6-Bromo-3H-oxazolo[4,5-b]pyridin-2-one

In a dry 3000 mL single-necked round-bottomed flask, 1500 mL of acetonitrile and 360 mL of acetic acid were added followed by a solution of 42. 8 g of 2, 3-dihydropyrido [2, 3-d] [1, 3] ketone. After complete dissolution, 64.2 g of NBS (N-bromosuccinimide) was added portionwise and the reaction mixture was stirred at room temperature for 14 hours. After confirming completion of the reaction by TLC and GC, 20 mL of sodium peroxodisulfate (24 g) The solvent was removed by rotary evaporation, 300 mL of water was added to the reaction flask, and the mixture was extracted twice with 300 mL of ethyl acetate.The organic phase was combined, washed with 180 mL of 2N sodium hydroxide And then washed with 300 mL of saturated brine. Dried over anhydrous sodium sulfate overnight. The sodium sulphate was removed by filtration, and the crude product was obtained by evaporation under reduced pressure. 64. 1 g of the crude product was obtained as a crude product, 6-bromo-3H-oxazolidine [4, 5-B] The crude product was recrystallized from methylene chloride and ethyl acetate to give pure product 6-bromo-3H-oxazolo [4, 5-b] pyridin-2-one 59. 9 g, yield 89percent . 2percent (GC). Melting point of 231 ° C to 234 ° C (literature 232 ° C ~ 233 ° C).Compound 21 (1.23 g, 9.04 mmol) was dissolved in DMF (9.04 ml) and then bromine (0.512 ml, 9.94 mmol) was added dropwise [J. Med. Chem. 1993, 36, 497-503]. The reaction mixture was stirred at room temperature for 1.5 hours, poured onto crushed ice and the solid was collected by filtration, washed with water and dried under high vacuum to afford title 00103] As shown in step 4-ii of Scheme 4, bromine (10.8 mL, 210.1 mmol) was added dropwise over 20 min to a stirring solution of Compound 1011 (26.0 g, 191 mmol) in DMF (200 mL). The reaction mixture was stirred at RT for 14 h. The mixture was poured onto crushed ice and the precipitate that formed was collected in a fritted funnel. The solid was washed with water (200 mL) and dried under vacuum to afford 6-bromooxazolo[4, 5- 6]pyridine-2(JH)-one (Compound 1012, 37.0 g, 91percent yield) as a light yellow solid: ESMS (M+Η) 215, 217; As shown in step 4-ii of Scheme 4, bromine (10.8 mL, 210.1 mmol) was added dropwise over 20 min to a stirring solution of Compound 1011 (26.0 g, 191 mmol) in DMF (200 mL). The reaction mixture was stirred at RT for 14 h. The mixture was poured onto crushed ice and the precipitate that formed was collected in a fritted funnel. The solid was washed with water (200 mL) and dried under vacuum to afford 6-bromooxazolo[4, 5- 6]pyridine-2(JH)-one (Compound 1012, 37.0 g, 91percent yield) as a light yellow solid: ESMS (M+Η) 215, 217; Preparation 7 A solution of 3H-oxazolo[4, 5-6]pyridin-2-one (20.0 g, 147 mmol) in DMF was added dropwise to a solution of Br1: To a solution of 3/+oxazolo[4, 5-6]pyridin-2-one (13.6 g, 100 mmol) in acetonitrile (600 mL) and acetic acid (120 mL) was added N-bromosuccinimide (21.4 g, 120 mmol). The mixture was stirred at room temperature for 4 hr and the reaction was quenched with NaTo the stirred solution of compound 2( 0.5 g, 3.35 mmol )in DMF ( 3 ml )was added bromine(0.53g, 3.35 mmol ) at 0°C.After 2h stirring at room temperature , reaction mass was poured onto crushed ice, solid was followed out , filtered the solid and dried under vacuum to get the desired compound 3 ( 0.25 g )Step-2 [0135] To the stirred solution of compound 2 (0.5 g, 3.35 mmol) in DMF (3 ml) was added bromine (0.53 g, 3.35 mmol) at 0° C. After 2 h stirring at room temperature, reaction mass was poured onto crushed ice, solid was followed out, filtered the solid and dried under vacuum to get the desired compound 3 (0.25 g)In a dry 3000 mL single-necked round-bottomed flask, 1500 mL of acetonitrile and 360 mL of acetic acid were added followed by a solution of 42. 