Sodium Bicarbonate → 5-{1-[(2,5-difluorophenyl)acetyl]-2,3-dihydro-1H-indol-5-yl}-7-(3-oxetanyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine

HRID 1910065ノート

反応式

HRID 1910065 の反応式
Br[C:2]1[C:10]2[C:9]([NH2:11])=[N:8][CH:7]=[N:6][C:5]=2[N:4]([CH:12]2[CH2:15][O:14][CH2:13]2)[CH:3]=1.[F:16][C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=1[CH2:24][C:25]([N:27]1[C:35]2[C:30](=[CH:31][C:32](B3OC(C)(C)C(C)(C)O3)=[CH:33][CH:34]=2)[CH2:29][CH2:28]1)=[O:26].C([O-])(O)=O.[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O1CCOCC1>[F:16][C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=1[CH2:24][C:25]([N:27]1[C:35]2[C:30](=[CH:31][C:32]([C:2]3[C:10]4[C:9]([NH2:11])=[N:8][CH:7]=[N:6][C:5]=4[N:4]([CH:12]4[CH2:15][O:14][CH2:13]4)[CH:3]=3)=[CH:33][CH:34]=2)[CH2:29][CH2:28]1)=[O:26]

参加物

6

反応物 3

HCID 516892Sodium BicarbonateHCID 668235701-[(2,5-difluorophenyl)acetyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-indoleHCID 668240635-bromo-7-(3-oxetanyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine

生成物 1

HCID 668234775-{1-[(2,5-difluorophenyl)acetyl]-2,3-dihydro-1H-indol-5-yl}-7-(3-oxetanyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine収率 61.8%

試薬・触媒・溶媒 2

HCID 178418397HCID 178418397、化合物触媒HCID 312751,4-Dioxane溶媒

反応条件

温度
100 °C

実験手順

To 5-bromo-7-(3-oxetanyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (50 mg, 0.186 mmol) and 1-[(2,5-difluorophenyl)acetyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-indole (104 mg, 0.260 mmol) were added 1,4-Dioxane (2 mL) and sat. NaHCO3 solution (1 mL) in a 5 ml sealable vial. N2 gas was bubbled through the mixture for 10 minutes then Pd(Ph3P)4 (21.47 mg, 0.019 mmol) was added and bubbled N2 for 5 minutes. The mixture was then capped and heated 100° C. overnight. The reaction was diluted with water (3 ml) then extracted with EtOAc (4×5 ml). The organics were then combined, washed with brine, dried over MgSO4, filtered and concentrated. The residual was then diluted with 3 ml of DMSO and purified on HPLC: (HPLC condition: Gilson using Trilution software with a Sunfire 5u C18(2) 100A. 50×30.00 mm 5 micron. 7.3-minute run (47 ml/min, 15% ACN/H2O, 0.1% TFA to 40% ACN/H2O, 0.1% TFA) with UV detection at 254 nm). Product fractions were combined and the volume was reduced to remove most of the MeCN. The water left behind was added saturated NaHCO3 and then extracted with EtOAc (3×15 mL). The organic was combined wash with saturated NaCl solution, dried over MgSO4, filtered and concentrated. The material was then transferred into a 40 mL vial with MeCN then water was added and the solution was freeze-dried to give 5-{1-[(2,5-difluorophenyl)acetyl]-2,3-dihydro-1H-indol-5-yl}-7-(3-oxetanyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (53 mg, 61.8% yield) as a white power. LC-MS (ES) m/z=462.4 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.15 (d, J=3.28 Hz, 1H), 8.08-8.13 (m, 1H), 7.70 (d, J=3.03 Hz, 1H), 7.41 (br. s., 1H), 7.15-7.33 (m, 4H), 6.17 (br. s., 2H), 5.82-5.93 (m, 1H), 4.95-5.07 (m, 4H), 4.30 (br. s., 2H), 3.96 (br. s., 2H), 3.29 (d, J=1.01 Hz, 2H).

後処理

  1. customN2 gas was bubbled through the mixture for 10 minutes
  2. custombubbled N2 for 5 minutes
  3. customThe mixture was then capped
  4. additionThe reaction was diluted with water (3 ml)
  5. extractionthen extracted with EtOAc (4×5 ml)
  6. washwashed with brine
  7. dry with materialdried over MgSO4
  8. filtrationfiltered
  9. concentrationconcentrated
  10. additionThe residual was then diluted with 3 ml of DMSO
  11. custompurified on HPLC
  12. custom7.3-minute
  13. customto remove most of the MeCN
  14. waitThe water left behind
  15. additionwas added saturated NaHCO3
  16. extractionextracted with EtOAc (3×15 mL)
  17. washThe organic was combined wash with saturated NaCl solution
  18. dry with materialdried over MgSO4
  19. filtrationfiltered
  20. concentrationconcentrated
  21. additionwater was added
  22. customthe solution was freeze-dried

出典と根拠

ORDレコード
ord-2287415564044728b28c112540060c0a
出典データセット
uspto-grants-2013_12
特許番号
US08598156B2

反応ノート

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