Cesium carbonate → Methyl 5-chloro-2-methyl-3-((1-(pyrimidin-4-yl)piperidin-4-yl)oxy)benzoate

HRID 1050452ノート

反応式

HRID 1050452 の反応式
CS([O:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][N:13]=2)[CH2:8][CH2:7]1)(=O)=O.[Cl:18][C:19]1[CH:20]=[C:21](O)[C:22]([CH3:29])=[C:23]([CH:28]=1)[C:24]([O:26][CH3:27])=[O:25].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C)C=O>[Cl:18][C:19]1[CH:20]=[C:21]([O:5][CH:6]2[CH2:11][CH2:10][N:9]([C:12]3[CH:17]=[CH:16][N:15]=[CH:14][N:13]=3)[CH2:8][CH2:7]2)[C:22]([CH3:29])=[C:23]([CH:28]=1)[C:24]([O:26][CH3:27])=[O:25]

参加物

5

反応物 3

HCID 10796Cesium carbonate2 回HCID 70904667Methyl 5-chloro-3-hydroxy-2-methylbenzoateHCID 902730741-(Pyrimidin-4-yl)piperidin-4-yl methanesulfonate

生成物 1

HCID 90272838Methyl 5-chloro-2-methyl-3-((1-(pyrimidin-4-yl)piperidin-4-yl)oxy)benzoate収率 41.7%

試薬・触媒・溶媒 1

HCID 6228Dimethylformamide溶媒

反応条件

温度
60 °C

実験手順

A 250 mL round bottom flask was charged with 1-(pyrimidin-4-yl)piperidin-4-yl methanesulfonate (713 mg, 2.77 mmol), methyl 5-chloro-3-hydroxy-2-methylbenzoate (0.301 mL, 2.218 mmol), Cs2CO3 (867 mg, 2.66 mmol) and N,N-dimethylformamide (6 mL). The flask was equipped with a reflux condenser and heated at 60° C. for 3 days, at which time the solvent was removed in vacuo. The residue was diluted with EtOAc (120 mL) and mixture filtered. LCMS showed some starting chlorophenol remained, so the EtOAc was removed in vacuo and the residue dissolved in N,N-dimethylformamide (6 mL). Cs2CO3 (867 mg, 2.66 mmol) was added and the reaction was heated to 80° C. overnight, at which time the solvent was removed in vacuo. The residue was diluted with EtOAc (120 mL) and mixture was filtered. The EtOAc was removed in vacuo and crude residue was purified by reverse phase HPLC (Column: Phenomenex Gemini-NX, 30×100, 5μ, C18. Gradient: 7 min, 30-60% acetonitrile/0.1% formic acid in water). Two additional HPLC purifications using the same column (Gradient: 7 min, 10-90% acetonitrile/0.1% formic acid in water; and Gradient: 7 min, 10-90% acetonitrile/0.1% TFA in water) were performed to provide methyl 5-chloro-2-methyl-3-((1-(pyrimidin-4-yl)piperidin-4-yl)oxy)benzoate (335 mg, 0.926 mmol, 41.7% yield) as a yellow viscous oil. 1H NMR (400 MHz, DMSO-d6) δ 8.82 (s, 1H), 8.34 (dd, J=1.52, 7.58 Hz, 1H), 7.44 (d, J=2.02 Hz, 1H), 7.34 (d, J=2.02 Hz, 1H), 7.27 (d, J=7.58 Hz, 1H), 4.85-4.96 (m, 1H), 4.05 (br. s., 2H), 3.91 (br. s., 2H), 3.83 (s, 3H), 2.30 (s, 3H), 2.01-2.13 (m, 2H), 1.71-1.87 (m, J=3.92, 7.03, 7.03, 13.61Hz, 2H). MS(ES) [M+H]+ 362.1.

後処理

  1. customThe flask was equipped with a reflux condenser
  2. customwas removed in vacuo
  3. additionThe residue was diluted with EtOAc (120 mL) and mixture
  4. filtrationfiltered
  5. customwas removed in vacuo
  6. dissolutionthe residue dissolved in N,N-dimethylformamide (6 mL)
  7. temperaturethe reaction was heated to 80° C. overnight, at which time the solvent
  8. customwas removed in vacuo
  9. additionThe residue was diluted with EtOAc (120 mL) and mixture
  10. filtrationwas filtered
  11. customThe EtOAc was removed in vacuo and crude residue
  12. customwas purified by reverse phase HPLC (Column: Phenomenex Gemini-NX, 30×100, 5μ, C18. Gradient: 7 min, 30-60% acetonitrile/0.1% formic acid in water)
  13. customthe same column (Gradient: 7 min, 10-90% acetonitrile/0.1% formic acid in water; and Gradient: 7 min, 10-90% acetonitrile/0.1% TFA in water)

出典と根拠

ORDレコード
ord-09c2c98214f942cf88ea74a3cd72e405
出典データセット
uspto-grants-2016_07
特許番号
US09382234B2

反応ノート

読み込み中…