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

HRID 246230노트

반응식

HRID 246230 반응식
[CH2:1]([N:8]1[CH2:12][CH2:11][C@@H:10]([NH:13][C:14]([C:16]2[C:24]3[C:19](=[N:20][CH:21]=[C:22]([C:25]4[C:33]5[C:28](=[CH:29][C:30]([F:34])=[CH:31][CH:32]=5)[N:27]([CH3:35])[N:26]=4)[N:23]=3)[N:18](COCC[Si](C)(C)C)[CH:17]=2)=[O:15])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[CH2:1]([N:8]1[CH2:12][CH2:11][C@@H:10]([NH:13][C:14]([C:16]2[C:24]3[C:19](=[N:20][CH:21]=[C:22]([C:25]4[C:33]5[C:28](=[CH:29][C:30]([F:34])=[CH:31][CH:32]=5)[N:27]([CH3:35])[N:26]=4)[N:23]=3)[NH:18][CH:17]=2)=[O:15])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1

참가 물질

4

반응물 2

HCID 2724141Tetrabutylammonium FluorideHCID 712860862-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((R)-1-benzyl-pyrrolidin-3-yl)-amide

생성물 1

HCID 712859212-(6-fluoro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((R)-1-benzyl-pyrrolidin-3-yl)-amide수율 29%

시약·촉매·용매 1

HCID 8028Tetrahydrofuran용매

실험 절차

To a 20 ml vial containing 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanylethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((R)-1-benzyl-pyrrolidin-3-yl)-amide (51 mg, 0.085 mmol) dissolved in THF (1 ml) was added TBAF (1.0 M in THF, 1.0 ml, 1.0 mmol). The vial was backfilled with nitrogen then sealed and placed in heat block at 80° C. for 3 h. The reaction was cooled to room temperature, quenched with acetone (2 ml) and sat'd NaHCO3 (20 ml). The mixture was stirred for 1 h then extracted with EtOAc and the organics washed with brine. The aqueous was again extracted with EtOAc and the organics washed with brine. The organics were combined, dried over MgSO4, filtered and concentrated. The crude was dissolved in MeOH and EtOAc, supported on Celite, and purified by flash chromatography (4 g silicycle) with 0% to 10% MeOH in dichloromethane to 10% MeOH in EtOAc. The appropriate fractions were combined and concentrated. The solid was triturated with dichloromethane, Et2O, and hexanes to isolate 11 mg (29%) of 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((R)-1-benzyl-pyrrolidin-3-yl)-amide as a white solid. LC-MS (M+H)+=470; 1H NMR (300 MHz, DMSO-d6) δ: 12.87 (br. s., 1H), 9.10 (s, 1H), 8.34-8.54 (m, 3H), 7.68 (dd, J=9.8, 1.8 Hz, 1H), 7.11-7.26 (m, 5H), 6.97 (td, J=9.1, 1.9 Hz, 1H), 4.60 (br. s., 1H), 4.16 (s, 3H), 3.61 (s, 2H), 2.82-2.97 (m, 1H), 2.58-2.75 (m, 2H), 2.29-2.44 (m, 2H), 1.75 (br. s., 1H).

후처리

  1. customthen sealed
  2. customquenched with acetone (2 ml) and sat'd NaHCO3 (20 ml)
  3. extractionthen extracted with EtOAc
  4. washthe organics washed with brine
  5. extractionThe aqueous was again extracted with EtOAc
  6. washthe organics washed with brine
  7. dry with materialdried over MgSO4
  8. filtrationfiltered
  9. concentrationconcentrated
  10. dissolutionThe crude was dissolved in MeOH
  11. custompurified by flash chromatography (4 g silicycle) with 0% to 10% MeOH in dichloromethane to 10% MeOH in EtOAc
  12. concentrationconcentrated
  13. customThe solid was triturated with dichloromethane, Et2O, and hexanes

출처 및 근거

ORD 기록
ord-754b7593163e4e74801e3cce640fe35d
출처 데이터셋
uspto-grants-2014_02
특허 번호
US08658646B2

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