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

HRID 2199349Notes

Reaction equation

HRID 2199349 reaction equation
[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:32][CH2:33][CH3:34])=[C:17]([NH:20][C:21](=[O:31])[CH2:22]P(OCC)(OCC)=O)[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].C1(C)C=CC=CC=1.[CH3:52][N:53]1[CH2:57][CH2:56][CH2:55][C@H:54]1[CH:58]=O>O1CCCC1.CO.O>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:32][CH2:33][CH3:34])=[C:17]([NH:20][C:21](=[O:31])/[CH:22]=[CH:58]/[C@@H:54]4[CH2:55][CH2:56][CH2:57][N:53]4[CH3:52])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8]

Participants

8

Reactant 4

HCID 1140TolueneHCID 2733832Lithium HexamethyldisilazideHCID 53829761(2S)-1-methylpyrrolidine-2-carbaldehydeHCID 86667264N-[4-[(3-chloro-4-fluoro-phenyl)amino]-7-ethoxy-quinazolin-6-yl]-2-diethoxyphosphoryl-acetamide

Product 1

HCID 51039031(E)-N-[4-[(3-chloro-4-fluoro-phenyl)amino]-7-ethoxy-quinazolin-6-yl]-3-[(2S)-1-methylpyrrolidin-2-yl]prop-2-enamideYield 65.2%

Reagents, catalysts & solvents 3

HCID 887MethanolSolventHCID 962WaterSolventHCID 8028TetrahydrofuranSolvent

Conditions

Temperature
-78 °C

Procedure

N-[4-[(3-Chloro-4-fluoro-phenyl)amino]-7-ethoxy-quinazolin-6-yl]-2-diethoxyphosphoryl-acetamide 7b (100 mg, 0.20 mmol) was dissolved in 10 mL of tetrahydrofuran. The mixture was cooled to −78° C. in a dry ice bath, followed by dropwise addition of a solution of lithium bis(trimethylsilyl)amide (1 M) in toluene (400 μL, 0.40 mmol), and the mixture was stirred for 45 minutes, added with (2S)-1-methylpyrrolidine-2-carbaldehyde 1b (100 mg, 0.85 mmol). 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 water (1 mL) and methanol (1 mL), extracted with dichloromethane (100 mL×3). The combined organic extracts were washed with saturated brine (30 mL×2), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure, then 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-fluoro-phenyl)amino]-7-ethoxy-quinazolin-6-yl]-3-[(2S)-1-methylpyrrolidin-2-yl]prop-2-enamide 7 (60 mg, yield 65.2%) as a yellow solid.

Workup

  1. stirringAfter stirring for another 1 hour
  2. temperaturethe reaction mixture was warmed up to room temperature
  3. stirringstirred for 12 hours
  4. extractionextracted with dichloromethane (100 mL×3)
  5. washThe combined organic extracts were washed with saturated brine (30 mL×2)
  6. dry with materialdried over anhydrous sodium sulfate
  7. filtrationfiltered
  8. concentrationthe filtrate was concentrated under reduced pressure
  9. customthe resulting residue was purified by silica gel column chromatography with elution system

Sources & evidence

ORD record
ord-966feafea5e648729b8ee05edf5466ab
Source dataset
uspto-grants-2016_06
Patent number
US09358227B2

Reaction notes

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