反应详情

A solution of 4-(1-(4-fluorophenyl)-1H-indazol-6-yl)butanoic acid (3, R1=4-Fluorophenyl) (13.86 g, 46.5 mmol) in DCM (225 mL) was treated with oxalyl dichloride (2M in DCM) (25.6 mL, 51.1 mmol). Two drops of DMF were added and the mixture was stirred for about 45 min at rt. A second portion of oxalyl dichloride (2M in DCM) (4.65 mL, 9.29 mmol) was added followed by 1 drop DMF. After about 15 min the solvent was removed under reduced pressure. The material was dissolved in DCM (225 mL) and the flask was fitted with a reflux condenser. Aluminum trichloride (8.2 g, 61.5 mmol) was added and the mixture was stirred for about 30 min. A second portion of aluminum trichloride (7.67 g, 57.5 mmol) was added to the mixture and stirring was continued for about 30 min. The reaction was quenched by slow addition of ice in small portions over about 30-45 min with vigorous stirring. After addition of about 50 g of ice, the biphasic mixture was transferred to a separatory funnel and the layers were separated. The aqueous layer was extracted with DCM (30 mL) and the combined organic solutions were washed with water (75 mL), 0.5 N aq. sodium hydroxide (100 mL) and brine (50 mL). The organic mixture was dried over MgSO4, filtered and concentrated under reduced pressure to a solid. The material was purified on silica gel (330 g) using a gradient of 0-15% EtOAc in DCM. Fractions containing >95% desired product were combined and concentrated under reduced pressure. Fractions containing desired product contaminated with the minor regioisomer [1-(4-fluorophenyl)-7,8-dihydro-1H-benzo[g]indazol-9(6H)-one] were combined and concentrated under reduced pressure separately. The residue was purified on silica gel (80 g) using a gradient of 0-10% EtOAc in DCM. Fractions containing >95% desired product were combined with those from the first column and concentrated under reduced pressure to yield 1-(4-fluorophenyl)-7,8-dihydro-1H-benzo[f]indazol-5(6H)-one (4, R1=4-Fluorophenyl) (8.73 g, 67%); LC/MS, method 3, Rt=2.43 min, MS m/z 281 (M+H)+. 1H NMR (400 MHz, DMSO) δ 8.52 (d, J=0.9 Hz, 1H), 8.49 (s, 1H), 7.86-7.78 (m, 2H), 7.69 (s, 1H), 7.51-7.41 (m, 2H), 3.12-3.09 (m, 2H), 2.70-2.63 (m, 2H), 2.11-2.02 (m, 2H). Note: 1H NMR shows ˜4% minor regioisomer.

1. customAfter about 15 min the solvent was removed under reduced pressure
2. dissolutionThe material was dissolved in DCM (225 mL)
3. customthe flask was fitted with a reflux condenser
4. stirringthe mixture was stirred for about 30 min
5. stirringstirring
6. waitwas continued for about 30 min
7. customThe reaction was quenched by slow addition of ice in small portions over about 30-45 min with vigorous stirring
8. additionAfter addition of about 50 g of ice
9. customthe biphasic mixture was transferred to a separatory funnel
10. customthe layers were separated
11. extractionThe aqueous layer was extracted with DCM (30 mL)
12. washthe combined organic solutions were washed with water (75 mL), 0.5 N aq. sodium hydroxide (100 mL) and brine (50 mL)
13. dry with materialThe organic mixture was dried over MgSO4
14. filtrationfiltered
15. concentrationconcentrated under reduced pressure to a solid
16. customThe material was purified on silica gel (330 g)
17. additionFractions containing >95% desired product
18. concentrationconcentrated under reduced pressure
19. additionFractions containing desired product
20. concentrationconcentrated under reduced pressure separately
21. customThe residue was purified on silica gel (80 g)
22. additionFractions containing >95% desired product
23. concentrationconcentrated under reduced pressure