1. 2-Bromoaniline (20.9 g) and 5-(methoxymethylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (22.6 g) were suspended in 2-propanol (240 mL) and heated to reflux for 1 hour. After completion of the reaction, it was cooled to 0 °C and the light yellow solid product (35.0 g) was collected by filtration.
2. The light yellow solid (10.0 g) obtained above was suspended in Dowtherm (100 mL) and heated at 210 °C for 1 hour. After cooling, hexane (100 mL) was added and filtered to obtain 8-bromoquinolin-4(1H)-one (6.3 g).
3. To 8-bromoquinolin-4(1H)-one (9 g) was added phosphoryl chloride (5.9 mL) and the mixture was heated to reflux for 2 hours. The solvent was removed by distillation under reduced pressure, the residue was dissolved in chloroform, neutralized with aqueous sodium hydroxide, and the organic and aqueous layers were separated after cooling in an ice bath. The organic layer was washed with brine, dried over anhydrous sodium sulfate, distilled to remove the solvent, and purified by neutral silica gel column chromatography (chloroform/methanol) to give 8-bromo-4-chloroquinoline (8.3 g) as a white solid.
4. Pd(PPh3)4 (0.0581 g) was added to a mixture of 8-bromo-4-chloroquinoline (0.242 g), 3-quinolineboronic acid (0.163 g) and 2M aqueous sodium carbonate under nitrogen protection, ethylene glycol dimethyl ether (3.0 mL) was added, and the reaction was stirred for 3 hours at 85 °C. Upon completion of the reaction, the mixture was partitioned with ethyl acetate and water, the organic layer was washed with brine, dried over anhydrous sodium sulfate, the solvent was removed by distillation, and the residue was purified by neutral silica gel column chromatography (chloroform/methanol) to afford 4'-chloro-3,8'-biquinoline (0.114 g) as a white solid.
5. The reaction was carried out according to the method of Example 3 (3) using the 4'-chloro-3,8'-biquinoline obtained above instead of compound (3b) to obtain the target compound (117) as a pale yellow solid (total yield in six steps: 37%).
6. 4-Cyano-3-(4-hydroxycyclohexylamino)benzeneboronic acid pinacol ester was used instead of 4-cyano-3-(ethylamino)benzeneboronic acid pinacol ester for the subsequent reaction.
