Hydrochloric Acid → 4-((2-(benzyloxy)-4,6-dimethylpyridin-3-yl)methyl)-9-bromo-7-isopropoxy-6-methyl-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one
Reaction equation
[CH2:1]([O:8][C:9]1[C:14]([CH2:15][NH:16][CH2:17][CH2:18][O:19][C:20]2[C:30]([Br:31])=[CH:29][C:28]([O:32]S(C)(=O)=O)=[C:27]([CH3:37])[C:21]=2[C:22]([O:24]CC)=O)=[C:13]([CH3:38])[CH:12]=[C:11]([CH3:39])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].Cl.[CH:43](N(CC)C(C)C)([CH3:45])[CH3:44].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(=O)([O-])[O-].[Cs+].[Cs+].IC(C)C>CO.O>[CH2:1]([O:8][C:9]1[C:14]([CH2:15][N:16]2[C:22](=[O:24])[C:21]3[C:27]([CH3:37])=[C:28]([O:32][CH:43]([CH3:45])[CH3:44])[CH:29]=[C:30]([Br:31])[C:20]=3[O:19][CH2:18][CH2:17]2)=[C:13]([CH3:38])[CH:12]=[C:11]([CH3:39])[N:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1Participants
Reactant 7
HCID 313Hydrochloric Acid
HCID 6362Isopropyl iodide
HCID 10796Cesium carbonate
HCID 14798Sodium Hydroxide
HCID 81531Diisopropylethylamine
HCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)
HCID 86723784Ethyl 2-(2-(((2-(benzyloxy)-4,6-dimethylpyridin-3-yl)methyl)amino)ethoxy)-3-bromo-6-methyl-5-((methylsulfonyl)oxy)benzoateProduct 1
Reagents, catalysts & solvents 2
Conditions
- Temperature
- 120 °C
Procedure
To a solution of ethyl 2-(2-(((2-(benzyloxy)-4,6-dimethylpyridin-3-yl)methyl)amino)-ethoxy)-3-bromo-6-methyl-5-((methylsulfonyl)oxy)benzoate (116f, 0.54 g, 0.86 mmol) in methanol (2 mL) was added sodium hydroxide solution (50% in water, 0.73 g, 9.2 mmol). The reaction mixture was heated at 120° C. in the microwave for 1 hour then diluted with water and acidified with concentrated hydrochloric acid to pH ˜4. The resulting precipitate was collected by vacuum filtration then taken up in N,N-dimethylacetamide (5 mL). N,N-diisopropylethyl amine (0.38 mL, 2.2 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU, 0.39 g, 1.0 mmol) were added and the reaction was stirred at room temperature overnight. The crude reaction was diluted with water (10 mL) and extracted with dichloromethane (2×15 mL). The combined organic layers were washed with brine (15 mL), dried over magnesium sulfate and concentrated under vacuum. The residue was dissolved in N,N-dimethylacetamide (5 mL) and cesium carbonate (0.51 g, 1.6 mmol) and 2-iodopropane (0.12 mL, 1.2 mmol) were added. The mixture was heated at 75° C. for 1 hour, cooled to room temperature then diluted with water (10 mL) and extracted with ethyl acetate (2×15 mL). The combined organic layers were washed with brine (15 mL), dried over magnesium sulfate, concentrated under vacuum, and purified by column chromatography (30% EtOAc/Heptane) to give 4-((2-(benzyloxy)-4,6-dimethylpyridin-3-yl)methyl)-9-bromo-7-isopropoxy-6-methyl-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one (116 g, 242 mg, 48% yield) as a clear sticky solid.
Workup
- filtrationThe resulting precipitate was collected by vacuum filtration
- customThe crude reaction
- extractionextracted with dichloromethane (2×15 mL)
- washThe combined organic layers were washed with brine (15 mL)
- dry with materialdried over magnesium sulfate
- concentrationconcentrated under vacuum
- dissolutionThe residue was dissolved in N,N-dimethylacetamide (5 mL)
- temperatureThe mixture was heated at 75° C. for 1 hour
- temperaturecooled to room temperature
- extractionextracted with ethyl acetate (2×15 mL)
- washThe combined organic layers were washed with brine (15 mL)
- dry with materialdried over magnesium sulfate
- concentrationconcentrated under vacuum
- custompurified by column chromatography (30% EtOAc/Heptane)
Sources & evidence
- ORD record
- ord-5d67d62296544f6f819c3d965d5d65be
- Source dataset
- uspto-grants-2015_05
- Patent number
- US09040515B2
Reaction notes
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