| 96% |
|
3-Hydroxy-2-nitropyridine (20 g, 0.143 mole) was dissolved in methanol (400 mL) and a solution of 25% sodium methoxide in methanol (33 mL, 0.13 mole) was added at room temperature. The mixture was stirred for 30 min, then was cooled to 0 0C, and bromine (7.2 mL, 0.14 mole) was added slowly. The reaction was stirred at 0 0C for 30 min, then was quenched with glacial AcOH (2.5 mL). The solvent was removed in vacuo to afford material (30 g, 96%), which was used without further purification.MS (ES) m/z219.0 (M + H)+. |
| 96% |
|
3-Hydroxy-2-nitropyridine (20 g, 0.143 mole) was dissolved in methanol (400 mL) and a solution of 25% sodium methoxide in methanol (33 mL, 0.13 mole) was added at room temperature. The mixture was stirred for 30 min, then was cooled to 0 C, and EPO <DP n="24"/>bromine (7.2 mL, 0.14 mole) was added slowly. The reaction was stirred at 0 0C for 30 min, then was quenched with glacial AcOH (2.5 mL). The solvent was removed in vacuo to afford material (30 g, 96%), which was used without further purification: MS (ES) m/z219.0 (M + H)+. |
| 96% |
|
Preparation 3; Preparation of 3-Oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-6-carboxaldehyde; a) 2-Bromo-5-hydroxy-6-nitropyridine; 3-Hydroxy-2-nitropyridine (20 g, 0.143 mole) was dissolved in methanol (400 mL) and a solution of 25% sodium methoxide in methanol (33 mL, 0.13 mole) was added at room temperature. The mixture was stirred for 30 min, then was cooled to 0 C., and bromine (7.2 mL, 0.14 mole) was added slowly. The reaction was stirred at 0 C. for 30 min, then was quenched with glacial AcOH (2.5 mL). The solvent was removed in vacuo to afford material (30 g, 96%), which was used without further purification. MS (ES) m/z219.0 (M+H)+.; Preparation 6; a) 2-Bromo-5-hydroxy-6-nitropyridine; 3-Hydroxy-2-nitropyridine (20 g, 0.143 mole) was dissolved in methanol (400 mL) and a solution of 25% sodium methoxide in methanol (33 mL, 0.13 mole) was added at room temperature. The mixture was stirred for 30 min, then was cooled to 0 C., and bromine (7.2 mL, 0.14 mole) was added slowly. The reaction was stirred at 0 C. for 30 min, then was quenched with glacial AcOH (2.5 mL). The solvent was removed in vacuo to afford material (30 g, 96%), which was used without further purification. MS (ES) m/z219.0 (M+H)30 . |
| 96% |
|
3-Hydroxy-2-nitropyridine (20 g, 0.143 mole) was dissolved in methanol (400 ml) and a solution of 25% sodium methoxide in methanol (33 ml, 0.13 mol) was added at room temperature. The mixture was stirred for 30 minutes, then cooled to 0 C, and bromine (7.2 ml, 0.14 mol) was added slowly. The reaction was then stirred at 0 C for 30 minutes, then was quenched with glacial AcOH (2.5 ml). The solvent was removed in vacuo to afford material (30 g, 96%), which was used without further purification. MS (+ve ion electrospray) m/z 219 (MH+). |
| 96% |
|
3-Hydroxy-2-nitropyridine (20 g, 0.143 mole) was dissolved in methanol (400 [ML)] and a solution of 25% sodium methoxide in methanol (33 mL, 0.13 mole) was added at room temperature. The mixture was stirred for 30 min, then was cooled to [0 C,] and bromine (7. [2] mL, 0.14 mole) was added slowly. The reaction was then stirred at [0 C] for 30 min, then was quenched with glacial [ACOH] (2.5 mL). The solvent was removed in vacuo to afford material (30 g, 96%), which was used without further purification. MS (ES) [NIEZ 219.] 0 [(M + H)] +. |
| 96% |
|
