1-Bromo-3-chlorobenzene → 1-((2S,4R)-4-((3-chlorophenyl)amino)-6-(1-(2-methoxyethyl)-1H-pyrazol-4-yl)-2-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone

HRID 628961ノート

反応式

HRID 628961 の反応式
[NH2:1][C@H:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]3[CH:13]=[N:14][N:15]([CH2:17][CH2:18][O:19][CH3:20])[CH:16]=3)[CH:10]=2)[N:5]([C:21](=[O:23])[CH3:22])[C@@H:4]([CH3:24])[CH2:3]1.Br[C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([Cl:32])[CH:27]=1.CN(C1C(C2C(P(C3CCCCC3)C3CCCCC3)=CC=CC=2)=CC=CC=1)C.CC(C)([O-])C.[Na+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:32][C:28]1[CH:27]=[C:26]([NH:1][C@H:2]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([C:12]4[CH:13]=[N:14][N:15]([CH2:17][CH2:18][O:19][CH3:20])[CH:16]=4)[CH:10]=3)[N:5]([C:21](=[O:23])[CH3:22])[C@@H:4]([CH3:24])[CH2:3]2)[CH:31]=[CH:30][CH:29]=1

参加物

7

反応物 4

HCID 79281-Bromo-3-chlorobenzeneHCID 27342172-(Dicyclohexylphosphino)-2'-(dimethylamino)biphenylHCID 23676156Sodium t-butoxideHCID 709775541-((2S,4R)-4-amino-6-(1-(2-methoxyethyl)-1H-pyrazol-4-yl)-2-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone

生成物 1

HCID 709777111-((2S,4R)-4-((3-chlorophenyl)amino)-6-(1-(2-methoxyethyl)-1H-pyrazol-4-yl)-2-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone収率 29%

試薬・触媒・溶媒 2

HCID 9811564Bis(dibenzylideneacetone)palladium触媒HCID 312751,4-Dioxane溶媒

反応条件

温度
120 °C

実験手順

1-((2S,4R)-4-Amino-6-(1-(2-methoxyethyl)-1H-pyrazol-4-yl)-2-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone (for a preparation see Intermediate 7) (100 mg, 0.304 mmol), 1-bromo-3-chlorobenzene (0.072 ml, 0.609 mmol), Davephos (24 mg, 0.061 mmol), Pd2(dba)3 (27.9 mg, 0.030 mmol) and sodium tert-butoxide (58.5 mg, 0.609 mmol) were combined in 1,4-dioxane (3 ml) and the mixture degassed over a period of 20 min. The mixture was heated at 120° C. for 25 min (microwave). The reaction mixture was partitioned between water (100 ml) and DCM (3×100 ml). The organics were combined, dried (hydrophobic frit) and evaporated under vacuum. The residual brown oil dissolved in DMSO (2×1 ml) and purified by MDAP (formate ×2). The solvent was evaporated under vacuum, the residue dissolved in DCM and applied to a silica cartridge (10 g). The cartridge was eluted with an ethyl acetate/cyclohexane gradient (0-100% over 10 CV followed by holding at 100% ethyl acetate for 5 CV). The appropriate fractions were combined and evaporated under vacuum to give 1-((2S,4R)-4-((3-chlorophenyl)amino)-6-(1-(2-methoxyethyl)-1H-pyrazol-4-yl)-2-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone (39 mg, 0.089 mmol, 29% yield) as a colourless glass. LCMS (formate), Rt 1.05 min, MH+ 438.

後処理

  1. customthe mixture degassed over a period of 20 min
  2. customThe reaction mixture was partitioned between water (100 ml) and DCM (3×100 ml)
  3. customdried (hydrophobic frit)
  4. customevaporated under vacuum
  5. dissolutionThe residual brown oil dissolved in DMSO (2×1 ml)
  6. custompurified by MDAP (formate ×2)
  7. customThe solvent was evaporated under vacuum
  8. dissolutionthe residue dissolved in DCM
  9. washThe cartridge was eluted with an ethyl acetate/cyclohexane gradient (0-100% over 10 CV followed by holding at 100% ethyl acetate for 5 CV)
  10. customevaporated under vacuum

出典と根拠

ORDレコード
ord-4ea5688824bc4006bd9dfc8ebe4504e6
出典データセット
uspto-grants-2016_04
特許番号
US09315487B2

反応ノート

読み込み中…