6-BROMO-2H-PYRIDO[3,2-B][1,4]OXAZIN-3(4H)-ONE

Compound 3.1 (2.7 g, 8.85 mmol) And iron powder (2.48g, 44.3mmol) Add to acetic acid (40 mL), The reaction system was stirred at 100 ° C for 2 hours. Cool to room temperature, The reaction solution was filtered through celite. Add water (100 mL) to the filtrate. Extracted with dichloromethane (20 mL x 3), Combine the organic phase, Drying with anhydrous sodium sulfate, concentrate, The residue was subjected to silica gel column chromatography ( petroleum ether / ethyl acetate = 3/1) Purification of compound 3.2 (1.9 g, yield: 95percent) It is a pale yellow liquid.Compound 1a was synthesized from 5 using same procedure as mentioned for compound 1c in 80percent yield. Step 3 To a solution of Compound (8) (5.50 g, 18.0 mmol) in acetic acid (60 mL), iron powder (10.1 g, 180 mmol) was added. The solution was then stirred at 100°C for 2 hours. The reaction solution was filtered through a Celite pad, and then the filtrate was concentrated in vacuo. The residue was dissolved in ethyl acetate, washed with aqueous saturated sodium bicarbonate, dried with anhydrous magnesium sulfate, and then concentrated in vacuo. The resulting powder was further washed with ethyl acetate and hexane to yield the subject compound (9) (3.12 g, 76percent) as a white powder.To a stirred solution of ethyl 2-((6-bromo-2-nitropyridin-3-yl)oxy)acetate, lb (21g, 0.0687mol) in glacial acetic acid (400ml), Iron powder(l 1.51g, 0.2063mol) was added and heated to 100°C for 6 hours. After completion of the reaction, reaction mixture was filtered through celite bed using ethyl acetate, 10percent Methanol and concentrated in vacuo. It was washed with Methanol to obtain pure 6-bromo-2H-pyrido[3, 2-b][l, 4]oxazin- 3(4H)-one, I (12g, 76.28percent ). LCMS = Calculated for CC. c) 6-Bromo-4H-pyrido[3, 2-b][1 , 4]oxazin-3-one; Ethyl (6-bromo-2-nitro-pyridin-3-yloxy)acetate (38 g, 0.125 mole) was dissolved in glacial AcOH (150 mL), and iron powder (20 g, 0.36 mole) was added. The mixture was mechanically stirred and heated at 90 (c) 6-Bromo-4f/-pyrido[3, 2-b][1 , 4]oxazin-3-one; Ethyl (6-bromo-2-nitro-pyridin-3-yloxy)acetate (38 g, 0.125 mole) was dissolved in glacial AcOH (150 ml_), and iron powder (20 g, 0.36 mole) was added. The mixture was mechanically stirred and heated at 90 Ethyl (6-bromo-2-nitro-pyridin-3-yloxy)acetate (38 g, 0.125 mole) was dissolved in glacial AcOH (150 mL), and iron powder (20 g, 0.36 mole) was added. The mixture was mechanically stirred and heated at 90 Ethyl (6-bromo-2-nitro-pyridin-3-yloxy)acetate (38 g, 0.125 mole) was dissolved in glacial AcOH (150 mL), and iron powder (20 g, 0.36 mole) was added. The mixture was mechanically stirred and heated at 90 Ethyl (6-bromo-2-nitro-pyridin-3-yloxy)acetate (38 g, 0.125 mole) was dissolved in glacial AcOH (150 mL), and iron powder (20 g, 0.36 mole) was added. The mixture was mechanically stirred and heated at 90 c) 6-Bromo-4H-pyrido[3, 2-b][1, 4]oxazin-3-one; Ethyl (6-bromo-2-nitro-pyridin-3-yloxy)acetate (38 g, 0.125 mole) was dissolved in glacial AcOH (150 mL), and iron powder (20 g, 0.36 mole) was added. The mixture was mechanically stirred and heated at 90° C. for 5 hr, then was cooled to room temperature and diluted with EtOAc (300 mL). The mixture was filtered through a pad of silica gel and the filtrate was concentrated in vacuo and the residue recrystallized from MeOH (15 g, 52percent); MS (ES) m/z229.0 (M+H)The nitropyridine (g) (38 g, 0.125 mol) was dissolved in glacial AcOH (150 ml), and iron powder (20 g, 0.36 mole) was added. The mixture was mechanically stirred and heated at 90°C for 5 hours, then was cooled to room temperature and diluted with EtOAc (300 ml). The mixture was filtered through a pad of silica gel and the