Benzyl Bromide → (4aS,7S,8R,9S,9aS)-8,9-bis(benzyloxy)-7-(4-chloro-3-(4-ethoxybenzyl)phenyl)-2-phenylhexahydro-4a,7-epoxy[1,3]dioxino[5,4-c]oxepine

HRID 1055611Notes

Reaction equation

HRID 1055611 reaction equation
[H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C@:10]23[O:27][C@@:14]4([CH2:17][O:18][CH:19]([C:21]5[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=5)[O:20][C@H:13]4[C@H:12]([OH:28])[C@H:11]2[OH:29])[CH2:15][O:16]3)=[CH:6][C:5]=1[CH2:30][C:31]1[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH3:39])=[CH:33][CH:32]=1.[CH2:40](Br)[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>O1CCCC1.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH2:40]([O:29][C@H:11]1[C@:10]2([C:7]3[CH:8]=[CH:9][C:4]([Cl:3])=[C:5]([CH2:30][C:31]4[CH:32]=[CH:33][C:34]([O:37][CH2:38][CH3:39])=[CH:35][CH:36]=4)[CH:6]=3)[O:27][C@@:14]3([CH2:17][O:18][CH:19]([C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=4)[O:20][C@H:13]3[C@@H:12]1[O:28][CH2:30][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:4]=1)[CH2:15][O:16]2)[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1

Participants

6

Reactant 3

HCID 7498Benzyl BromideHCID 24758Sodium hydrideHCID 117986152HCID 117986152, compound

Product 1

HCID 118391147(4aS,7S,8R,9S,9aS)-8,9-bis(benzyloxy)-7-(4-chloro-3-(4-ethoxybenzyl)phenyl)-2-phenylhexahydro-4a,7-epoxy[1,3]dioxino[5,4-c]oxepineYield 182.8%

Reagents, catalysts & solvents 2

HCID 67553Tetrabutylammonium IodideCatalystHCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
0 °C

Procedure

To a mixture of sodium hydride (6.5 g, 163.8 mmol, 60% dispersion in Mineral oil) in anhydrous tetrahydrofuran (30 mL) was added dropwise a solution of (4aS,7S,8R,9R,9aS)-7-(4-chloro-3-(4-ethoxybenzyl)phenyl)-2-phenylhexahydro-4a,7-epoxy[1,3]dioxino[5,4-c]oxepine-8,9-diol 28b (14.3 g, 27.3 mmol) in anhydrous tetrahydrofuran (10 mL) at 0° C. The mixture was stirred at 0° C. for 30 min and room temperature for 1 hour. To the mixture were added benzyl bromide (13 g, 109.2 mmol) and a catalytic amount of tetrabutylammonium iodide at 0° C. The resulting mixture was stirred at room temperature for 12 hours. The reaction mixture was quenched with water at 0° C., adjusted with saturated aqueous ammonium chloride till pH becomes 7 and extracted with ethyl acetate (100 mL×3). The combined organic layers were washed with saturated aqueous sodium chloride (30 mL×2), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo and the residue was purified by silica gel chromatography eluted with PE/EtOAc(v/v)=10/1 to give the title compound 28c as a white solid (17.6 g, 91.4%). The compound was characterized by the following spectroscopic data: 1H NMR (400 MHz, CDCl3) δ (ppm): 7.44-7.41 (m, 4H), 7.37 (m, 4H), 7.35-7.30 (m, 5H), 7.21 (d, 1H), 7.16 (m, 2H), 7.08 (d, 2H), 6.86 (d, 2H), 6.78 (d, 2H), 5.67 (s, 1H), 4.94 (d, 1H), 4.79 (d, 1H), 4.73 (s, 1H), 4.64 (d, 1H), 4.39 (d, 1H), 4.25 (d, 1H), 4.18 (d, 1H), 4.07-3.94 (m, 6H), 3.87 (d, 1H), 3.72 (d, 1H), 1.41 (t, 3H).

Workup

  1. customat 0° C
  2. stirringThe resulting mixture was stirred at room temperature for 12 hours
  3. customThe reaction mixture was quenched with water at 0° C.
  4. extractionextracted with ethyl acetate (100 mL×3)
  5. washThe combined organic layers were washed with saturated aqueous sodium chloride (30 mL×2)
  6. dry with materialdried over anhydrous sodium sulfate
  7. filtrationfiltered
  8. concentrationThe filtrate was concentrated in vacuo
  9. customthe residue was purified by silica gel chromatography
  10. washeluted with PE/EtOAc(v/v)=10/1

Sources & evidence

ORD record
ord-b0704881c424431fb109dca3862a9b4d
Source dataset
uspto-grants-2016_07
Patent number
US09394329B2

Reaction notes

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