Potassium Carbonate → 7-[3-chloro4-(2-ethoxy)ethoxyphenyl]-1-formyl-N-[4-[[N-methyl-N-(tetrahydro-2H-pyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide

HRID 586897Notes

Reaction equation

HRID 586897 reaction equation
B([O-])([O-])O[C:3]1[CH:8]=[CH:7][C:6]([O:9][CH2:10][CH2:11][O:12][CH2:13][CH3:14])=[C:5]([Cl:15])[CH:4]=1.Br[C:19]1[CH:20]=[CH:21][C:22]2[N:28]([CH:29]=[O:30])[CH2:27][CH2:26][C:25]([C:31]([NH:33][C:34]3[CH:39]=[CH:38][C:37]([CH2:40][N:41]([CH3:48])[CH:42]4[CH2:47][CH2:46][O:45][CH2:44][CH2:43]4)=[CH:36][CH:35]=3)=[O:32])=[CH:24][C:23]=2[CH:49]=1.C(=O)([O-])[O-].[K+].[K+]>C(O)C.O.C1(C)C=CC=CC=1.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:15][C:5]1[CH:4]=[C:3]([C:19]2[CH:20]=[CH:21][C:22]3[N:28]([CH:29]=[O:30])[CH2:27][CH2:26][C:25]([C:31]([NH:33][C:34]4[CH:35]=[CH:36][C:37]([CH2:40][N:41]([CH3:48])[CH:42]5[CH2:47][CH2:46][O:45][CH2:44][CH2:43]5)=[CH:38][CH:39]=4)=[O:32])=[CH:24][C:23]=3[CH:49]=2)[CH:8]=[CH:7][C:6]=1[O:9][CH2:10][CH2:11][O:12][CH2:13][CH3:14]

Participants

7

Reactant 3

HCID 11430Potassium CarbonateHCID 22329057HCID 22329057, compoundHCID 867567953-Chloro-4-(2-ethoxyethoxy)phenyl borate

Product 1

HCID 223290747-[3-chloro4-(2-ethoxy)ethoxyphenyl]-1-formyl-N-[4-[[N-methyl-N-(tetrahydro-2H-pyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamideYield 73%

Reagents, catalysts & solvents 3

HCID 178418397HCID 178418397, compoundCatalystHCID 8857Ethyl AcetateSolventHCID 86587398Ethanol toluene waterSolvent

Procedure

In a mixture of water ethanol:toluene (1:1:10; v/v, 18.0 ml) were dissolved 3-chloro-4-(2-ethoxy)ethoxyphenyl borate (280 mg) and 7-bromo-1-formyl-N-[4-[[N-methyl-N-(tetrahydro-2H-pyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (380 mg). To the solution was added potassium carbonate (253 mg), and the mixture was stirred under argon atmosphere at room temperature for 30 minutes. To the mixture was added tetrakistriphenylphosphinepalladium (35 mg), and the mixture was heated to reflux under argon atmosphere for 10 hours. The mixture was diluted with ethyl acetate, and washed with water and saturated brine, and the organic layer was dried with anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified with silica gel column chromatography (25 g, ethyl acetate→ethyl acetate:ethanol=10:1→ethyl acetate:ethanol:triethylamine=100:10:0.5) and recrystallized from ethanol to give 7-[3-chloro4-(2-ethoxy)ethoxyphenyl]-1-formyl-N-[4-[[N-methyl-N-(tetrahydro-2H-pyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 21) (342 mg, 73%) as white crystals.

Workup

  1. temperaturethe mixture was heated
  2. temperatureto reflux under argon atmosphere for 10 hours
  3. washwashed with water and saturated brine
  4. dry with materialthe organic layer was dried with anhydrous magnesium sulfate
  5. customThe solvent was evaporated under reduced pressure
  6. customthe residue was purified with silica gel column chromatography (25 g, ethyl acetate→ethyl acetate:ethanol=10:1→ethyl acetate:ethanol:triethylamine=100:10:0.5)
  7. customrecrystallized from ethanol

Sources & evidence

ORD record
ord-45fa1dc7e2434611b1d44c551dadcdc4
Source dataset
uspto-grants-2005_08
Patent number
US06936602B1

Reaction notes

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