filtrate was concentrated ira vacuo and the residue recrystallized from MeOH (15 g, 52percent). MS (+ve ion electrospray) m/z 229 (MH+).The nitropyridine (g) (38 g, 0.125 mole) was dissolved in glacial [ACOH] (150 mL), and iron powder (20 g, 0.36 mole) was added. The mixture was mechanically stirred and heated at [90 °C] for 5 hr, then was cooled to room temperature and diluted with EtOAc (300 mL). The mixture was filtered through a pad of silica gel and the filtrate was concentrated [IN VACUO] and the residue recrystallized from MeOH (15 g, 52percent). MS (ES) [M/Z] 229.0 (M + H) +.Ethyl ester (3b) (38 g, 0.125 mol) was dissolved in glacial AcOH (150 mL), and iron powder (20 g, 0.36 mol) was added. The mixture was mechanically stirred and heated at 90 degree;C for 5 h, then was cooled to room temperature and diluted with EtOAc (300 mL). The mixture was filtered through a pad of silica gel and the filtrate was concentrated in vacuo and the residue recrystallized from MeOH (15 g, 52percent). MS (ES) m/z 229.0 (M + H)+The nitropyridine (305b) (38 g, 0.125 mole) was dissolved in glacial AcOH (150 ml), and iron powder (20 g, 0.36 mole) was added. The mixture was mechanically stirred and heated at 90 °C for 5 hr, then was cooled to room temperature and diluted with EtOAc (300 ml). The mixture was filtered through a pad of silica gel and the filtrate was concentrated in vacuo and the residue recrystallized from MeOH (15 g, 52percent). MS (ES) m/z 229.0 (M + H) +.c) 6-Bromo-4/-/-pyrido[3, 2-b][1 , 4]oxazin-3-one; Ethyl (6-bromo-2-nitro-pyridin-3-yloxy)acetate (38 g, 0.125 mole) was dissolved in glacial AcOH (150 ml_), and iron powder (20 g, 0.36 mole) was added. The mixture was mechanically stirred and heated at 90 °C for 5 hr, then was cooled to room temperature and diluted with EtOAc (300 mL). The mixture was filtered through a pad of silica gel and the filtrate was concentrated in vacuo and the residue recrystallized from MeOH (15 g, 52percent); MS (ES) m/z 229.0 (M + H)+.c) 6-Bromo-4H-pyrido[3, 2-b][1, 4]oxazin-3-one; Ethyl (6-bromo-2-nitro-pyridin-3-yloxy)acetate (38 g, 0.125 mole) was dissolved inglacial AcOH (150 mL), and iron powder (20 g, 0.36 mole) was added. The mixture wasmechanically stirred and heated at 90 °C for 5 hr, then was cooled to room temperatureand diluted with EtOAc (300 mL). The mixture was filtered through a pad of silica gel andthe filtrate was concentrated in vacua and the residue recrystallized from MeOH (15 g, 52percent); MS (ES) m/z 229.0 (M + H)+.; c) 6-Bromo-4/-/-pyrido[3, 2-b][1, 4]oxazin-3-one; The nitropyridine (38 g, 0.125 mole) was dissolved in glacial AcOH (150 mL), andiron powder (20 g, 0.36 mole) was added. The mixture was mechanically stirred andheated at 90 °C for 5 hr, then was cooled to room temperature and diluted with EtOAcrni(c) 6-Bromo-4/-/-pyrido[3, 2-b][1, 4]oxazin-3-one; Ethyl (6-bromo-2-nitro-pyridin-3-yloxy)acetate (38 g, 0.125 mole) was dissolved in glacial AcOH (150 mL), and iron powder (20 g, 0.36 mole) was added. The mixture was mechanically stirred and heated at 90 °C for 5 h, then was cooled to room temperature and diluted with EtOAc (300 mL). The mixture was filtered through a pad of silica gel and the filtrate was concentrated in vacuo and the residue recrystallized from MeOH (15 g, 52percent); MS (ES) m/z 229.0 (M + H)+.c) 6-Bromo-4H-pyrido[3, 2-b][1 , 4]oxazin-3-one Ethyl (6-bromo-2-nitro-pyridin-3-yloxy)acetate (38 g, 0.125 mole) was dissolved in glacial AcOH (150 ml_), and iron powder (20 g, 0.36 mole) was added. The mixture was mechanically stirred and heated at 90 0C for 5 hr, then was cooled to room temperature and diluted with EtOAc (300 ml_). The mixture was filtered through a pad of silica gel and the filtrate was concentrated in vacuo