2 h. The reaction was cooled to room temperature, quenched with acetone (5 ml) and sat'd NaHCO3 (10 ml). The mixture was stirred for 1 h then diluted with water and extracted with EtOAc. Brine was added and the aqueous layer was extracted twice with EtOAc. The combined organics were washed with water and brine then dried over MgSO4, filtered and concentrated. The crude solid was triturated with Et2O, EtOAc, and hexanes to afford 54 mg (33%) of 2-(6-Fluoro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((R)-1-cyanomethyl-pyrrolidin-3-yl)-amide as a white solid. LC-MS (M+H)+=419; 1H NMR (300 MHz, DMSO-d6) δ: 12.87 (br. s., 1H), 9.10 (s, 1H), 8.39-8.52 (m, 2H), 8.31 (d, J=7.8 Hz, 1H), 7.63-7.73 (m, 1H), 7.18-7.31 (m, 1H), 4.64 (br. s., 1H), 4.14 (s, 3H), 3.81-4.05 (m, 2H), 2.97 (td, J=8.6, 4.6 Hz, 1H), 2.86 (dd, J=9.2, 6.7 Hz, 1H), 2.72 (dd, J=9.3, 3.5 Hz, 1H), 2.52-2.62 (m, 1H), 2.36-2.45 (m, 1H), 1.70-1.85 (m, 1H).

Workup

  1. customthen sealed
  2. temperatureThe reaction was cooled to room temperature
  3. customquenched with acetone (5 ml) and sat'd NaHCO3 (10 ml)
  4. additionthen diluted with water
  5. extractionextracted with EtOAc
  6. additionBrine was added
  7. extractionthe aqueous layer was extracted twice with EtOAc
  8. washThe combined organics were washed with water and brine
  9. dry with materialthen dried over MgSO4
  10. filtrationfiltered
  11. concentrationconcentrated
  12. customThe crude solid was triturated with Et2O, EtOAc, and hexanes

Sources & evidence

ORD record
ord-d582ec7530824a1c96f6f6e9d11ad4f0
Source dataset
uspto-grants-2014_02
Patent number
US08658646B2

Reaction notes

Loading…