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

HRID 2199352Notes

Reaction equation

HRID 2199352 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][CH2:34][O:35][CH3:36])=[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.[CH3:54][N:55]1[CH2:59][CH2:58][CH2:57][C@@H:56]1[CH:60]=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][CH2:34][O:35][CH3:36])=[C:17]([NH:20][C:21](=[O:31])/[CH:22]=[CH:60]/[C@H:56]4[CH2:57][CH2:58][CH2:59][N:55]4[CH3:54])[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 86667265N-[4-[(3-chloro-4-fluoro-phenyl)amino]-7-(2-methoxyethoxy)quinazolin-6-yl]-2-diethoxyphosphoryl-acetamide

Product 1

HCID 51038277(E)-N-[4-[(3-chloro-4-fluoro-phenyl)amino]-7-(2-methoxyethoxy)quinazolin-6-yl]-3-[(2R)-1-methylpyrrolidin-2-yl]prop-2-enamideYield 54.2%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Conditions

Temperature
-78 °C

Procedure

N-[4-[(3-Chloro-4-fluoro-phenyl)amino]-7-(2-methoxyethoxy)quinazolin-6-yl]-2-diethoxyphosphoryl-acetamide 8d (200 mg, 0.37 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 (740 μL, 0.74 mmol) was added dropwise. After stirring for 30 minutes, (2R)-1-methylpyrrolidine-2-carbaldehyde 5c (84 mg, 0.74 mmol) was added to the reaction solution. The reaction mixture was stirred for another 1 hour, then warmed 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-(2-methoxyethoxy)quinazolin-6-yl]-3-[(2R)-1-methylpyrrolidin-2-yl]prop-2-enamide 8 (100 mg, yield 54.2%) as a yellow solid.

Workup

  1. stirringThe reaction mixture was stirred for another 1 hour
  2. temperaturewarmed 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-b0bd99224c01461792366a6ca779ca44
Source dataset
uspto-grants-2016_06
Patent number
US09358227B2

Reaction notes

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