Reaktion #818133

Reaktionsgleichung

HCl

bis(trimethylsilyl)trifluoroacetamide

pyridine

(3,4-Dichloro-phenyl)-methanesulfonyl chloride

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

→

4-(3-{1-Benzhydryl-5-chloro-2-[2-(3,4-dichloro-phenylmethanesulfonylamino)-ethyl]-1H-indol-3-yl}-propyl)-benzoic acid

Ausbeute 72.0%

Lösungsmittel

Water

dichloromethane

heptane

toluene

dichloromethane

Reaktionsbedingungen

Aufarbeitung

1. 1
   TemperaturAfter refluxing for 0.5 hours
2. 2
   TemperaturThe reaction mixture was refluxed for 0.5 h
3. 3
   Temperaturcooled to room temperature
4. 4
   WaschenThe organic layer was washed with water (600 mL×2)
5. 5
   Einengenconcentrated
6. 6
   workup.DISSOLUTIONThe concentrate was dissolved in 2-propanol (710 mL)
7. 7
   workup.ADDITIONadded to cold water (2.45 L)
8. 8
   Sonstigethe crude product (173.0 g, yield 97%, HPLC 78%, SLI 11%) was collected
9. 9
   Filtrationafter filtration

Vorschrift

To a suspension of 4-{3-[2-(2-Amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]-propyl}-benzoic acid (125.0 g, 0.239 mol) in dichloromethane (1.25 L) at ambient temperature, bis(trimethylsilyl)trifluoroacetamide (89.2 g, 0.347 mol) was added. After refluxing for 0.5 hours, the reaction mixture was cooled to 35° C. To the reaction mixture solution, pyridine (49.1 g, 0.621 mol) and a solution of (3,4-Dichloro-phenyl)-methanesulfonyl chloride (68.2 g, 0.263 mol) in dichloromethane (200 mL) were added successively. The reaction mixture was refluxed for 0.5 h and then cooled to room temperature. Water (1.25 L) and conc.HCl (61.6 g) were added to the reaction mixture successively. The organic layer was washed with water (600 mL×2) and concentrated. The concentrate was dissolved in 2-propanol (710 mL) added to cold water (2.45 L) and the crude product (173.0 g, yield 97%, HPLC 78%, SLI 11%) was collected after filtration. Pure 4-(3-{1-Benzhydryl-5-chloro-2-[2-(3,4-dichloro-phenylmethanesulfonylamino)-ethyl]-1H-indol-3-yl}-propyl)-benzoic acid (WAY-195902, 125.0 g, yield 72%, HPLC 98%, SLI 033%) was obtained by successive treatment of the crude product with a mixture of toluene and heptane followed by a mixture of ethyl acetate and heptane. 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).

Quelle