Potassium Carbonate → 1-{2-[4-(2-Benzyloxy-6-methoxy-naphthalen-1-yloxy)-phenoxy]ethyl}-azepane

HRID 1513895Notes

Reaction equation

HRID 1513895 reaction equation
[CH2:1]([O:8][C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:19][CH3:20])[CH:15]=2)[C:10]=1Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:22]1([CH2:29][CH2:30][O:31][C:32]2[CH:37]=[CH:36][C:35]([OH:38])=[CH:34][CH:33]=2)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1.C(=O)([O-])[O-].[K+].[K+]>[Cu].N1C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:19][CH3:20])[CH:15]=2)[C:10]=1[O:38][C:35]1[CH:34]=[CH:33][C:32]([O:31][CH2:30][CH2:29][N:22]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)=[CH:37][CH:36]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1

Participants

6

Reactant 3

HCID 11430Potassium CarbonateHCID 117029082-Benzyloxy-1-bromo-6-methoxy-naphthaleneHCID 670048004-(2-Azepan-1-yl-ethoxy)-phenol

Product 1

HCID 670044981-{2-[4-(2-Benzyloxy-6-methoxy-naphthalen-1-yloxy)-phenoxy]ethyl}-azepaneYield 43%

Reagents, catalysts & solvents 2

HCID 23978CopperCatalystHCID 1049PyridineSolvent

Procedure

Combine 2-benzyloxy-1-bromo-6-methoxy-naphthalene (31 g, 90 mmol), 4-(2-azepan-1-yl-ethoxy)-phenol (31 g, 132 mmol), copper bronze (12 g, 189 mmol), potassium carbonate (25 g, 181 mmol) and pyridine (400 mL). Heat the reaction mixture to reflux for 85 hours. Cool and filter the residue with celite and elute with methanol and methylene chloride (500 mL, V/V=1:5). Evaporate solvent under reduced pressure and chromatograph the residue on a silica gel column eluting the material with a step gradient of methanol/dichloromethane (0 to 10%) to get 19 g (43%) of 1-{2-[4-(2-benzyloxy-6-methoxy-naphthalen-1-yloxy)-phenoxy]-ethyl}-azepane. Dissolve 1-{2-[4-(2-benzyloxy-6-methoxy-naphthalen-1-yloxy)-phenoxy]-ethyl}-azepane (19 g, 38 mmol) in ethyl acetate (500 mL) and methanol (600 mL). Heat the mixture to obtain a clear solution. Cool to room temperature. Add ammonium formate (30 g, 476 mmol) and palladium on carbon (2 g, 1.9 mmol). Heat to reflux for 30 minutes. Add ammonium formate (7 g, 111 mmol) and palladium on carbon (0.7 g, 0.7 mmol). Heat to reflux for 30 minutes. Filter the suspension through a pad of celite and elute with ethyl acetate (500 mL). Evaporate solvent under reduced pressure and add water (100 mL). Dilute the mixture with ethyl acetate (500 mL) and separate layers. Wash the organic layer with saturated sodium bicarbonate solution (2×200 mL), dry with magnesium sulfate, filter and evaporate solvent under reduced pressure to give 15.1 g (97%) of 1-[4-(2-azepan-1-yl-ethoxy)-phenoxy]-6-methoxy-naphthalen-2-ol.

Workup

  1. temperatureHeat the reaction mixture
  2. temperatureto reflux for 85 hours
  3. temperatureCool
  4. filtrationfilter the residue with celite
  5. washelute with methanol and methylene chloride (500 mL, V/V=1:5)
  6. washEvaporate solvent under reduced pressure and chromatograph the residue on a silica gel column eluting the material with a step gradient of methanol/dichloromethane (0 to 10%)

Sources & evidence

ORD record
ord-7552ecf0fc504f4f818938d920cd8ac8
Source dataset
uspto-grants-2012_07
Patent number
US08217032B2

Reaction notes

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