Cyclohexane → 4-((5R,7S)-7-(3,4-dimethylphenyl)-7-hydroxy-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-5-yl)-3-fluorobenzonitrile

HRID 2036032

Reaktionsgleichung

Reaktionsgleichung von HRID 2036032
Br[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[C:4]([CH3:9])[CH:3]=1.[Li]C(CC)C.C1CCCCC1.[F:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][C:29]=1[C@@H:30]1[N:34]2[CH:35]=[N:36][CH:37]=[C:33]2[C:32](=[O:38])[CH2:31]1)[C:25]#[N:26]>C1COCC1>[CH3:9][C:4]1[CH:3]=[C:2]([C@:32]2([OH:38])[C:33]3[N:34]([CH:35]=[N:36][CH:37]=3)[C@@H:30]([C:29]3[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][C:22]=3[F:21])[CH2:31]2)[CH:7]=[CH:6][C:5]=1[CH3:8]

Komponenten

6

Edukt 4

HCID 8078CyclohexaneHCID 685044-Bromo-o-xyleneHCID 67216150(R)-3-fluoro-4-(7-oxo-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-5-yl)benzonitrileHCID 178418400CID 53628100

Produkt 1

HCID 532366644-((5R,7S)-7-(3,4-dimethylphenyl)-7-hydroxy-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-5-yl)-3-fluorobenzonitrileAusbeute 10,7 %

Reagenzien, Katalysatoren, Lösungsmittel 1

HCID 8028TetrahydrofuranLösungsmittel2×

Reaktionsbedingungen

Temperatur
-40 °C

Versuchsvorschrift

To a solution of 4-bromo-1,2-dimethylbenzene (77 mg, 0.42 mmol) in THF (1 mL) at −78° C. was added a solution of 1.4 M s-BuLi in cyclohexane (0.33 ml, 0.46 mmol). The crude was warmed to −40° C. and stirred between −40° C. and −30° C. for 1 hr. The crude was cooled to −60° C. A solution of 3-fluoro-4-((R)-7-oxo-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-5-yl)-benzonitrile (50 mg, 0.21 mmol) in THF (1 mL) was added. The crude was stirred at −60° C. for 1 hr. The crude was warmed to room temperature in 4 hrs. The crude was quenched with NH4Cl and diluted with EtOAc. The organic layer was washed with brine, dried over MgSO4, filtered, and concentrated. The crude was purified via preparation plate using 7% (2M NH3 in MeOH)/CH2Cl2 to give 7.8 mg of the entitled product as the major diastereomer. MS 348.1 (M+H); LCMS condition A, retention time 1.31 min. 1H NMR (400 MHz, CDCl3) δ ppm 2.20 (s, 3H), 2.20 (s, 3H), 2.91 (dd, 1H), 3.29 (dd, 1H), 5.71 (d, 1H), 6.87 (s, 1H), 7.07 (d, 1H), 7.10-7.20 (m, 2H), 7.21 (s, 1H), 7.34 (d, 1H), 7.36 (s, 1H), 7.39-7.43 (m, 1H).

Aufarbeitung

  1. temperatureThe crude was cooled to −60° C
  2. stirringThe crude was stirred at −60° C. for 1 hr
  3. temperatureThe crude was warmed to room temperature in 4 hrs
  4. customThe crude was quenched with NH4Cl
  5. additiondiluted with EtOAc
  6. washThe organic layer was washed with brine
  7. dry with materialdried over MgSO4
  8. filtrationfiltered
  9. concentrationconcentrated
  10. customThe crude was purified via preparation plate

Quellen und Nachweise

ORD-Eintrag
ord-a63f6677f1c843b4a389eae11cef69d0
Quelldatensatz
uspto-grants-2013_11
Patentnummer
US08575160B2

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