Water → 4-(3-Fluoro-2-methoxyphenyl)-1-[(2-methylquinazolin-5-yl)imino]-2-(trifluoromethyl)heptan-2-ol

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Reaction Steps

300 mg (0.97 mmol) of 4-(3-fluoro-2-methoxyphenyl)-2-hydroxy-2-(trifluoromethyl)heptanal and 138 mg (0.87 mmol) of 5-amino-2-methylquinazoline are dissolved in 28 ml of toluene and the solution is admixed with 0.48 ml of titanium tetraethoxide. The reaction mixture is heated at 100° for 2 hours, cooled, 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 washed with saturated sodium chloride solution and dried over sodium sulphate and the solvent is removed in vacuo to give 350 mg of crude 4-(3-fluoro-2-methoxyphenyl)-1-[(2-methylquinazolin-5-yl)imino]-2-(trifluoromethyl)heptan-2-ol as a crude product. The crude imine is dissolved in 35 ml of CH2Cl2 and the solution is cooled to −20° C. 5.8 ml (5.8 mmol) of a 1 M BBr3 solution in dichloromethane are added slowly dropwise over 5 minutes and the mixture is allowed to warm to room temperature over 1.5 hours. The reaction solution is poured onto a mixture of saturated NaHCO3 solution and ice. Extraction is carried out repeatedly with ethyl acetate and the extracts are washed with saturated NaCl solution and dried over Na2SO4. Purification by column chromatography on silica gel (hexane/isopropanol 0-15%) and subsequent HPLC separation on chiral stationary phase afford 16 mg of product and 26 mg of the corresponding (5α,6α,8α) compound (Example 62).

Provenance & Evidence