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

HRID 1397069Notes

Reaction equation

HRID 1397069 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>[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

6

Reactant 4

HCID 1140TolueneHCID 2733832Lithium HexamethyldisilazideHCID 53829762(2R)-1-methylpyrrolidine-2-carbaldehydeHCID 86667264N-[4-[(3-chloro-4-fluoro-phenyl)amino]-7-ethoxy-quinazolin-6-yl]-2-diethoxyphosphoryl-acetamide

Product 1

HCID 51039044(E)-N-[4-[(3-Chloro-4-fluoro-phenyl)amino]-7-ethoxy-quinazolin-6-yl]-3-[(2R)-1-methylpyrrolidin-2-yl]prop-2-enamide

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Conditions

Temperature
-78 °C

Procedure

N-[4-[(3-Chloro-4-fluoro-phenyl)amino]-7-ethoxy-quinazolin-6-yl]-2-diethoxyphosphoryl-acetamide 7b (300 mg, 0.59 mmol) was dissolved in 10 mL of tetrahydrofuran. The mixture was cooled to −78° C. in a dry ice bath. Under argon, a solution of lithium bis(trimethylsilyl)amide (1 M) in toluene (1.2 mL, 1.18 mmol) was added dropwise. After the mixture was stirred for 30 minutes, (2R)-1-methylpyrrolidine-2-carbaldehyde 5c (133 mg, 1.18 mmol) was added, and the mixture was stirred for another 1 hour, then warm up to room temperature and stirred for 12 hours. The reaction mixture was concentrated, added with 10 mL of water, extracted with dichloromethane (25 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-fluoro-phenyl)amino]-7-ethoxy-quinazolin-6-yl]-3-[(2R)-1-methylpyrrodin-2-yl]prop-2-enamide 9 (130 mg, yield 47.3%) as a yellow solid.

Workup

  1. stirringthe mixture was stirred for another 1 hour
  2. temperaturewarm up to room temperature
  3. stirringstirred for 12 hours
  4. concentrationThe reaction mixture was concentrated
  5. additionadded with 10 mL of water
  6. extractionextracted with dichloromethane (25 mL×3)
  7. washThe combined organic extracts were washed with saturated brine (30 mL×2)
  8. dry with materialdried over anhydrous sodium sulfate
  9. filtrationfiltered
  10. concentrationconcentrated under reduced pressure
  11. customthe resulting residue was purified by silica gel column chromatography with elution system

Sources & evidence

ORD record
ord-c177188e944048829e722094ac22e3da
Source dataset
uspto-grants-2014_12
Patent number
US08901140B2

Reaction notes

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