8 g of 2, 3-dihydropyrido [2, 3-d] [1, 3] ketone. After complete dissolution, 64.2 g of NBS (N-bromosuccinimide) was added portionwise and the reaction mixture was stirred at room temperature for 14 hours. After confirming completion of the reaction by TLC and GC, 20 mL of sodium peroxodisulfate (24 g) The solvent was removed by rotary evaporation, 300 mL of water was added to the reaction flask, and the mixture was extracted twice with 300 mL of ethyl acetate.The organic phase was combined, washed with 180 mL of 2N sodium hydroxide And then washed with 300 mL of saturated brine. Dried over anhydrous sodium sulfate overnight. The sodium sulphate was removed by filtration, and the crude product was obtained by evaporation under reduced pressure. 64. 1 g of the crude product was obtained as a crude product, 6-bromo-3H-oxazolidine [4, 5-B] The crude product was recrystallized from methylene chloride and ethyl acetate to give pure product 6-bromo-3H-oxazolo [4, 5-b] pyridin-2-one 59. 9 g, yield 89% . 2% (GC). Melting point of 231 C to 234 C (literature 232 C ~ 233 C).Compound 21 (1.23 g, 9.04 mmol) was dissolved in DMF (9.04 ml) and then bromine (0.512 ml, 9.94 mmol) was added dropwise [J. Med. Chem. 1993, 36, 497-503]. The reaction mixture was stirred at room temperature for 1.5 hours, poured onto crushed ice and the solid was collected by filtration, washed with water and dried under high vacuum to afford title 00103] As shown in step 4-ii of Scheme 4, bromine (10.8 mL, 210.1 mmol) was added dropwise over 20 min to a stirring solution of Compound 1011 (26.0 g, 191 mmol) in DMF (200 mL). The reaction mixture was stirred at RT for 14 h. The mixture was poured onto crushed ice and the precipitate that formed was collected in a fritted funnel. The solid was washed with water (200 mL) and dried under vacuum to afford 6-bromooxazolo[4, 5- 6]pyridine-2(JH)-one (Compound 1012, 37.0 g, 91% yield) as a light yellow solid: ESMS (M+Eta) 215, 217; 1H NMR (DMSO-d6) delta 12.6 (br, 1Eta), 8.2 (s, 1Eta), 8.0 (s, 1Eta).As shown in step 4-ii of Scheme 4, bromine (10.8 mL, 210.1 mmol) was added dropwise over 20 min to a stirring solution of Compound 1011 (26.0 g, 191 mmol) in DMF (200 mL). The reaction mixture was stirred at RT for 14 h. The mixture was poured onto crushed ice and the precipitate that formed was collected in a fritted funnel. The solid was washed with water (200 mL) and dried under vacuum to afford 6-bromooxazolo[4, 5- 6]pyridine-2(JH)-one (Compound 1012, 37.0 g, 91% yield) as a light yellow solid: ESMS (M+Eta) 215, 217; 1H NMR (DMSO-d6) delta 12.6 (br, 1Eta), 8.2 (s, 1Eta), 8.0 (s, 1Eta).Preparation 7 6-BROMO-3H-OXAZOLO[4, 5-b]-PYRIDIN-2-ONE 0.01 mol of oxazolo[4, 5-b]pyridin-2-one is dissolved in 100 ml of dimethylformamide. 0.011 mol of bromine is added via a dropping funnel. Stirring is maintained for 1 hour 30 minutes at room temperature and an ice/water mixture is added. The product is filtered off. It is washed with water. The product is dried. Yield: 90%. Melting point: 234 C.A solution of 3H-oxazolo[4, 5-6]pyridin-2-one (20.0 g, 147 mmol) in DMF was added dropwise to a solution of Br2 (8.30 mL, 162 mmol) in DMF at 0 C. The mixture was heated to reflux under a nitrogen atmosphere for 2h. After 2h, ice water (250 mL) was added dropwise and the mixture was stirred for 15 minutes. The resulting precipitate was isolated by filtration, washed with water and dried under vacuum at 50 0C overnight to give the title compound (28.0 g, 89%) as a yellow solid: 1H NMR (SOO MHZ, DMSO-^) S 12.6 (br s, lH), 8.10 (s, IH), 8.01 (s, IH); ESI MS m/z 216 (M + H)+.1: To a solution of 3H-oxazolo[4, 5-b]pyridin-2-one (13.6 g, 100 mmol) in acetonitrile (600 mL) and acetic acid (120 mL) was added N-bromosuccinimide (21.4 g, 120 mmol). The mixture was stirred at room temperature for 4 hr and the reaction was quenched with Na2S2O5 solution. After evaporation, the residue was partitioned between ethyl acetate and water. The organic layer was washed with 2N NaOH solution, brine, and dried over Na2SO4. The crude product was purified on a silica gel column to provide 6-bromo-3H-oxazolo[4, 5-b]pyridin-2-one (11.5 g, 55% yield).To a solution of 3/+oxazolo[4, 5-6]pyridin-2-one (13.6 g, 100 mmol) in acetonitrile (600 mL) and acetic acid (120 mL) was added