Borane;tetrahydrofuran → 1-(4-Bromo-2-chloro-5-fluorobenzyl)pyrrolidine

HRID 1694403Notizen

Reaktionsgleichung

Reaktionsgleichung von HRID 1694403
[Br:1][C:2]1[C:14]([F:15])=[CH:13][C:5]([C:6]([N:8]2[CH2:12][CH2:11][CH2:10][CH2:9]2)=O)=[C:4]([Cl:16])[CH:3]=1.B.C1COCC1>C1COCC1>[Br:1][C:2]1[C:14]([F:15])=[CH:13][C:5]([CH2:6][N:8]2[CH2:12][CH2:11][CH2:10][CH2:9]2)=[C:4]([Cl:16])[CH:3]=1

Komponenten

4

Edukt 2

HCID 2723981Borane;tetrahydrofuranHCID 67278263HCID 67278263, Verbindung

Produkt 1

HCID 672787301-(4-Bromo-2-chloro-5-fluorobenzyl)pyrrolidineAusbeute 94 %

Reagenzien, Katalysatoren, Lösungsmittel 1

HCID 8028TetrahydrofuranLösungsmittel

Reaktionsbedingungen

Temperatur
65 °C

Versuchsvorschrift

To Intermediate 10, 1-(4-bromo-2-chloro-5-fluorobenzoyl)pyrrolidine (48.0 g, 156.5 mmol) in THF (200 mL) at rt was slowly added a solution of BH3.THF complex (400 mL, 400 mmol, 1M THF). The resulting reaction was heated to 65° C. (oil bath) for 16 hr, and then the reaction was cooled to rt and slowly quenched with MeOH (dropwise addition). The reaction mixture was heated to reflux for 2 hr, cooled to rt, and concentrated under reduced pressure. This material was taken up in EtOAc and further quenched slowly with 6N HCl, then neutralized with aqueous NaOH (15%). The layers were separated and the aqueous layer was back extracted with EtOAc. The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure. Purification of this material was accomplished by flash column chromatography using a Biotage™ 75L column, eluting with a gradient of 5%, 10% MeOH/CH2Cl2. The product containing fractions were collected and concentrated to give the title compound (43 g, 94% yield) as a light yellow oil: Rf=0.6 (10% MeOH/CH2Cl2); LRMS m/z Calcd for C11H12BrClFN, 292.6, found, 292, 294, 296 (M+1) APCI; 1H NMR (300 MHz, CDCl3): δ 7.51 (d, J=6.6 Hz, 1H), 7.33 (d, J=9.5 Hz, 1H), 3.66 (s, 2H), 2.59-2.55 (m, 4H), 1.82-1.79 (m, 4H); 100 MHz 13C NMR (CDCl3) δ 158.3 (d, JC-F=247.2 Hz), 139.3, 133.3, 128.9, 117.8 (d, JC-F=24.9 Hz), 107.3 (d, JC-F=22.6 Hz), 56.7, 54.4, 23.9.

Aufarbeitung

  1. customThe resulting reaction
  2. temperaturethe reaction was cooled to rt
  3. customslowly quenched with MeOH (
  4. additiondropwise addition)
  5. temperatureThe reaction mixture was heated
  6. temperatureto reflux for 2 hr
  7. temperaturecooled to rt
  8. concentrationconcentrated under reduced pressure
  9. customfurther quenched slowly with 6N HCl
  10. customThe layers were separated
  11. extractionthe aqueous layer was back extracted with EtOAc
  12. dry with materialThe combined organic layers were dried over MgSO4
  13. filtrationfiltered
  14. concentrationconcentrated under reduced pressure
  15. customPurification of this material
  16. washeluting with a gradient of 5%, 10% MeOH/CH2Cl2
  17. additionThe product containing fractions
  18. customwere collected
  19. concentrationconcentrated

Quellen und Nachweise

ORD-Eintrag
ord-1d8716b49fc648cbbed638bd27ca5388
Quelldatensatz
uspto-grants-2012_04
Patentnummer
US08158673B2

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