Ethanol → HCID 70675711, compound

HRID 628957

Reaction equation

HRID 628957 reaction equation
[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10](Br)=[CH:11][CH:12]=2)[C@H:7]([NH:15][C:16]2[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][N:17]=2)[CH2:6][C@@H:5]1[CH3:24])(=[O:3])[CH3:2].[OH-].[K+].[CH3:27][O:28][CH2:29][CH2:30][N:31]1[CH:35]=[C:34](B2OC(C)(C)C(C)(C)O2)[CH:33]=[N:32]1.CCO>C1(C)C=CC=CC=1.O>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:34]3[CH:33]=[N:32][N:31]([CH2:30][CH2:29][O:28][CH3:27])[CH:35]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:15][C:16]2[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][N:17]=2)[CH2:6][C@@H:5]1[CH3:24])(=[O:3])[CH3:2]

Participants

7

Reactant 4

HCID 702EthanolHCID 14797Potassium HydroxideHCID 112304911-(2-Methoxyethyl)-1H-pyrazole-4-boronic acid, pinacol esterHCID 709779596-(((2S,4R)-1-acetyl-6-bromo-2-methyl-1,2,3,4-tetrahydroquinolin-4-yl)amino)nicotinonitrile2×

Product 1

HCID 70675711HCID 70675711, compound

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 1140TolueneSolvent

Procedure

6-(((2S,4R)-1-acetyl-6-bromo-2-methyl-1,2,3,4-tetrahydroquinolin-4-yl)amino)nicotinonitrile (Intermediate 6) (10 g, 26.0 mmol), PEPPSI™ (1.764 g, 2.60 mmol), KOH (4.37 g, 78 mmol) and 1-(2-methoxyethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (CAS No. 847818-71-7 available from Milestone PharmTech USA Inc.) (11.78 g, 46.7 mmol) were combined in a mixture of toluene (80 mL), EtOH (40 mL) and water (50 mL). The mixture was degassed and then heated at reflux under a nitrogen atmosphere for 6 h. The solution was cooled, diluted with EtOAc (200 mL) and washed with water (200 mL). The organic layer was dried over sodium sulphate and concentrated in vacuo to give a pale yellow gum. This yellow gum was purified by silica gel column chromatography (330 g column, eluting with 0-100% EtOAC/cyclohexane followed by 10% MeOH/EtOAc). The appropriate fractions were collected and the solvent evaporated in vacuo to give the crude product which was further purified by preparative HPLC (Method HpH) and then dried overnight in a vacuum oven at 55° C. to give 6-(((2S,4R)-1-acetyl-6-(1-(2-methoxyethyl)-1H-pyrazol-4-yl)-2-methyl-1,2,3,4-tetrahydroquinolin-4-yl)amino)nicotinonitrile (4.62 g).

Workup

  1. customThe mixture was degassed
  2. temperatureheated
  3. temperatureat reflux under a nitrogen atmosphere for 6 h
  4. temperatureThe solution was cooled
  5. additiondiluted with EtOAc (200 mL)
  6. washwashed with water (200 mL)
  7. dry with materialThe organic layer was dried over sodium sulphate
  8. concentrationconcentrated in vacuo
  9. customto give a pale yellow gum
  10. customThis yellow gum was purified by silica gel column chromatography (330 g column, eluting with 0-100% EtOAC/cyclohexane followed by 10% MeOH/EtOAc)
  11. customThe appropriate fractions were collected
  12. customthe solvent evaporated in vacuo
  13. customto give the crude product which
  14. customwas further purified by preparative HPLC (Method HpH)
  15. customdried overnight in a vacuum oven at 55° C.

Sources & evidence

ORD record
ord-83ffdd6a539d46f4887a6b32b6de85c0
Source dataset
uspto-grants-2016_04
Patent number
US09315487B2

Linked notes

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