3,3-Dimethyl-1-butanol → (S)-2-(5-fluoro-2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-4-ylamino)-3,3-dimethylbutan-1-ol

HRID 1055060ノート

反応式

HRID 1055060 の反応式
[F:1][C:2]1[CH:3]=[C:4]2[C:10](B3OC(C)(C)C(C)(C)O3)=[CH:9][N:8]([S:20]([C:23]3[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=3)(=[O:22])=[O:21])[C:5]2=[N:6][CH:7]=1.[CH3:30][C:31]([CH3:36])([CH3:35])[CH2:32][CH2:33][OH:34].ClC1N=[C:42]([NH:44][C@@H:45]([C:48](C)(C)C)CO)[C:41]([F:52])=[CH:40][N:39]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>[F:52][C:41]1[C:40]([NH:39][C@@H:32]([C:31]([CH3:36])([CH3:35])[CH3:30])[CH2:33][OH:34])=[CH:48][C:45]([C:10]2[C:4]3[C:5](=[N:6][CH:7]=[C:2]([F:1])[CH:3]=3)[N:8]([S:20]([C:23]3[CH:24]=[CH:25][C:26]([CH3:29])=[CH:27][CH:28]=3)(=[O:22])=[O:21])[CH:9]=2)=[N:44][CH:42]=1

参加物

8

反応物 4

HCID 122333,3-Dimethyl-1-butanolHCID 62657Potassium Phosphate, TribasicHCID 672856905-fluoro-1-((4-methylphenyl)sulfonyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo(2,3-b)pyridine2 回HCID 86714732(S)-2-((2-chloro-5-fluoropyrimidin-4-yl)amino)-3,3-dimethylbutan-1-ol

生成物 1

HCID 71247626(S)-2-(5-fluoro-2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-4-ylamino)-3,3-dimethylbutan-1-ol

試薬・触媒・溶媒 3

HCID 9811564Bis(dibenzylideneacetone)palladium触媒HCID 111557942-Dicyclohexylphosphino-2',4',6'-triisoprophylbiphenyl触媒HCID 962Water溶媒

反応条件

温度
120 °C

実験手順

A mixture of 5-fluoro-1-(p-tolylsulfonyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[2,3-b]pyridine, 7a, (11.09 g, 26.64 mmol), (S)-2-(2-chloro-5-fluoropyrimidin-4-yl)amino)-3,3-dimethylbutan-1-ol, 14a, (6.00 g, 24.22 mmol) and K3PO4 (15.42 g, 72.66 mmol) in 2-methyl THF (90 mL) and water (12.00 mL) was purged with nitrogen for 30 minutes. X-Phos (0.92 g, 1.94 mmol) and Pd2(dba)3 (0.44 g, 0.48 mmol) were added and the reaction mixture was heated at 120° C. in a pressure vial for 2 hr. The reaction mixture was cooled to room temperature, filtered and concentrated in vacuo. The residue was dissolved in EtOAc (100 mL) and washed with water. The organic layer was dried (MgSO4), filtered and concentrated in vacuo. The crude product was purified by silica gel chromatography (0-40% EtOAc/Hexanes gradient) to afford 10 g of the desired product as a foamy solid: 1H NMR (400 MHz, CDCl3) δ 8.54-8.40 (m, 2H), 8.22 (s, 1H), 8.09-8.00 (m, 3H), 7.29-7.16 (m, 2H), 5.15 (m, 1H), 4.32-4.14 (m, 1H), 3.98 (m, 1H), 3.70 (m, 1H), 2.30 (s, 3H), 1.01 (m, 9H); LC/MS (60-90% ACN/water 5 min with 0.9% FA, C4) m/z 502.43 (M+H) RT=1.52 min.

後処理

  1. customwas purged with nitrogen for 30 minutes
  2. temperatureThe reaction mixture was cooled to room temperature
  3. filtrationfiltered
  4. concentrationconcentrated in vacuo
  5. dissolutionThe residue was dissolved in EtOAc (100 mL)
  6. washwashed with water
  7. dry with materialThe organic layer was dried (MgSO4)
  8. filtrationfiltered
  9. concentrationconcentrated in vacuo
  10. customThe crude product was purified by silica gel chromatography (0-40% EtOAc/Hexanes gradient)

出典と根拠

ORDレコード
ord-f673813773424becbd96e8e073925156
出典データセット
uspto-grants-2016_07
特許番号
US09394302B2

反応ノート

読み込み中…