Toluene → (E)-N-[4-[[3-chloro-4-(2-pyridylmethoxy)phenyl]amino]-3-cyano-7-ethoxy-6-quinolyl]-3-[(2S)-1-methylpyrrolidin-2-yl]prop-2-enamide

HRID 1397048Notizen

Reaktionsgleichung

Reaktionsgleichung von HRID 1397048
[Cl:1][C:2]1[CH:3]=[C:4]([NH:16][C:17]2[C:26]3[C:21](=[CH:22][C:23]([O:39][CH2:40][CH3:41])=[C:24]([NH:27][C:28](=[O:38])[CH2:29]P(OCC)(OCC)=O)[CH:25]=3)[N:20]=[CH:19][C:18]=2[C:42]#[N:43])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].C1(C)C=CC=CC=1.[CH3:61][N:62]1[CH2:66][CH2:65][CH2:64][C@H:63]1[CH:67]=O>O1CCCC1.CO.O>[Cl:1][C:2]1[CH:3]=[C:4]([NH:16][C:17]2[C:26]3[C:21](=[CH:22][C:23]([O:39][CH2:40][CH3:41])=[C:24]([NH:27][C:28](=[O:38])/[CH:29]=[CH:67]/[C@@H:63]4[CH2:64][CH2:65][CH2:66][N:62]4[CH3:61])[CH:25]=3)[N:20]=[CH:19][C:18]=2[C:42]#[N:43])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1

Komponenten

8

Edukt 4

HCID 1140TolueneHCID 2733832Lithium HexamethyldisilazideHCID 53829761(2S)-1-methylpyrrolidine-2-carbaldehydeHCID 86667261Diethyl (2-((4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-3-cyano-7-ethoxyquinolin-6-yl)amino)-2-oxoethyl)phosphonate

Produkt 1

HCID 51038981(E)-N-[4-[[3-chloro-4-(2-pyridylmethoxy)phenyl]amino]-3-cyano-7-ethoxy-6-quinolyl]-3-[(2S)-1-methylpyrrolidin-2-yl]prop-2-enamideAusbeute 53,6 %

Reagenzien, Katalysatoren, Lösungsmittel 3

HCID 887MethanolLösungsmittelHCID 962WaterLösungsmittelHCID 8028TetrahydrofuranLösungsmittel

Versuchsvorschrift

N-[4-[[3-Chloro-4-(2-pyridylmethoxy)phenyl]amino]-3-cyano-7-ethoxy-6-quinolyl]-2-diethoxyphosphoryl-acetamide 1d (50 mg, 0.08 mmol) was dissolved in 2 mL of tetrahydrofuran at −78° C., followed by dropwise addition of a solution of lithium bis(trimethylsilyl)amide (1 M) in toluene (80 μL, 0.08 mmol). After the mixture was stirred for 45 minutes, (2S)-1-methylpyrrolidine-2-carbaldehyde 1b (20 mg, 0.17 mmol) was added. After stirring for another 1 hour, the reaction mixture was warmed up to room temperature and stirred for 12 hours. The reaction mixture was added with 1 mL of water and 1 mL of methanol, then the organic extracts were extracted with dichloromethane (50 mL×3). The combined organic extracts were washed with saturated brine (30 mL×2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography with elution system A to obtain the title compound (E)-N-[4-[[3-chloro-4-(2-pyridylmethoxy)phenyl]amino]-3-cyano-7-ethoxy-6-quinolyl]-3-[(2S)-1-methylpyrrolidin-2-yl]prop-2-enamide 1 (25 mg, yield 53.5%) as a yellow solid.

Aufarbeitung

  1. stirringAfter stirring for another 1 hour
  2. stirringstirred for 12 hours
  3. extractionthe organic extracts were extracted with dichloromethane (50 mL×3)
  4. washThe combined organic extracts were washed with saturated brine (30 mL×2)
  5. dry with materialdried over anhydrous sodium sulfate
  6. filtrationfiltered
  7. concentrationconcentrated under reduced pressure
  8. customthe resulting residue was purified by silica gel column chromatography with elution system

Quellen und Nachweise

ORD-Eintrag
ord-9ff3416b606d47f9abca492ca889eced
Quelldatensatz
uspto-grants-2014_12
Patentnummer
US08901140B2

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