Reaction equation
[F:1][C:2]1[C:3]([O:30][CH3:31])=[C:4]([CH:8]([CH3:29])[CH2:9][C:10]([C:25]([F:28])([F:27])[F:26])([OH:24])[CH:11]=NC2C=CC=C3C=2C=CC(C)=N3)[CH:5]=[CH:6]C=1.B(Br)(Br)Br.C([O-])(O)=[O:37].[Na+].[CH2:41]([Cl:43])Cl>>[Cl:43][C:41]1[CH:6]=[CH:5][C:4]([CH:8]([CH3:29])[CH2:9][C:10]([OH:24])([C:25]([F:26])([F:27])[F:28])[CH:11]=[O:37])=[C:3]([O:30][CH3:31])[C:2]=1[F:1]Participants
Conditions
- Temperature
- -5 °C
Procedure
100 mg (0.3 mmol) of 4-(4-chloro-3-fluoro-2-methoxyphenyl)-2-hydroxy-2-(trifluoromethyl)pentanal, 48 mg (0.3 mmol) of 5-amino-2-methylquinazoline and 0.1 ml of titanium tetraethoxide are stirred in 9 ml of toluene at 100° C. for 2 h. After cooling, the mixture is poured into water and stirred vigorously. The suspension is filtered through Celite, the filter bed being rinsed thoroughly with ethyl acetate. The phases of the filtrate are separated and extraction is carried out again with ethyl acetate. The extracts are dried over sodium sulphate and the solvent is removed in vacuo to give 130 mg of 4-(3-fluoro-2-methoxyphenyl)-1-[(2-methylquinolin-5-yl)imino]-2-(trifluoromethyl)pentan-2-ol as a crude product. 130 mg of the crude imine in 6 ml of CH2Cl2 are admixed dropwise at −30° C. with 3 ml (3 mmol) of a 1 M of boron tribromide solution. The batch is allowed to warm to −5° C. over 3 hours. It is admixed with saturated NaHCO3 solution, the phases are separated, the aqueous phase is extracted with ethyl acetate and the combined organic phases are dried (Na2SO4) and concentrated in vacuo. Column chromatography on silica gel (hexane/ethyl acetate 0-75%) yields 30 mg as a mixture of the title compound and 5α,6α,8β)-3-chloro-2-fluoro-8-methyl-5-[(2-methylquinazolin-5-yl)amino]-6-(trifluoromethyl)-5,6,7,8-tetrahydronaphthalene-1,6-diol (Ex. 23). Preparative thin-layer chromatography on amine phase (Merck) with ethyl acetate/methanol/triethylamine 25:3:1 yields 5 mg of product.
Workup
- customthe phases are separated
- extractionthe aqueous phase is extracted with ethyl acetate
- dry with materialthe combined organic phases are dried (Na2SO4)
- concentrationconcentrated in vacuo
- customColumn chromatography on silica gel (hexane/ethyl acetate 0-75%) yields 30 mg
Sources & evidence
- ORD record
- ord-e19bf8a964f1490c94230e3b11daf3c5
- Source dataset
- uspto-grants-2011_02
- Patent number
- US07880042B2
Linked notes
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