Reaktion #518248

Reaktionsgleichung

3-(1,2,3,6-Tetrahydro-4-pyridinyl)-1H-indole-5-carbonitrile

potassium carbonate

(S)-(−)-2,2′-Bis(di-p-tolylphosphino)-1,1′-binaphthyl

2-bromo-3-[(2S)-oxiranylmethoxy]pyridine

→

desired product

Ausbeute 42.0%

3-{1-[2,3-Dihydro[1,4]dioxino[2,3-b]pyridin-3-ylmethyl]-1,2,3.6-tetrahydro-4-pyridinyl}-1H-indole-5-carbonitrile

Ausbeute 42.0%

Lösungsmittel

DMSO

toluene

Reaktionsbedingungen

Aufarbeitung

1. 1
   TemperaturAfter completion, the reaction was cooled to room temperature
2. 2
   Sonstigepartitioned between 250 mL each of ethyl acetate and saturated sodium bicarbonate
3. 3
   WaschenThe organic phase was washed with brine
4. 4
   Trocknendried over magnesium sulfate
5. 5
   Einengenconcentrated in vacuum
6. 6
   Sonstigechromatographed on silica gel using first methylene chloride as eluant
7. 7
   Sonstigeto remove impurities
8. 8
   Waschen3% methanol in methylene chloride to elute the product, which
9. 9
   TemperaturThe heterogeneous mixture was heated at 100° C. for a period of 30 hours
10. 10
    TemperaturAfter the mixture cooled to room temperature
11. 11
    Sonstigethe catalysts were removed by filtration
12. 12
    Einengenthe filtrate was concentrated in vacuum
13. 13
    Sonstigecolumn chromatographed on silica gel with 3% methanol in methylene chloride

Vorschrift

3-(1,2,3,6-Tetrahydro-4-pyridinyl)-1H-indole-5-carbonitrile (1.62 g, 7.26 mmole) and 2-bromo-3-[(2S)-oxiranylmethoxy]pyridine (0.84 g, 3.65 mmol) were combined in DMSO (40 mL). This solution was heated at 75-80° C. under nitrogen for 5 hours. After completion, the reaction was cooled to room temperature and partitioned between 250 mL each of ethyl acetate and saturated sodium bicarbonate. The organic phase was washed with brine, dried over magnesium sulfate and concentrated in vacuum. The crude residue was column chromatographed on silica gel using first methylene chloride as eluant to remove impurities and then 3% methanol in methylene chloride to elute the product, which was a yellow foam (0.30 g, 18%). The intermediate (0.30 g, 0.66 mmole) was then cyclized in toluene (40 mL) in the presence of palladium (II) acetate (0.015 g, 0.067 mmole), (S)-(−)-2,2′-Bis(di-p-tolylphosphino)-1,1′-binaphthyl (0.032 g, 0.047 mmole), and potassium carbonate (0.13 g, 0.94 mmole). The heterogeneous mixture was heated at 100° C. for a period of 30 hours. After the mixture cooled to room temperature, the catalysts were removed by filtration and the filtrate was concentrated in vacuum. The resulting crude brown oil was then column chromatographed on silica gel with 3% methanol in methylene chloride to give the desired product as a brown oil (0.100 g, 42%). The oil was crystallized from ethanol with the addition of a solution of oxalic acid in hot ethanol to give 0.050 g of the (S)-enantiomer of the title compound as a white solid, m.p. 165° C.

Quelle