Sodium hydride → 6-Chloro-4-[(2-methyl-1-oxo-3,4-dihydroisoquinolin-8-yl)amino]pyridine-3-carbonitrile

HRID 1045903

反応式

HRID 1045903 の反応式
[H-].[Na+].[NH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:13]=1[C:12](=[O:14])[N:11]([CH3:15])[CH2:10][CH2:9]2.Cl[C:17]1[CH:22]=[C:21]([Cl:23])[N:20]=[CH:19][C:18]=1[C:24]#[N:25]>C1COCC1.CCOC(C)=O>[Cl:23][C:21]1[N:20]=[CH:19][C:18]([C:24]#[N:25])=[C:17]([NH:3][C:4]2[CH:5]=[CH:6][CH:7]=[C:8]3[C:13]=2[C:12](=[O:14])[N:11]([CH3:15])[CH2:10][CH2:9]3)[CH:22]=1

参加物

6

反応物 3

HCID 24758Sodium hydrideHCID 162026268-amino-2-methyl-3,4-dihydroisoquinolin-1(2H)-oneHCID 455880804,6-Dichloropyridine-3-carbonitrile

生成物 1

HCID 866551326-Chloro-4-[(2-methyl-1-oxo-3,4-dihydroisoquinolin-8-yl)amino]pyridine-3-carbonitrile収率 21.2%

試薬・触媒・溶媒 2

HCID 8028Tetrahydrofuran溶媒HCID 8857Ethyl Acetate溶媒

実験手順

Sodium hydride (2.78 g, 69.46 mmol) was added portionwise to 8-amino-2-methyl-3,4-dihydroisoquinolin-1-one (3.06 g, 17.37 mmol), in THF (8 mL) under an atmosphere of nitrogen. The resulting suspension was stirred at room temperature for 20 minutes and then 4,6-dichloropyridine-3-carbonitrile (3.00 g, 17.37 mmol) was added portionwise and the mixture heated overnight at 60° C. The mixture was allowed to cool to room temperature and then diluted with EtOAc (100 mL). The mixture was washed sequentially with water (100 mL), a saturated solution of NaHCO3 (100 mL), and finally with a saturated solution of NaCl (100 mL). The organic layer was dried over MgSO4 and then evaporated. The residue was loaded onto an SCX column and the product was eluted using a mixture of MeOH in CH2Cl2. Fractions containing product were combined and evaporated. The residue was purified by chromatography on silica, eluting with a gradient of 50-70% EtOAc in isohexane. Fractions containing the required product were combined and evaporated to afford 6-chloro-4-[(2-methyl-1-oxo-3,4-dihydroisoquinolin-8-yl)amino]pyridine-3-carbonitrile (1.149 g, 21% yield). The mixed fractions were combined and repurified by silica chromatography, eluting with a gradient of 0-20% EtOAc in CH2Cl2. Fractions containing the required product were combined and evaporated to leave 6-chloro-4-[(2-methyl-1-oxo-3,4-dihydroisoquinolin-8-yl)amino]pyridine-3-carbonitrile (1.287 g, 24% yield); 1H NMR spectrum: (300 MHz, DMSO) δ 2.98 (2H, t), 3.06 (3H, s), 3.58 (2H, t), 7.07 (1H, dd), 7.36 (1H, s), 7.48-7.52 (2H, m), 8.63 (1H, s), 12.00 (1H, s); Mass spectrum: m/z (ESI+) (M+H)+=313.34 and 315.33.

後処理

  1. temperaturethe mixture heated overnight at 60° C
  2. temperatureto cool to room temperature
  3. washThe mixture was washed sequentially with water (100 mL)
  4. dry with materialThe organic layer was dried over MgSO4
  5. customevaporated
  6. washthe product was eluted
  7. additiona mixture of MeOH in CH2Cl2
  8. additionFractions containing product
  9. customevaporated
  10. customThe residue was purified by chromatography on silica
  11. washeluting with a gradient of 50-70% EtOAc in isohexane
  12. additionFractions containing the required product
  13. customevaporated

出典と根拠

ORDレコード
ord-6689258e82a04deeb9da4c269b8ccbe5
出典データセット
uspto-grants-2013_10
特許番号
US08569298B2

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