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 2199352ノート

反応式

HRID 2199352 の反応式
[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]

参加物

6

反応物 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

生成物 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-enamide収率 54.2%

試薬・触媒・溶媒 1

HCID 8028Tetrahydrofuran溶媒

反応条件

温度
-78 °C

実験手順

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.

後処理

  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

出典と根拠

ORDレコード
ord-b0bd99224c01461792366a6ca779ca44
出典データセット
uspto-grants-2016_06
特許番号
US09358227B2

反応ノート

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