Acetic Acid → Way-196025

Temperature

-9 °C

A solution of boron trifluoride etherate (55 g, 0.387 mol) and methylene chloride (75 mL) was added over 10 min to a stirred, cooled (−20° C.) mixture of N-[2-(1-benzhydryl-5-chloro-1H-indol-2-yl)-ethyl]-C-(2,6-dimethylphenyl)-methanesulfonamide (300 g, 0.552 mol), triethylsilane (192 g,1.66 mol), 4-(3-oxo-propyl)-benzoic acid ethyl ester (250 g, 1.21 mol), and methylene chloride (2.8 L). An exotherm was observed and the reaction temperature increased to −9° C. The reaction mixture was cooled to and maintained at −20° C. Trifluoroacetic acid (63 g, 0.553 mol) was added to the reaction mixture 30 min after complete addition of boron trifluoride. The reaction mixture was stirred at −20° C. for 2 h. The reaction mixture was added to a stirred solution of sodium bicarbonate (138 g, 1.64 mol) and water (1.50 L). The mixture was filtered through a celite pad and the pad was washed with methylene chloride (150 mL). The layers were separated. The aqueous layer was washed with methylene chloride (300 mL). The combined organic layers were concentrated to 1.2 L at ambient pressure. Ethanol (1.50 L) was added to the mixture. The mixture was concentrated to 1.2 L at ambient pressure. The stirred mixture was cooled to 50° C. and tetrahydrofuran (450 mL) and 50% aqueous sodium hydroxide (221 g, 2.76 mol) was added. The mixture was warmed to reflux for 30 min. The mixture was cooled to 50° C. and toluene (1.50 L), water (300 mL), and acetic acid (166 g, 2.76 mol) was added. The mixture was stirred for 30 min. The mixture was filtered through a celite pad. The layers were separated and the aqueous layer was washed with a solution of tetrahydrofuran and toluene (1/1 v/v, 100 mL). The organic layer was washed consecutively with 3% aqueous sodium bicarbonate (100 ml), saturated sodium chloride (100 mL), and water (2×125 mL). The organic layer was concentrated to 1.2 L at ambient pressure. Toluene (600 mL) was added and the mixture was concentrated to 1.2 L at ambient pressure. The mixture was allowed to cool to room temperature and stirred overnight. Heptane (100 mL) was added to the stirred mixture after precipitation of solid product was observed. The solid product was collected by filtration and washed with cold toluene (3×300 mL). The product was vacuum dried at 66° C. to give 4-{3-[1-benzhydryl-5-chloro-2-(2-{[(2,6-dimethylbenzyl)sulfonyl]-amino}ethyl)-1H-indol-3-yl]propyl}benzoic acid (317 g, 81%) with a purity of 96% (as determined by HPLC). The product can be recrystallized from ethanol/water in 91% recovery. MP 193° C.

1. temperaturecooled
2. temperatureThe reaction mixture was cooled to and
3. temperaturemaintained at −20° C
4. filtrationThe mixture was filtered through a celite pad
5. washthe pad was washed with methylene chloride (150 mL)
6. customThe layers were separated
7. washThe aqueous layer was washed with methylene chloride (300 mL)
8. concentrationThe combined organic layers were concentrated to 1.2 L at ambient pressure
9. additionEthanol (1.50 L) was added to the mixture
10. concentrationThe mixture was concentrated to 1.2 L at ambient pressure
11. temperatureThe stirred mixture was cooled to 50° C.
12. temperatureThe mixture was warmed
13. temperatureto reflux for 30 min
14. temperatureThe mixture was cooled to 50° C.
15. stirringThe mixture was stirred for 30 min
16. filtrationThe mixture was filtered through a celite pad
17. customThe layers were separated
18. washthe aqueous layer was washed with a solution of tetrahydrofuran and toluene (1/1 v/v, 100 mL)
19. washThe organic layer was washed consecutively with 3% aqueous sodium bicarbonate (100 ml), saturated sodium chloride (100 mL), and water (2×125 mL)
20. concentrationThe organic layer was concentrated to 1.2 L at ambient pressure
21. additionToluene (600 mL) was added
22. concentrationthe mixture was concentrated to 1.2 L at ambient pressure
23. temperatureto cool to room temperature
24. stirringstirred overnight
25. additionHeptane (100 mL) was added to the stirred mixture
26. customafter precipitation of solid product
27. filtrationThe solid product was collected by filtration
28. washwashed with cold toluene (3×300 mL)
29. customdried at 66° C.

ORD record

ord-8d54f20a3cd24d8e9091501c19d67ddf

Source dataset

uspto-grants-2009_09

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07582772B2