Dimethylformamide → N-[2-(1-benzhydryl-5-chloro-1H-indol-2-yl)-ethyl]-C-(2,6-dimethylphenyl)-methanesulfonamide

Temperature

55 °C

A warm (40-45° C.) solution of N-Boc-N-but-3-ynyl-(2,6-dimethylphenyl)-methanesulfonamide (44.4 g, 0.106 mol), dichlorobis(triphenylphosphine)palladium (II) (0.50 g, 0.713 mmol), and DMF (125 mL) was added slowly over 7 h to a warm (55° C.), stirred mixture of benzhydryl-(4-chloro-2-iodo-phenyl)-amine (50 g, 0.119 mol), dichlorobis(triphenylphosphine)palladium (II) (0.50 g, 0.713 mmol), copper (I) iodide (3.0 g, 15.7 mmol), triethylamine, (42.2 g, 0.418 mol), and DMF (75 mL). Toluene (250 mL) and water (250 mL) were added to the reaction mixture. The aqueous phase was separated and washed with toluene (2×100 mL). The combined organic phases were filtered through a celite pad. The filtrate was washed with an 8.3% aqueous solution of N-acetylcysteine (2×150 mL), then again with water (150 mL). The organic phase was washed with 5% aqueous sodium bicarbonate (150 mL), then again with water (150 mL). The organic phase was concentrated to a heavy oil under reduced pressure. The oil was dissolved in N,N-dimethylacetamide (DMA, 175 mL). This DMA solution was added over 1 hour to a stirred mixture of copper iodide (2.26 g, 11.8 mmol) and DMA at 150° C. The reaction mixture was stirred at 150° C. for an additional 2.25 hours. The reaction mixture was cooled to room temperature and filtered through a celite pad with a DMA wash (2×25 mL). 2-Propanol (400 mL) was added to the warmed (45-40° C.), stirred filtrate. Then water (600 mL) was added to the stirred, warm (45-50° C.) mixture over 1 hour. The mixture was cooled to room temperature and stirred for a minimum of 12 hours. The solid was collected by filtration and washed with 2-propanol (2×50 mL). The solid was vacuum dried at 50° C. to give N-[2-(1-benzhydryl-5-chloro-1H-indol-2-yl)-ethyl]-C-(2,6-dimethylphenyl)-methanesulfonamide (60.6 g, 94%) with 98% purity (as determined by HPLC).

1. additionwas added slowly over 7 h to
2. customThe aqueous phase was separated
3. washwashed with toluene (2×100 mL)
4. filtrationThe combined organic phases were filtered through a celite pad
5. washThe filtrate was washed with an 8.3% aqueous solution of N-acetylcysteine (2×150 mL)
6. washThe organic phase was washed with 5% aqueous sodium bicarbonate (150 mL)
7. concentrationThe organic phase was concentrated to a heavy oil under reduced pressure
8. dissolutionThe oil was dissolved in N,N-dimethylacetamide (DMA, 175 mL)
9. stirringThe reaction mixture was stirred at 150° C. for an additional 2.25 hours
10. temperatureThe reaction mixture was cooled to room temperature
11. filtrationfiltered through a celite pad with a DMA
12. washwash (2×25 mL)
13. addition2-Propanol (400 mL) was added to the
14. temperaturewarmed (45-40° C.)
15. stirringstirred filtrate
16. additionThen water (600 mL) was added to the stirred
17. temperaturewarm (45-50° C.) mixture over 1 hour
18. temperatureThe mixture was cooled to room temperature
19. stirringstirred for a minimum of 12 hours
20. filtrationThe solid was collected by filtration
21. washwashed with 2-propanol (2×50 mL)
22. customdried at 50° C.

ORD record

ord-67373096ecf642a895553a6d7ca882a2

Source dataset

uspto-grants-2009_09

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07582772B2