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 2199332Notes

Reaction equation

HRID 2199332 reaction equation
[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

Participants

8

Reactant 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

Product 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-enamideYield 53.6%

Reagents, catalysts & solvents 3

HCID 887MethanolSolventHCID 962WaterSolventHCID 8028TetrahydrofuranSolvent

Procedure

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.

Workup

  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

Sources & evidence

ORD record
ord-f0e8b6d063704b418d2c3cb21b411bf5
Source dataset
uspto-grants-2016_06
Patent number
US09358227B2

Reaction notes

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