Citric Acid → 2-[4-(cyclopropylsulfonyl)-1H-indazol-1-yl]-N-methoxy-N-methyl-3-(tetrahydro-2H-pyran-4-yl)propanamide

HRID 1802884ノート

反応式

HRID 1802884 の反応式
Br[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][N:6]2[CH:11]([CH2:17][CH:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)[C:12]([O:14]CC)=O.CNCC[NH:28][CH3:29].[C:30](=[O:33])([O-])[O-].[K+].[K+].[CH:36]1([S:39]([O-:41])=[O:40])[CH2:38][CH2:37]1.[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[Cu]I.CS(C)=O>[CH:36]1([S:39]([C:2]2[CH:10]=[CH:9][CH:8]=[C:7]3[C:3]=2[CH:4]=[N:5][N:6]3[CH:11]([CH2:17][CH:18]2[CH2:19][CH2:20][O:21][CH2:22][CH2:23]2)[C:12]([N:28]([O:33][CH3:30])[CH3:29])=[O:14])(=[O:41])=[O:40])[CH2:38][CH2:37]1

参加物

8

反応物 5

HCID 311Citric AcidHCID 8070N,N'-DimethylethylenediamineHCID 11430Potassium CarbonateHCID 42643363Sodium cyclopropanesulfinateHCID 58380603ethyl 2-(4-bromo-1H-indazol-1-yl)-3-(tetrahydro-2H-pyran-4-yl)propanoate

生成物 1

HCID 583806202-[4-(cyclopropylsulfonyl)-1H-indazol-1-yl]-N-methoxy-N-methyl-3-(tetrahydro-2H-pyran-4-yl)propanamide収率 67%

試薬・触媒・溶媒 2

HCID 24350Copper(1+) iodide; Copper(I) iodide; Cuprous iodide; Cuprous iodide (CuI)触媒HCID 679Dimethyl Sulfoxide溶媒

反応条件

温度
100 °C

実験手順

A mixture of ethyl 2-(4-bromo-1H-indazol-1-yl)-3-(tetrahydro-2H-pyran-4-yl)propanoate (3.10 g), copper(I) iodide (0.46 g), N,N′-dimethylethylenediamine (0.26 mL), potassium carbonate (3.37 g), sodium cyclopropanesulfinate (3.1 g) and dimethyl sulfoxide (30 mL) was stirred overnight at 100° C. To the reaction mixture was added 10% aqueous citric acid solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4), and concentrated. To a mixture of the obtained residue, tetrahydrofuran (10 mL) and methanol (10 ml) was added 2M aqueous sodium hydroxide solution (8.0 mL), and the mixture was stirred at 50° C. for 4 hr. To the reaction mixture was added 10% aqueous citric acid solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4), and concentrated. To a mixture of the obtained residue, N,O-dimethylhydroxylamine hydrochloride (1.60 g), triethylamine (2.3 mL), 1H-1,2,3-benzotriazol-1-ol (1.84 g) and N,N-dimethylformamide (25 mL) was added N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (0.88 g), and the mixture was stirred overnight at room temperature. To the reaction mixture was added 10% aqueous citric acid solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed successively with saturated brine, saturated aqueous sodium hydrogen carbonate and saturated brine, dried (MgSO4), and concentrated. The obtained residue was subjected to silica gel column chromatography to give the title compound (2.30 g, yield 67%) as a yellow oil from the fraction eluted with ethyl acetate. MS: 422 (MH+).

後処理

  1. extractionthe mixture was extracted with ethyl acetate
  2. washThe ethyl acetate layer was washed with saturated brine
  3. dry with materialdried (MgSO4)
  4. concentrationconcentrated
  5. additionTo a mixture of the obtained residue, tetrahydrofuran (10 mL) and methanol (10 ml)
  6. additionwas added 2M aqueous sodium hydroxide solution (8.0 mL)
  7. stirringthe mixture was stirred at 50° C. for 4 hr
  8. additionTo the reaction mixture was added 10% aqueous citric acid solution
  9. extractionthe mixture was extracted with ethyl acetate
  10. washThe ethyl acetate layer was washed with saturated brine
  11. dry with materialdried (MgSO4)
  12. concentrationconcentrated
  13. additionTo a mixture of the obtained residue, N,O-dimethylhydroxylamine hydrochloride (1.60 g), triethylamine (2.3 mL), 1H-1,2,3-benzotriazol-1-ol (1.84 g) and N,N-dimethylformamide (25 mL)
  14. additionwas added N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (0.88 g)
  15. stirringthe mixture was stirred overnight at room temperature
  16. additionTo the reaction mixture was added 10% aqueous citric acid solution
  17. extractionthe mixture was extracted with ethyl acetate
  18. washThe ethyl acetate layer was washed successively with saturated brine, saturated aqueous sodium hydrogen carbonate and saturated brine
  19. dry with materialdried (MgSO4)
  20. concentrationconcentrated

出典と根拠

ORDレコード
ord-8682aa133005458aa25342ee3bbc9049
出典データセット
uspto-grants-2013_01
特許番号
US08349886B2

反応ノート

読み込み中…