Acetic Acid → Efipladib

温度

-20 °C

N-[2-(1-Benzhydryl-5-chloro-1H-indol-2-yl)-ethyl]-C-(3,4-dichlorophenyl)-methanesulfonamide (20.0 g, 34.25 mmol), 4-(3-Oxo-propyl)-benzoic acid ethyl ester (10.5 g, 50.97 mmol), triethylsilane (12.0 g, 103.5 mmol), magnesium sulfate (0.30 g), and dichloromethane (100 mL) were combined, stirred, and cooled to −20° C. A solution of boron trifluoride diethyl etherate (3.26 g, 22.96 mmol) in dichloromethane (10 mL) was added to the reaction mixture over 2 min. After 40 min, trifluoroacetic acid (1.95 g, 17.11) was added to the reaction mixture. After three hours, the reaction mixture was filtered cold through a celite pad into aqueous sodium bicarbonate (9 g/100 mL). The organic layer was concentrated to 60 g, then methanol (100 mL) was added. The solution was concentrated to 82 g. Methanol (40 mL) and aqueous sodium hydroxide (8.2 g of a 50% solution, 102.5 mmol) were added to the mixture. The mixture was stirred and warmed to 65° C. for 6 h. After cooling the reaction mixture to room temperature, acetic acid (6.2 g, 102.5 mmol) was added and the solvent (40 g) was removed. Toluene (200 mL) and water (50 mL) were added to the mixture. The organic layer was separated and washed with water (10 mL), then concentrated to 78 g. The solid product was collected by filtration after standing overnight, then recrystallized from 10 parts of toluene to give 13.2 g (52%) of the title compound. 1H NMR (DMSO-d6): δ12.80 (br.s, 1H), 7.89 (d, 2H, J=2 Hz), 7.59 (d, 1H, J=1.5 Hz), 7.53 (d, 1H, J=6 Hz), 7.48 (d, 1H, J=1.5 Hz), 7.38 (m, 9H), 7.20 (m, 5H), 6.77 (dd, 1H, J=6.9 & 1.5 Hz), 6.46 (d, 1H, J=6.9 Hz), 4.36 (s, 2H), 3.18 (m, 2H), 2.96 (m, 2H), 2.76 (m, 4H), 1.90(m, 2H). MS: 744 MW, 99.8%.

1. waitAfter three hours
2. filtrationthe reaction mixture was filtered cold through a celite pad into aqueous sodium bicarbonate (9 g/100 mL)
3. concentrationThe organic layer was concentrated to 60 g
4. additionmethanol (100 mL) was added
5. concentrationThe solution was concentrated to 82 g
6. additionMethanol (40 mL) and aqueous sodium hydroxide (8.2 g of a 50% solution, 102.5 mmol) were added to the mixture
7. stirringThe mixture was stirred
8. temperaturewarmed to 65° C. for 6 h
9. temperatureAfter cooling the reaction mixture to room temperature
10. customthe solvent (40 g) was removed
11. additionToluene (200 mL) and water (50 mL) were added to the mixture
12. customThe organic layer was separated
13. washwashed with water (10 mL)
14. concentrationconcentrated to 78 g
15. filtrationThe solid product was collected by filtration
16. waitafter standing overnight
17. customrecrystallized from 10 parts of toluene

ORDレコード

ord-5db98af86727488ca26f0adfe6d4b4cb

出典データセット

uspto-grants-2007_10

DOI

10.6084/m9.figshare.5104873.v1

特許番号

US07282594B2