1-BENZOXEPIN-5(2H)-ONE, 8-BROMO-3,4-DIHYDRO-

A mixture of polyphosphoric acid (590 g), Celite (400 g) and toluene (1.5 L) were stirred for 0.5 h under N2and then 4- (3-BROMO-PHENOXY)-BUTYRIC acid (135.8 g, 0.5264 mol) was added. The reaction mixture was refluxed for 2.5 h, and then cooled to room temperature. The reaction mixture was filtered and the Celite/PPA residue was washed with EtOAc (1.5 L). The organic solution was washed with 1 N NAOH (3 x 0.75 L), H20 (1 L), brine, and then dried over NA2SO4. Concentration of the combined organic layers gave 94.3 g (75percent) of 8- bromo-3, 4-dihydro-2H-benzo [b] oxepin-5-one. This material was combined with 85.0 g of 8-bromo-3, 4-dihydro-2H-benzo [b] oxepin-5-one from other runs (total weight-179.3 g) and distilled (oven temperature 130 5#x0;, 0.18-0. 20 mm) using a Kugelrohr apparatus to give 158.4 g of the title compound, mp 38.4-38. 5 #x0;C.Step No.3: 8-Bromo-3, 4-dihydrobenzo[b]oxepin-5(211)-one (138)A round bottom flask with stir bar was charged with polyphosphoric acid (254 g). The material was heated to about 75° C. then 4-(3-bromophenoxy)butanoic acid (137) (20.0 g, 77.0 mmol) was added. The mixture was stirred at about 75° C. until the materials were mixed. The mixture was heated to about 100° C. for about 30 min then cooled in an ice bath. Water (250 mL) was slowly added to the reaction mixture then the mixture was added to water (250 mL). After stirring for about 30 min the mixture was extracted with EtOAc (2.x.150 mL) then the combined organics were washed with 1 N aqueous NaOH (250 mL) and saturated aqueous NaCl (200 mL). The organic solution was dried over MgSO[0515j To a solution of 3 -[(3 -Bromo-benzyl)-(toluene-4-sulfonyl)-amino] -propionyl chloride (47.0 g, 0.11 mol) in anhydrous DCM (1200 mL) was added A1C13 (29.3 g, 0.22 mol)portion-wise at rt. The reaction mixture was stirred at 55 °C for 2 h. The reaction mixture was poured into ice water (1.2 L) and extracted with DCM (500 mL). The organic layer was concentrated in vacuo to give the crude product. The crude product was purified by column chromatography on silica gel (petroleum ether: EtOAc = 5:1 to 2:1) to afford 8-bromo-2- (toluene-4-sulfonyl)-1 , 2, 3, 4-tetrahydro-benzo[c]azepin-5-one (35 g, yield: 81percent) as a white solid. [0527j Synthesis of 8-bromo-3, 4-dihydrobenzo[b]oxepin-5(2H)-one was similar to that of 8-bromo-2-(toluene-4-sulfonyl)- 1, 2, 3 , 4-tetrahydro-benzo [c] azepin-5 -one. The crude product was purified by silica gel column chromatography (petroleum ether: EtOAc = 4:1) to give 8- bromo-3, 4-dihydrobenzo[b]oxepin-5(2H)-one as a white solid (1.2 g, yield: 71percent). ESI-MS (M+H) : 241.1. ‘H NMR (400 MHz, CDC13) 5: 7.64 (d, J = 8.8 Hz, 1H), 7.27-7.23 (m, 2H), 4.25 (t, J = 6.8 Hz, 2H), 2.89 (t, J = 7.2 Hz, 2H), 2.25-2.18 (m, 2H).To a solution of 4-(3-bromophenoxy)butanoic acid (1.82 g, 7.04 mmol) in DCM (35 mL) was added SOClPreparation 55C: 8-Bromo-3, 4-dih drobenzo[b]oxepin-5(2H)-one[00407] To 4-(3-bromophenoxy)butanoic acid (Preparation 55B, 2.9 g, 1 1.19 mmol) was added PPA (13.6 mL, 11.2 mmol) at room temperature. The reaction mixture was heated at 100 °C for 14 h. To the dark reaction mixture was added ice cubes over a period of 5 min. (~ 5g). The mixture was brought to room temperature, and stirred for 20 min. The dark reaction mixture was partitioned between ethyl acetate (120 mL) and water (50 mL). The organic layer was washed with brine (20 mL), dried over sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography using a mixture of ethyl acetate and hexane (4.5:0.5) to yield 8-bromo- 3, 4-dihydrobenzo [b]oxepin-5(2H)-one (0.170 g, 0.705 mmol, 6.3 percent yield) as a yellow oil.

Molecular Weight:241.08
XLogP3:2.4
Hydrogen Bond Acceptor Count:2
Exact Mass:239.97859
Monoisotopic Mass:239.97859
Topological Polar Surface Area:26.3
Heavy Atom Count:13
Complexity:205
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes