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Triethylamine → 4-ethyl-5,6-difluoro-4-(4-fluorophenyl)-3-(2,2,2-trifluoroethyl)-3,4-dihydroquinazolin-2(1H)-one

HRID 19689
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Druckvorschau

Reaktionsgleichung

Reaktionsgleichung von HRID 19689
[F:1][C:2]1[C:3]([C:18](=O)[C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)=[C:4]([NH:9][C:10]([NH:12][CH2:13][C:14]([F:17])([F:16])[F:15])=[O:11])[CH:5]=[CH:6][C:7]=1[F:8].F[C:28]1C(F)=CC=C2[C:29]=1C(C1C=CC(F)=CC=1)(O)N(CC(F)(F)F)C(=O)N2.C(N(CC)CC)C.S(Cl)(Cl)=O.C([Mg]Br)C>C1COCC1>[CH2:28]([C:18]1([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)[C:3]2[C:4](=[CH:5][CH:6]=[C:7]([F:8])[C:2]=2[F:1])[NH:9][C:10](=[O:11])[N:12]1[CH2:13][C:14]([F:17])([F:16])[F:15])[CH3:29]
KomponentenReaktionsbedingungenVersuchsvorschriftAufarbeitungQuellen und NachweiseNotizen zur Reaktion

Komponenten

7

Edukt 5

HCID 8471TriethylamineHCID 24386Thionyl ChlorideHCID 59346588N-[3,4-difluoro-2-(4-fluorobenzoyl)phenyl]-N'-(2,2,2-trifluoroethyl)ureaHCID 593465935,6-difluoro-4-(4-fluorophenyl)-4-hydroxy-3-(2,2,2-trifluoroethyl)-3,4-dihydroquinazolin-2(1H)-oneHCID 178418443HCID 178418443, Verbindung

Produkt 1

HCID 11853815
4-ethyl-5,6-difluoro-4-(4-fluorophenyl)-3-(2,2,2-trifluoroethyl)-3,4-dihydroquinazolin-2(1H)-one

Reagenzien, Katalysatoren, Lösungsmittel 1

HCID 8028TetrahydrofuranLösungsmittel

Reaktionsbedingungen

Temperatur
-78 °C

Versuchsvorschrift

To a solution of 1.5 g (3.987 mmol) N-[3,4-difluoro-2-(4-fluorobenzoyl)phenyl]-N′-(2,2,2-trifluoroethyl)urea (open form) and 5,6-difluoro-4-(4-fluorophenyl)-4-hydroxy-3-(2,2,2-trifluoroethyl)-3,4-dihydroquinazolin-2(1H)-one (closed form) in 8 ml THF was added 2.0 mL (19.933 mmol) triethylamine. After 1 h at 80° C., the reaction mixture was cooled to −78° C. To this solution was added 0.498 mL (4.186 mmol) thionyl chloride. After 30 minutes at −78° C., 5 mL (12.358 mmol) ethylmagnesium bromide (3.0M solution in diethyl ether) was added dropwise. After 1 h at −78° C., the reaction mixture was quenched with saturated NH4Cl and warmed to room temperature. The reaction mixture was extracted three times with EtOAc and washed with brine. The organic layer was dried over NaSO4, filtered and concentrated in vacuo. Purification by flash chromatography (1×14 cm silica gel, linear gradient 0-50% EtOAc:hexane) afforded 4-ethyl-5,6-difluoro-4-(4-fluorophenyl)-3-(2,2,2-trifluoroethyl)-3,4-dihydroquinazolin-2(1H)-one. Chiral Separation (ChiralPak AD column, 5 cm×50 cm, 20μ, 10-40% ethanol/hexane, modifier: DEA 1 mL/L, 60 mins) afforded 350 mg of the second isomer.

Aufarbeitung

  1. waitAfter 30 minutes at −78° C.
  2. waitAfter 1 h at −78° C.
  3. customthe reaction mixture was quenched with saturated NH4Cl
  4. temperaturewarmed to room temperature
  5. extractionThe reaction mixture was extracted three times with EtOAc
  6. washwashed with brine
  7. dry with materialThe organic layer was dried over NaSO4
  8. filtrationfiltered
  9. concentrationconcentrated in vacuo
  10. customPurification by flash chromatography (1×14 cm silica gel, linear gradient 0-50% EtOAc:hexane)

Quellen und Nachweise

ORD-Eintrag
ord-42b83f343627477086aea8b9bda4a116
Quelldatensatz
uspto-grants-2010_06
DOI
10.6084/m9.figshare.5104873.v1
Patentnummer
US07745452B2

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