Cycloheptanone → 4-[Cycloheptylidene-(3-fluoro-4-hydroxy-phenyl)-methyl]-benzoic acid (HRID 1716100)｜HGS AIchem

실험 절차

AlCl3 (0.97 g, 7.28 mmol) was added portionwise via an addition funnel to a solution of 4-(3-fluoro-4-methoxy-benzoyl)-benzoic acid methyl ester (73) (0.50 g, 1.73 mmol) in toluene (8 mL). The reaction mixture was heated at reflux for 20 h and allowed to cool to RT. Water (10 mL) was slowly added to the reaction mixture. The reaction mixture was transferred to a separatory funnel and extracted with EtOAc, the organic extract was washed with brine, dried over Na2SO4, filtered, and concentrated to give a solid. The resulting solid was triturated with dicholormethane. The suspension was filtered, and the filtered solid was dried to give 0.37 g of the crude product as a mixture of 4-(3-fluoro-4-hydroxy-benzoyl)-benzoic acid and 4-(3-fluoro-4-hydroxy-benzoyl)-benzoic acid methyl ester according to 1H NMR and LCMS (ESI). The crude product was used without further purification. To a slurry of zinc powder (0.67 g, 10.3 mmol) in dry THF (11 mL) was slowly added TiCl4 (0.55 mL, 4.99 mmol) at RT under a nitrogen atmosphere. The reaction mixture was heated at reflux for 2.5 h. To the reaction mixture was added a solution of cycloheptanone (0.48 mL, 4.05 mmol) and the aforementioned mixture of 4-(3-fluoro-4-hydroxy-benzoyl)-benzoic acid and 4-(3-fluoro-4-hydroxy-benzoyl)-benzoic acid methyl ester (0.37 g) in dry tetrahydrofuran (11 mL). The reaction mixture was heated at reflux under a nitrogen atmosphere for 2 h. The reaction mixture was cooled to room temperature, water (15 mL) was added followed by 10% K2CO3 (15 mL). The reaction was filtered through a pad of Celite, and the pad was washed with EtOAc. The filtrate was transferred to a separatory funnel and the layers were separated. The aqueous layer was extracted with EtOAc and the combined organic extracts were washed with brine, dried over Na2SO4, filtered and concentrated. The crude material was loaded onto silica gel and partially purified by flash chromatography with a CH2Cl2:MeOH gradient (100:0 to 98:2) to yield the impure title compound (0.15 g) as well as impure 4-[cycloheptylidene-(3-fluoro-4-hydroxy-phenyl)-methyl]-benzoic acid methyl ester (0.22 g) according to 1H NMR. The impure benzoic acid was purified by reverse phase preparative HPLC using a C-18 column and a CH3CN:H2O gradient (50:50 to 100:0) with 0.05% TFA as a modifier to give 0.072 g (12% based on 4-(3-fluoro-4-methoxy-benzoyl)-benzoic acid methyl ester) of compound 174 as a yellow amorphous solid. 1H NMR (400 MHz, DMSO-d6): δ 1.51 (m, 8H), 2.16 (m, 2H), 2.18 (m, 2H), 6.71 (d, J=1.8 Hz, 1H), 6.75-6.88 (m, 2H), 7.21 (d, J=8 Hz, 2H), 7.85 (d, J=8.2 Hz, 2H), 9.76 (s, 1H), 12.84 (s, 1H). HRMS (ESI) Calcd for C21H20FO3: 339.1396 (M−H)−. Found: 339.1411.