Sodium hydride → Tert-butyl 4-((2-chloro-5-iodopyridin-4-ylamino)methyl)-4-fluoropiperidine-1-carboxylate

HRID 556864Notizen

Reaktionsgleichung

Reaktionsgleichung von HRID 556864
[H-].[Na+].[Cl:3][C:4]1[CH:9]=[C:8]([NH2:10])[C:7]([I:11])=[CH:6][N:5]=1.[F:12][C:13]1([CH2:26]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1>CN(C=O)C>[Cl:3][C:4]1[CH:9]=[C:8]([NH:10][CH2:26][C:13]2([F:12])[CH2:14][CH2:15][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:17][CH2:18]2)[C:7]([I:11])=[CH:6][N:5]=1

Komponenten

5

Edukt 3

HCID 24758Sodium hydride2×HCID 454803662-Chloro-5-iodopyridin-4-amineHCID 59455784Tert-butyl 4-fluoro-4-((tosyloxy)methyl)piperidine-1-carboxylate

Produkt 1

HCID 59613359Tert-butyl 4-((2-chloro-5-iodopyridin-4-ylamino)methyl)-4-fluoropiperidine-1-carboxylateAusbeute 13,2 %

Reagenzien, Katalysatoren, Lösungsmittel 1

HCID 6228DimethylformamideLösungsmittel2×

Reaktionsbedingungen

Temperatur
80 °C

Versuchsvorschrift

Sodium hydride (60% by wt) (32.7 mg, 0.817 mmol) was added to a solution of 2-chloro-5-iodopyridin-4-amine (160 mg, 0.629 mmol) in DMF (3930 μL) at room temperature and the mixture was stirred for 10 min. The temperature was raised to 80° C. and tert-butyl 4-fluoro-4-(tosyloxymethyl)piperidine-1-carboxylate (244 mg, 0.629 mmol) in DMF (1 mL) was added. The reaction mixture was stirred at 80° C. for 2 hr before further NaH (1.3 eq.) was added after first cooling the reaction to room temperature again. The reaction mixture was heated at 120° C. for 10 hr. After cooling, the solution was partitioned between EtOAc (150 mL) and 1M aqueous NaHCO3. The organic layer was washed with 1M NaHCO3 aq., sat. NaHCO3 and brine, then dried (MgSO4) and concentrated. The residue was dissolved in dichloromethane/hexane and loaded onto a 25+M Biotage silica column. Chromatography, eluting with 1% MeOH in dichloromethane gave partial purification. Further purification by preparative thin layer chromatography, eluting with 16% EtOAc in dichloromethane, gave tert-butyl 4-((2-chloro-5-iodopyridin-4-ylamino)methyl)-4-fluoropiperidine-1-carboxylate (39 mg, 0.083 mmol, 13%) as a colourless solid.

Aufarbeitung

  1. additionwas added
  2. temperatureafter first cooling
  3. customthe reaction to room temperature again
  4. temperatureThe reaction mixture was heated at 120° C. for 10 hr
  5. temperatureAfter cooling
  6. customthe solution was partitioned between EtOAc (150 mL) and 1M aqueous NaHCO3
  7. washThe organic layer was washed with 1M NaHCO3 aq., sat. NaHCO3 and brine
  8. dry with materialdried (MgSO4)
  9. concentrationconcentrated
  10. dissolutionThe residue was dissolved in dichloromethane/hexane
  11. washChromatography, eluting with 1% MeOH in dichloromethane
  12. customgave partial
  13. custompurification
  14. customFurther purification by preparative thin layer chromatography
  15. washeluting with 16% EtOAc in dichloromethane

Quellen und Nachweise

ORD-Eintrag
ord-2e67336c35a74e9fbc3b73dbfc2f72b1
Quelldatensatz
uspto-grants-2011_11
Patentnummer
US08058045B2

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