Potassium Carbonate → tert-butyl(3S)-4-((1R)-1-(6-fluoro-3-pyridinyl)ethyl)-3-methyl-1-piperazinecarboxylate

HRID 1621804

Reaktionsgleichung

Reaktionsgleichung von HRID 1621804
Br[CH:2]([C:4]1[CH:5]=[CH:6][C:7]([F:10])=[N:8][CH:9]=1)[CH3:3].[CH3:11][C@@H:12]1[NH:17][CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13]1.C([O-])([O-])=O.[K+].[K+]>C(#N)C>[F:10][C:7]1[N:8]=[CH:9][C:4]([C@H:2]([N:17]2[CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13][C@@H:12]2[CH3:11])[CH3:3])=[CH:5][CH:6]=1

Komponenten

5

Edukt 3

HCID 11430Potassium CarbonateHCID 7023035(S)-1-Boc-3-methylpiperazineHCID 666000025-(1-Bromoethyl)-2-fluoropyridine

Produkt 1

HCID 68514890tert-butyl(3S)-4-((1R)-1-(6-fluoro-3-pyridinyl)ethyl)-3-methyl-1-piperazinecarboxylateAusbeute 35,4 %

Reagenzien, Katalysatoren, Lösungsmittel 1

HCID 6342AcetonitrileLösungsmittel

Reaktionsbedingungen

Temperatur
70 °C

Versuchsvorschrift

A mixture of 5-(1-bromoethyl)-2-fluoropyridine (Example 146, Step 2; 8.95 g, 43.9 mmol) and (S)-tert-butyl 3-methylpiperazine-1-carboxylate (9.22 g, 46.1 mmol) (CNH Technologies Inc.) in acetonitrile (200 mL) was treated with K2CO3 (7.27 g, 52.6 mmol) and KI (1.456 g, 8.77 mmol). The mixture was placed into a pre-heated (70° C.)oil bath and allowed to stir under an inert atmosphere overnight. The heating bath was then removed and the reaction mixture was allowed to cool to ambient temperature. The reaction mixture was diluted with chloroform (200 mL) and water (300 mL). The organic layer was separated, and the aqueous layer was extracted with chloroform (1×100 mL). The combined organic layers were then washed with a saturated brine solution, dried over Na2SO4, filtered, and concentrated. The crude material was adsorbed onto silica gel and purified by column chromatography (120 g silica gel, 0% to 40% EtOAc/hexanes) to provide tert-butyl (3S)-4-((1R)-1-(6-fluoro-3-pyridinyl)ethyl)-3-methyl-1-piperazinecarboxylate (5.02 g, 15.52 mmol, 35.4% yield) (lower Rf diastereomer) as a viscous yellow-orange oil. m/z (ESI, +ve) 324.1 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 8.09-8.14 (m, 1H); 7.75 (td, J=8.0, 2.2 Hz, 1H); 6.90 (dd, J=8.5, 2.8 Hz, 1H); 3.94 (br. s., 1H, =); 3.55 (br. s., 1H); 3.37 (br. s., 2H); 3.20 (br. s., 1H); 2.71 (ddd, J=11.3, 7.6, 3.5 Hz, 1H); 2.43 (dd, J=9.6, 5.5 Hz, 2H); 1.43 (s, 9H); 1.38 (d, J=6.8 Hz, 3H); 0.99 (d, J=6.3 Hz, 3H).

Aufarbeitung

  1. customThe heating bath was then removed
  2. temperatureto cool to ambient temperature
  3. additionThe reaction mixture was diluted with chloroform (200 mL) and water (300 mL)
  4. customThe organic layer was separated
  5. extractionthe aqueous layer was extracted with chloroform (1×100 mL)
  6. washThe combined organic layers were then washed with a saturated brine solution
  7. dry with materialdried over Na2SO4
  8. filtrationfiltered
  9. concentrationconcentrated
  10. custompurified by column chromatography (120 g silica gel, 0% to 40% EtOAc/hexanes)

Quellen und Nachweise

ORD-Eintrag
ord-ea5f36bac0344a599bbc132a9dc883a4
Quelldatensatz
uspto-grants-2014_07
Patentnummer
US08772480B2

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