Potassium Carbonate → 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

HRID 431066

반응식

HRID 431066 반응식
[NH:1]1[CH2:6][CH:5]=[C:4]([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:16]#[N:17])[CH:14]=3)[NH:9][CH:8]=2)[CH2:3][CH2:2]1.Br[C:19]1[C:24]([O:25][CH2:26][C@@H:27]2[CH2:29][O:28]2)=[CH:23][CH:22]=[CH:21][N:20]=1.CC1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC(C)=CC=2)C2C=CC(C)=CC=2)C2C=CC(C)=CC=2)=CC=1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[O:25]1[C:24]2[C:19](=[N:20][CH:21]=[CH:22][CH:23]=2)[O:28][CH:27]([CH2:29][N:1]2[CH2:2][CH:3]=[C:4]([C:7]3[C:15]4[C:10](=[CH:11][CH:12]=[C:13]([C:16]#[N:17])[CH:14]=4)[NH:9][CH:8]=3)[CH2:5][CH2:6]2)[CH2:26]1

참가 물질

8

반응물 4

HCID 11430Potassium CarbonateHCID 4189906(S)-(-)-2,2'-Bis(di-p-tolylphosphino)-1, 1'-binaphthylHCID 113335543-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole-5-carbonitrileHCID 120981832-bromo-3-[(2S)-oxiranylmethoxy]pyridine

생성물 1

HCID 222566783-{1-[2,3-Dihydro[1,4]dioxino[2,3-b]pyridin-3-ylmethyl]-1,2,3,6-tetrahydro-4-pyridinyl}-1H-indole-5-carbonitrile수율 42%

시약·촉매·용매 3

HCID 167845palladium(II) acetate촉매HCID 679Dimethyl Sulfoxide용매HCID 1140Toluene용매

반응 조건

온도
77.5 °C

실험 절차

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.

후처리

  1. temperatureAfter completion, the reaction was cooled to room temperature
  2. custompartitioned between 250 mL each of ethyl acetate and saturated sodium bicarbonate
  3. washThe organic phase was washed with brine
  4. dry with materialdried over magnesium sulfate
  5. concentrationconcentrated in vacuum
  6. customchromatographed on silica gel using first methylene chloride as eluant
  7. customto remove impurities
  8. wash3% methanol in methylene chloride to elute the product, which
  9. temperatureThe heterogeneous mixture was heated at 100° C. for a period of 30 hours
  10. temperatureAfter the mixture cooled to room temperature
  11. customthe catalysts were removed by filtration
  12. concentrationthe filtrate was concentrated in vacuum
  13. customcolumn chromatographed on silica gel with 3% methanol in methylene chloride

출처 및 근거

ORD 기록
ord-1ff56c77f6264d8497d7d273f89543ab
출처 데이터셋
uspto-grants-2003_12
특허 번호
US06656950B2

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