Reaktion #818578

Reaktionsgleichung

acetic acid

N-[2-(1-benzhydryl-5-chloro-1H-indol-2-yl)-ethyl]-C-(3,4-dichloro-phenyl)-methanesulfonamide

triethylsilane

4-(3-oxo-propyl)-benzoic acid ethyl ester

Trifluoroacetic acid

sodium bicarbonate

boron trifluoride

boron trifluoride etherate

sodium hydroxide

→

4-{3-[1-benzhydryl-5-chloro-2-(2-{[(3,4-dichlorobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]propyl}benzoic acid

Ausbeute 85.2%

Lösungsmittel

water

toluene

methylene chloride

water

methylene chloride

tetrahydrofuran

Reaktionsbedingungen

Aufarbeitung

1. 1
   Temperaturcooled
2. 2
   TemperaturThe reaction mixture was cooled to and
3. 3
   Temperaturmaintained at −20° C
4. 4
   FiltrationThe mixture was filtered through a celite pad
5. 5
   Waschenthe pad was washed with methylene chloride (50 mL)
6. 6
   SonstigeThe layers were separated
7. 7
   WaschenThe aqueous layer was washed with methylene chloride (200 mL)
8. 8
   EinengenThe combined organic layers were concentrated to 1.1 L at ambient pressure
9. 9
   workup.ADDITIONEthanol (1.38 L) was added to the mixture
10. 10
    EinengenThe mixture was concentrated to 1.1 L at ambient pressure
11. 11
    TemperaturThe stirred mixture was cooled to 50° C.
12. 12
    TemperaturThe mixture was warmed
13. 13
    Temperaturto reflux for 30 min
14. 14
    TemperaturThe mixture was cooled to 50° C.
15. 15
    workup.STIRRINGThe mixture was stirred for 30 min
16. 16
    FiltrationThe mixture was filtered through a celite pad
17. 17
    SonstigeThe layers were separated
18. 18
    Waschenthe aqueous layer was washed with a solution of tetrahydrofuran and toluene (1/1 v/v, 100 mL)
19. 19
    WaschenThe organic layer was washed consecutively with 3% aqueous sodium bicarbonate (100 ml), saturated sodium chloride (100 mL), and water (2×125 mL)
20. 20
    EinengenThe organic layer was concentrated to 1.1 L at ambient pressure
21. 21
    workup.ADDITIONToluene (550 mL) was added
22. 22
    Einengenthe mixture was concentrated to 1.1 L at ambient pressure
23. 23
    Temperaturto cool to room temperature
24. 24
    workup.STIRRINGstirred overnight
25. 25
    workup.ADDITIONHeptane (110 mL) was added to the stirred mixture
26. 26
    Sonstigeafter precipitation of solid product
27. 27
    FiltrationThe solid product was collected by filtration
28. 28
    Waschenwashed with cold toluene (2×275 mL)
29. 29
    Sonstigedried at 66° C.

Vorschrift

A solution of boron trifluoride etherate (50.7 g, 0.357 mol) and methylene chloride (83 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-(3,4-dichloro-phenyl)-methanesulfonamide (275 g, 0.471 mol), triethylsilane (1.42 mol), 4-(3-oxo-propyl)-benzoic acid ethyl ester (213.6 g, 1.04 mol), and methylene chloride (2.6 L). An exotherm was observed and the reaction temperature increased to −13° C. The reaction mixture was cooled to and maintained at −20° C. Trifluoroacetic acid (53.7 g, 0.471 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 (127 g, 1.51 mol) and water (1.37 L). The mixture was filtered through a celite pad and the pad was washed with methylene chloride (50 mL). The layers were separated. The aqueous layer was washed with methylene chloride (200 mL). The combined organic layers were concentrated to 1.1 L at ambient pressure. Ethanol (1.38 L) was added to the mixture. The mixture was concentrated to 1.1 L at ambient pressure. The stirred mixture was cooled to 50° C. and tetrahydrofuran (275 mL) and 50% aqueous sodium hydroxide (188 g, 2.35 mol) was added. The mixture was warmed to reflux for 30 min. The mixture was cooled to 50° C. and toluene (1.38 L), water (225 mL), and acetic acid (141 g, 2.35 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 1.1 L at ambient pressure. Toluene (550 mL) was added and the mixture was concentrated to 1.1 L at ambient pressure. The mixture was allowed to cool to room temperature and stirred overnight. Heptane (110 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 (2×275 mL). The product was vacuum dried at 66° C. to give 4-{3-[1-benzhydryl-5-chloro-2-(2-{[(3,4-dichlorobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]propyl}benzoic acid (227 g, 65%) with a purity of 99% (as determined by HPLC). The product can be recrystallized from ethanol in 91% recovery. MP 190° C.

Quelle