反应详情

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.

1. temperatureThe reaction mixture was heated
2. temperatureat reflux for 20 h
3. customThe reaction mixture was transferred to a separatory funnel
4. extractionextracted with EtOAc
5. extractionthe organic extract
6. washwas washed with brine
7. dry with materialdried over Na2SO4
8. filtrationfiltered
9. concentrationconcentrated
10. customto give a solid
11. customThe resulting solid was triturated with dicholormethane
12. filtrationThe suspension was filtered
13. customthe filtered solid was dried
14. customto give 0.37 g of the crude product
15. customThe crude product was used without further purification
16. customat RT
17. temperatureThe reaction mixture was heated
18. temperatureat reflux for 2.5 h
19. temperatureThe reaction mixture was heated
20. temperatureat reflux under a nitrogen atmosphere for 2 h
21. temperatureThe reaction mixture was cooled to room temperature
22. filtrationThe reaction was filtered through a pad of Celite
23. washthe pad was washed with EtOAc
24. customThe filtrate was transferred to a separatory funnel
25. customthe layers were separated
26. extractionThe aqueous layer was extracted with EtOAc
27. washthe combined organic extracts were washed with brine
28. dry with materialdried over Na2SO4
29. filtrationfiltered
30. concentrationconcentrated
31. custompartially purified by flash chromatography with a CH2Cl2