N-bromosuccinimide (21.4 g, 120 mmol). The mixture was stirred at room temperature for 4 hr and the reaction was quenched with Na2S205 solution. After evaporation, the residue was partitioned between ethyl acetate and water. The organic layer was washed with 2N NaOH solution, brine, and dried over Na2S04. The crude product was purified on a silica gel column to provide e-bromo-SAfoxazoloK.S-bJpyridin^-one (11.5 g, 55% yield).To the stirred solution of compound 2( 0.5 g, 3.35 mmol )in DMF ( 3 ml )was added bromine(0.53g, 3.35 mmol ) at 0C.After 2h stirring at room temperature , reaction mass was poured onto crushed ice, solid was followed out , filtered the solid and dried under vacuum to get the desired compound 3 ( 0.25 g )Step-2 [0135] To the stirred solution of compound 2 (0.5 g, 3.35 mmol) in DMF (3 ml) was added bromine (0.53 g, 3.35 mmol) at 0 C. After 2 h stirring at room temperature, reaction mass was poured onto crushed ice, solid was followed out, filtered the solid and dried under vacuum to get the desired compound 3 (0.25 g)To a stirred suspension of [1 , 3]oxazolo[4, 5-o]pyridin-2(3H)-one (1-51) (34 g, 0.25 mol) in MeCN (0.35 L) was added NBS (47.6 g, 0.275 mol) in a portionwise manner at 0 C. After addition, the reaction mixture was stirred at room temperature for 3 h. TLC (EtOAc/hexane = 1 :1) indicated the reaction was complete. The precipitate was filtered, washed with cold MeCN (150 ml_) and dried under vacuum to yleld 6-bromo[1 , 3]oxazolo[4, 5-o]pyridin-2(3H)-one (I-52) (45 g, 84%) as a yellow solid, which was used directly in the next step.Compound WXO7O-5 (1.80 g, 8.37 mmol), 2-fluo- rophenylboronic acid (1.41 g, 10.04 mmol) was dissolved in dioxane (30.00 mE) at room temperature, followed by the addition of [1, 1 ?-bis(diphenylphosphino)ferrocene] palladium dichloride dichloromethane complex (341.76 mg, 418. 50 jtmol), potassium carbonate (4.68 g, 33.89 mmol) and water (10.00 mE). The reaction mixture was heated to 80 C. and stirred for 3 hours under nitrogen atmosphere. After the reaction, the mixture was cooled to room temperature, quenched with saturated brine (10 mE), diluted with water (30 mE) and extracted with ethyl acetate (10 mEx3). The organic phases were combined, washed with water (30 mEx2) and dried over anhydrous sodium sulfate, followed by filtration. The filtrate was concentrated under reduced pressure. The obtained residue was isolated by silica gel colunm chromatography (eluent: petroleum ether/ethyl acetate3/1 -1/1, volume ratio) to obtain the target product WXO71-1. MS-ESI m/z: 231.0 [M+H].Compound WXO7O-5 (230.00 mg, 1.07 mmol), triphenylphosphine (336.78 mg, 1.28 mmol) and compound WXO7O-2 (293.53 mg, 1.07 mmol) were dissolved in tetrahydrofuran (4.00 mE) at room temperature, followed by the addition of diisopropyl azodicarboxylate (259.64 mg, 1.28 mmol) at 0 C. The reaction mixture was stirred at 0-20 C. for 12 hours under nitrogen atmosphere. After the reaction, the mixture was diluted with water (20 mE).10323] The separated aqueous phase was extracted with ethyl acetate (20 mEx3). The organic phases were combined, washed with saturated brine (20 mE) and dried over anhydrous sodium sulfate, followed by filtration. The filtrate was concentrated under reduced pressure to remove the solvent. The obtained residue was isolated by silica gel colunm chromatography (eluent: petroleum ether/ethyl acetate=1/1, volume ratio) to obtain the target productWXO7O. MS-ESI mlz: 470.9 [M+H], 473.0 [M+H+2]. 'H NMR (400 MHz, CDC13) oe: 1.47 (t, J=6.9 Hz, 3H), 2.85 (s, 3H), 3.81 (dd, J=14.6, 4.52 Hz, 1H), 3.85 (s, 3H), 4.07-4.13 (m, 2H), 4.73 (dd, J=14.3, 10.3 Hz, 1H), 6.02 (dd, J=10.2, 4.4 Hz, 1H), 6.84 (d, J8.5 Hz, 1H), 7.19 (dd, J8.3, 2.0 Hz, 1H), 7.24 (d, J2.0 Hz, 1H), 7.56 (d, J2.0 Hz, 1H), 8.22 (d, J2.0 Hz, 1H).

Molecular Weight:215.00
XLogP3:1.1
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:3
Exact Mass:213.93779
Monoisotopic Mass:213.93779
Topological Polar Surface Area:51.2
Heavy Atom Count:11
Complexity:187
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes