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Diisopropylamine → (4-(Tert-butyldimethylsilyl)-3,5,6-trifluoropyridin-2-yl)(2-fluoropyridin-3-yl)methanone

HRID 717603
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HRID 717603 반응식
C(NC(C)C)(C)C.[Li]CCCC.[C:13]([Si:17]([CH3:28])([CH3:27])[C:18]1[C:23]([F:24])=[CH:22][N:21]=[C:20]([F:25])[C:19]=1[F:26])([CH3:16])([CH3:15])[CH3:14].[F:29][C:30]1[C:35]([C:36](N(OC)C)=[O:37])=[CH:34][CH:33]=[CH:32][N:31]=1>C1COCC1>[Si:17]([C:18]1[C:19]([F:26])=[C:20]([F:25])[N:21]=[C:22]([C:36]([C:35]2[C:30]([F:29])=[N:31][CH:32]=[CH:33][CH:34]=2)=[O:37])[C:23]=1[F:24])([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:28])[CH3:27]
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6

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HCID 7912DiisopropylamineHCID 534170672-Fluoro-N-methoxy-N-methylnicotinamideHCID 667966984-(Tert-butyldimethylsilyl)-2,3,5-trifluoropyridineHCID 178418339Butyllithium

생성물 1

HCID 66797448(4-(Tert-butyldimethylsilyl)-3,5,6-trifluoropyridin-2-yl)(2-fluoropyridin-3-yl)methanone

시약·촉매·용매 1

HCID 8028
Tetrahydrofuran
용매

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온도
0 °C

실험 절차

A solution of diisopropylamine (66.78 g, 92.49 mL, 659.9 mmol) in THF (1.360 L) was cooled to −20° C. under nitrogen. nBuLi (2.5M in hexane) (253.0 mL of 2.5 M, 632.4 mmol) was added dropwise via cannula at such a rate as to maintain the internal temperature below −15° C. The solution was warmed to 0° C. then immediately re-cooled to −90° C. Tert-butyl-dimethyl-(2,3,5-trifluoro-4-pyridyl)silane (136 g, 549.9 mmol) was added dropwise via cannula at such a rate as to maintain the internal temperature below −85° C. After complete addition the solution became an orange suspension. The reaction mixture was stirred at −85° C. for 1 h then 2-fluoro-N-methoxy-N-methylpyridine-3-carboxamide (116.5 g, 632.4 mmol) was added dropwise over 1 h keeping the internal temperature below −85° C. The mixture turned dark green then dark red during addition. The mixture was stirred at −85° C. for 45 min after which time Lc/Ms indicated the reaction was complete. The cooling bath was removed and the mixture warmed to −50° C. Saturated ammonium chloride solution NH4Cl (300 mL) was added and the mixture allowed to warm up to RT. The mixture was diluted with EtOAc (2.5 L). The aqueous phase was separated and extracted with more EtOAc (500 ml). The combined organics were washed with brine and partially concentrated in vacuo. The solution was dried over magnesium sulfate, filtered and concentrated in vacuo to a brown oil. The crude was purified on silica gel, eluting with 0-20% ethyl acetate in petroleum ether. This gave the title compound as a yellow oil which solidified on standing (159.6 g, 78%); 1H NMR (CDCl3) 0.35 (6H, s), 0.88 (9H, s), 7.29 (1H, m), 8.13 (1H, m), 8.37 (1H, m); 19F NMR (decoupled) −112.47, −106.7, −89.3, −61.95; MS ES (+) 371.14 (M+1).

후처리

  1. temperatureto maintain the internal temperature below −15° C
  2. temperaturethen immediately re-cooled to −90° C
  3. temperatureto maintain the internal temperature below −85° C
  4. additionAfter complete addition the solution
  5. customthe internal temperature below −85° C
  6. additiondark red during addition
  7. stirringThe mixture was stirred at −85° C. for 45 min after which time Lc/Ms
  8. customThe cooling bath was removed
  9. temperaturethe mixture warmed to −50° C
  10. additionSaturated ammonium chloride solution NH4Cl (300 mL) was added
  11. temperatureto warm up to RT
  12. additionThe mixture was diluted with EtOAc (2.5 L)
  13. customThe aqueous phase was separated
  14. extractionextracted with more EtOAc (500 ml)
  15. washThe combined organics were washed with brine
  16. concentrationpartially concentrated in vacuo
  17. dry with materialThe solution was dried over magnesium sulfate
  18. filtrationfiltered
  19. concentrationconcentrated in vacuo to a brown oil
  20. customThe crude was purified on silica gel
  21. washeluting with 0-20% ethyl acetate in petroleum ether

출처 및 근거

ORD 기록
ord-f9c5a307dbdd435e8eb83c9d1a7983dc
출처 데이터셋
uspto-grants-2015_11
DOI
10.6084/m9.figshare.5104873.v1
특허 번호
US09193722B2

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