Acetic Acid → (e)-11-(Bromomethylene)-3-fluoro-6,11-dihydrodibenzo[b,e]oxepine

HRID 244345Notes

Reaction equation

C(OC(=O)[CH:5]=[C:6]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[CH2:10][O:9][C:8]2[CH:17]=[C:18]([F:21])[CH:19]=[CH:20][C:7]1=2)C.[OH-].[Li+].C(O)(=O)C.[Br:29]N1C(=O)CCC1=O>C(O)(C)C.O>[Br:29]/[CH:5]=[C:6]1/[C:7]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:8]=2[O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]/1=2

Participants

Conditions

Temperature: 70 °C

Procedure

To a suspension of (3-fluoro-6H-dibenzo[b,e]oxepin-11-ylidene)-acetic acid ethyl ester (69.5 g, 0.23 mol) in isopropanol (725 mL) add a solution of lithium hydroxide (12.0 g, 0.53 mol) in water (125 mL) and warm to 70° C. for 4 h. Allow the mixture to cool to 40° C. and then treat with glacial acetic acid (0.44 mol, 25 mL). After stirring for 15 min, add N-bromosuccinimide (0.25 mol, 44 g). Bubbling ensues, the temperature rises to 45° C., and solids form after a few minutes. Stir the mixture at 40-45° C. for one hour and cool to room temperature. Add sodium bisulfite (4.5 g) in water (150 mL), saturated aqueous sodium bicarbonate (150 mL), and water (450 mL). Filter the resulting suspension and rinse with cold 1:1 isopropanol/water (300 mL). Dry the solid at 60° C./20 mm Hg overnight to obtain the title compound (65.8 g, 93%). 1H NMR (400 MHz, DMSO-d6) δ 4.9-5.4 (br d, 2H), 6.63 (dd, 1H), 6.77 (dt, 1H), 7.13 (s, 1H), 7.32-7.46 (m, 4H), 7.52 (dd, 1H).

Workup

temperatureAllow the mixture to cool to 40° C.
customBubbling
customrises to 45° C.
waitsolids form after a few minutes
stirringStir the mixture at 40-45° C. for one hour
temperaturecool to room temperature
filtrationFilter the resulting suspension
washrinse with cold 1:1 isopropanol/water (300 mL)
customDry the solid at 60° C./20 mm Hg overnight

Sources & evidence

ORD record: ord-ccc6ac4c04834afe901c4b20806f6d56
Source dataset: uspto-grants-2014_02
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US08658638B2

Reaction notes

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