3-Hydroxy-2-nitropyridine (20 g, 0.143 mol) was dissolved in methanol (400 mL) and a solution of 25% sodium methoxide in methanol (33 mL, 0.13 mol) was added at room temperature. The mixture was stirred for 30 min, then was cooled to 0 °ree;C, and bromine (7.2 mL, 0.14 mol) was added slowly. The reaction was then stirred at 0 °ree;C for 30 min, then was quenched with glacial AcOH (2.5 mL). The solvent was removed in vacuo to afford material (30 g, 96%), which was used without further purification. MS (ES) m/z 219.0 (M + H)+. |
| 96% |
|
3-Hydroxy-2-nitropyridine (20 g, 0.143 mole) was dissolved in methanol (400 ml) and a solution of 25% sodium methoxide in methanol (33 ml, 0.13 mole) was added at room temperature. The mixture was stirred for 30 min, then was cooled to 0 C, and bromine (7.2 ml, 0.14 mole) was added slowly. The reaction was then stirred at 0 C for 30 min, then was quenched with glacial AcOH (2.5 ml). The solvent was removed in vacuo to afford material (30 g, 96%), which was used without further purification. MS (ES) m/z 219.0 (M + H) +. |
| 96% |
|
Preparation 16; Preparation of 3-Oxo-3,4-dihvdro-2/-/-pyridor3,2-jb1H ,41oxazine-6-carboxaldehyde; a) 2-Bromo-5-hydroxy-6-nitropyridine; 3-Hydroxy-2-nitropyridine (20 g, 0.143 mole) was dissolved in methanol (400 mL) and a solution of 25% sodium methoxide in methanol (33 mL, 0.13 mole) was added at room temperature. The mixture was stirred for 30 min, then was cooled to 0 C, and bromine (7.2 mL, 0.14 mole) was added slowly. The reaction was stirred at 0 0C for 30 min, then was quenched with glacial AcOH (2.5 ml_). The solvent was removed in vacuo to afford material (30 g, 96%), which was used without further purification. MS (ES) m/z 219.0 (M + H)+. |
| 96% |
|
Preparation 10; Preparation of 3-Oxo-3.4-dihvdro-2H-pvrido[3.2-foiri ,41oxazine-6-carboxalde; a) 2-Bromo-5-hydroxy-6-nitropyridine; 3-Hydroxy-2-nitropyridine (20 g, 0.143 mole) was dissolved in methanol (400 ml)and a solution of 25% sodium methoxide in methanol (33 mL, 0.13 mole) was added atroom temperature. The mixture was stirred for 30 min, then was cooled to 0 C, andbromine (7.2 mL, 0.14 mole) was added slowly. The reaction was stirred at 0 C for 30mm, irien was quenuneu wiui yiauitil AcOH (2.5 mL). The solvent was removed in vacuato afford material (30 g, 96%), which was used without further purification.MS(ES)m/z219.0(M + H)+.; Preparation 11; Preparation of 7-chloro-3-oxo-3,4-dihydro-2/-/-1.4-benzoxazine-6-carbaldehyde; a) 2-Bromo-5-hydroxy-6-nitropyridine; 3-Hydroxy-2-nitropyridine (20 g, 0.143 mole) was dissolved in methanol (400 ml)and a solution of 25% sodium methoxide in methanol (33 mL, 0.13 mole) was added atroom temperature. The mixture was stirred for 30 min, then was cooled to 0 C, andbromine (7.2 mL, 0.14 mole) was added slowly. The reaction was stirred at 0 C for 30min, then was quenched with glacial AcOH (2.5 mL). The solvent was removed in vacuato afford material (30 g, 96%), which was used without further purification.MS(ES)m/z219.0(M + H)+. |
| 96% |
|
Preparation 5; Preparation of 3-Oxo-3.4-dihvdro-2H-pvridof3.2-/?in ,41oxazine-6-carboxaldehvde; (a) 2-Bromo-5-hydroxy-6-nitropyridine; 3-Hydroxy-2-nitropyridine (20 g, 0.143 mole) was dissolved in methanol (400 mL) and a solution of 25% sodium methoxide in methanol (33 mL, 0.13 mole) was added at room temperature. The mixture was stirred for 30 min, then was cooled to 0 C, and bromine (7.2 mL, 0.14 mole) was added slowly. The reaction was stirred at 0 C for 30 min, then was quenched with glacial AcOH (2.5 mL). The solvent was removed in vacuo to afford material (30 g, 96%), which was used without further purification: MS (ES) m/z 219.0 (M + H)+. |