and the residue recrystallized from MeOH (15 g, 52percent); MS (ES) m/z 229.0 (M + H)+.Ethyl (6-bromo-2-nitro-pyridin-3-yloxy)acetate (38 g, 0.125 mole) was dissolved in glacial AcOH (150 mL), and iron powder (20 g, 0.36 mole) was added. The mixture was mechanically stirred and heated at 90 0C for 5 hr, then was cooled to room temperature and diluted with EtOAc (300 mL). The mixture was filtered through a pad of silica gel and the filtrate was concentrated in vacuo and the residue recrystallized from MeOH (15 g, 52percent); MS (ES) m/z 229.0 (M + H)+.Ethyl (6-bromo-2-nitro-pyridin-3-yloxy)acetate (38 g, 0.125 mole) was dissolved in glacial AcOH (150 mL), and iron powder (20 g, 0.36 mole) was added. The mixture was mechanically stirred and heated at 90 A suspension of the crude D4 and iron powder (162 g, 2.90 mol) in acetic acid (1.2 L) was heated at 90 ° C for 1.5 hours. After dilution of the mixture with EtOAc (2.4 L), the resulting precipitates were filtered off. The filtrate was concentrated under reduced pressure. Flash column chromatography (hexane/EtOAc = 2: 1) of the residue gave D5 (69.0 g, 30percent). 1H NMR (400 MHz, CDC1To a stirred solution of IVa (32 g, 0.139 mol) and III (31.7 g, 0.139 mol) in dry l, 4-dioxane (50 mL), were added t-butyl-X-Phos mesyl chloride complex ( 5.5 g, 0.0069 mol) and sodium tert-butoxide (19.94 g, 0.207 mol) and degassed for 20 mins. Then, it was heated in sealed tube at 100 C for 16 h. After completion of the reaction, reaction mixture was concentrated under reduced pressure. It was purified by column chromatography on silica gel (230-400 mesh, 25-30% ethyl acetate in pet ether) to afford IVb (45.6 g, 86%). LC-MS Calc for Ci7H25N305Si: 379.49; Obs.: 380.0; XH NMR (400 MHz, DMSO-de): d 7.60 (d, J = 8.68 Hz, 1H), 7.43 (d, J = 8.68 Hz, 1H), 4.77-4.73 (m, 1H), 4.67 (s, 2H), 4.15-4.10 (m, 1H), 3.93-3.89 (m, 3H), 0.79 (s, 9H), 0.04 (s, 6H).To a stirred solution of lla (32 g, 0.139 mol) and 6-bromo-2H-pyrido[3, 2-b][l, 4]oxazin- 3(4H)-one (WO2017199265, 31.7 g, 0.139 mol) in dry l, 4-dioxane (50 mL), were added t-butyl-X-Phos mesyl chloride complex( 5.5 g, 0.0069 mol) and sodium tert-butoxide (19.94 g, 0.207 mol) and was degassed for 20 mins. Then, it was heated in sealed tube at 100 C for 16 h. After completion of the reaction, reaction mixture was concentrated under reduced pressure. It was purified by column chromatography on silica gel (230-400 mesh, 25-30% ethyl acetate in pet ether) to afford lib (45.6 g, 86%). LC_MS Calculated for C17H25N3O5S1, 379.49, Observed 380.0. lH NMR (400 MHz, DMSO-d6). d 7.60 (d, J = 8.68 Hz, 1H), 7.43 (d, J = 8.68 Hz, 1H), 4.77-4.73 (m, 1H), 4.67 (s, 2H), 4.15-4.10 (m, 1H), 3.93-3.89 (m, 3H), 0.79 (s, 9H), 0.04 (s, 6H).To a stirred solution of Ila (3.92 g, 0.0171 mol) and I (3.6 g, 0.0155 mol) in dry 1, 4-dioxane (50 mL), were added t-butyl-X-Phos mesyl chloride complex (0.618 g, 0.0077 mol) and sodium tert-butoxide (2.24 g, 0.0234 mol) and degassed for 20 mins. Then, it was heated in sealed tube at 100 C for 16 h. After completion of the reaction, reaction mixture was concentrated under reduced pressure. It was purified by column chromatography on silica gel (230-400 mesh, 25-30% ethyl acetate in pet ether) to afford lib (3.5 g, 59%); LC-MS Calculated for C17H25N3O5S1, 379.49, Observed 380.0; 1H NMR (400 MHz, DMSO-d6): delta 7.60 (d, J = 8.68 Hz, 1H), 7.43 (d, J = 8.68 Hz, 1H), 4.77-4.73 (m, 1H), 4.67 (s, 2H), 4.15-4.10 (m, 1H), 3.93-3.89 (m, 3H), 0.79 (s, 9H), 0.04 (s, 6H).

Molecular Weight:229.03
XLogP3:1.2
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:3
Exact Mass:227.95344
Monoisotopic Mass:227.95344
Topological Polar Surface Area:51.2
Heavy Atom Count:12
Complexity:200
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes