Diisopropylamine → o-Fluorobenzaldehyde

Temperatur

-78 °C

A solution of diisopropylamine (0.60 mL, 4.57 mmol) in tetrahydrofuran (27 mL) was chilled to -78° C. and butyllithium (1.30 mL, 3.25 mmol, 2.5 N in hexanes) was added dropwise. The solution was stirred 10 minutes and then a solution 3-(2-chloro-phenyl)-6-fluoro-2-methyl-3H-quinazolin-4-one (1.04 g, 3.60 mmol) in tetrahydrofuran (7 mL) was added dropwise. The solution became intense red and was stirred 30 minutes. In a separate vessel a solution of 2-fluorobenzaldehyde (0.575 mL, 6.33 mmol) in tetrahydrofuran (20 mL) was prepared and chilled to -78 ° C. The cold red anion solution was added to the cold methyl 2-fluorobenzaldehyde solution via canula over 30 seconds. The resulting mixture was stirred 1 hour at -78° C. and then quenched with saturated aqueous bicarbonate and warmed to ambient temperature. The mixture was concentrated and the residue was diluted with water (50 mL), ethyl acetate (10 mL) and saturated aqueous sodium bisulfite (50 mL). This mixture was stirred 1 h and then repeatedly extracted with ethyl acetate. The combined extracts were washed with water and brine, dried over magnesium sulfate and concentrated. The residues from the two side by side reactions were combined and flash chromatographed on silica gel (45×150 mm) with elution proceeding as follows: 20% ethyl acetate/hexane (500 mL), nil; 30% ethyl acetate/hexane (500 mL) and 40% ethyl acetate/hexane (500 mL), two diastereomers of 3-(2-chloro-phenyl)-6-fluoro-2-[2-(2-fluoro-phenyl)-2-hydroxy-ethyl]-3H-quinazolin-4-one, both as viscous oils. The faster eluting diastereomer weighed 0.231 g (17%) and had: 1H NMR δ7.92 (dd, J=3, 8.5 Hz, 1 H), 7.77 (dd, J=5, 9 Hz, 1 H), 7.60 (dd, J=1.5, 7.5 Hz, 1 H), 7.57-7.55 (m, 1 H), 7.53 (dd, J=3,8 Hz, 1 H), 7.48-7.42 (sym m, 2 H), 7.36-7.31 (m, 1 H), 7.24-7.18 (m,1 H), 7.12 (t, J=7.5 Hz, 1 H), 6.96-6.90 (m, 1 H), 5.65 (br s, 1 H), 5.55 (dd, J=2.5, 9 Hz, 1 H), 2.70 (dd, J=2.5, 17 Hz, 1 H), 2.61 (dd, J=9, 17 Hz, 1 H). The slower eluting diastereomer weighed 0.283 g (21%) and had: 1H NMR δ7.91 (dd, J=3, 9 Hz, 1 H), 7.76 (dd, J=5, 9 Hz, 1 H), 7.58 (dd, J=1.5, 8 Hz, 1 H), 7.54 (dd, J=3, 9 Hz, 1 H), 7.51 (dd, J=1.5, 8 Hz, 1 H), 7.44 (dt, J=2, 8 Hz, 1 H), 7.39 (dt, J=1.5, 8 Hz, 1 H), 7.23-7.17 (m, 1 H), 7.13-7.07 (m, 2 H), 6.98-6.91 (m, 1 H), 5.61 (br s, 1 H), 5.57 (dd, J=4, 8 Hz, 1 H), 2.72-2.60 (m, 2 H).

1. stirringwas stirred 30 minutes
2. stirringThe resulting mixture was stirred 1 hour at -78° C.
3. customquenched with saturated aqueous bicarbonate
4. temperaturewarmed to ambient temperature
5. concentrationThe mixture was concentrated
6. additionthe residue was diluted with water (50 mL), ethyl acetate (10 mL) and saturated aqueous sodium bisulfite (50 mL)
7. stirringThis mixture was stirred 1 h
8. extractionrepeatedly extracted with ethyl acetate
9. washThe combined extracts were washed with water and brine
10. dry with materialdried over magnesium sulfate
11. concentrationconcentrated
12. customflash chromatographed on silica gel (45×150 mm) with elution proceeding
13. washThe faster eluting diastereomer
14. washThe slower eluting diastereomer

ORD-Eintrag

ord-6dedee4f0cb6484f84591e867df20df9

Quelldatensatz

uspto-grants-2000_05

DOI

10.6084/m9.figshare.5104873.v1

Patentnummer

US06060479