| 96% |
With bromine; sodium methylate; In methanol; at 0℃; for 0.5h; |
a) 2-Bromo-5-hydroxy-6-nitropyridine3-Hydroxy-2-nitropyridine (20 g, 0.143 mole) was dissolved in methanol (400 mL) and a solution of 25% sodium methoxide in methanol (33 mL, 0.13 mole) was added at room temperature. The mixture was stirred for 30 min, then was cooled to 0 0C, and bromine (7.2 mL, 0.14 mole) was added slowly. The reaction was stirred at 0 0C for 30 min, then was quenched with glacial AcOH (2.5 mL). The solvent was removed in vacuo to afford material (30 g, 96%), which was used without further purification. MS (ES) m/z219.0 (M + H)+. |
| 96% |
|
3-Hydroxy-2-nitropyridine (20 g, 0.143 mole) was dissolved in methanol (400 ml_) and a solution of 25% sodium methoxide in methanol (33 mL, 0.13 mole) was added at room temperature. The mixture was stirred for 30 min, then was cooled to 0 0C, and bromine (7.2 mL, 0.14 mole) was added slowly. The reaction was stirred at 0 0C for 30 min, then was quenched with glacial AcOH (2.5 mL). The solvent was removed in vacuo to afford material (30 g, 96%), which was used without further purification. MS (ES) m/z219.0 (M + H)+. a. 2-bromo-5-hydroxy-6-nitropyridine 3-Hydroxy-2-nitropyridine (20 g, 0.143 mole) was dissolved in methanol (400 ml_) and a solution of 25% sodium methoxide in methanol (33 mL, 0.13 mole) was added at room temperature. The mixture was stirred for 30 min, then was cooled to 0 0C1 and bromine (7.2 mL, 0.14 mole) was added slowly. The reaction was stirred at 0 C for 30 min, then was quenched with glacial AcOH (2.5 mL). The solvent was removed in vacuo to afford material (30 g, 96%), which was used without further purification. MS (ES) m/z 219.0 (M + H)+. |
| 96% |
|
3-Hydroxy-2-nitropyridine (20 g, 0.143 mole) was dissolved in methanol (400 mL) and a solution of 25% sodium methoxide in methanol (33 mL, 0.13 mole) was added at room temperature. The mixture was stirred for 30 min, and then was cooled to 0 0C, and bromine (7.2 mL, 0.14 mole) was added slowly. The reaction was stirred at 0 0C for 30 min, then was quenched with glacial AcOH (2.5 mL). The solvent was removed in vacuo to afford material (30 g, 96%), which was used without further purification: MS (ES) m/z219.0 (M + H)+ |
| 86.4% |
With N-Bromosuccinimide; In N,N-dimethyl-formamide; at 20℃; for 12h; |
3-Hydroxy-2-nitropyridine (50 g, 357 mmol) was dissolved in 900 mL of N, N-dimethylformamide. N-bromosuccinimide (82.57 g, 464 mmol) was slowly added thereto and stirred at room temperature for 12 hours. After the reaction was completed, the solution was concentrated using a rotary evaporator, and then extracted twice with distilled water and dichloromethane.The precipitate was formed using methyl alcohol and distilled water and filtered to obtain a mixture of compound 1 and dibrominated compound (67.5 g, Y = 86.4%) in an 8: 2 ratio. |
| 62% |
With N-Bromosuccinimide; In N,N-dimethyl-formamide; at 0 - 20℃; for 3h; |
(Example 2 Synthesis of Compounds I-113 and 1-144) [Show Image]Step 1 A solution of 2-nitropyridin-3-ol (6) (16.0 g, 114 mmol) in dimethylformamide (120 mL) was cooled to 0C, and then N-bromosuccinimide (26.4 g, 1.48 mmol) was gradually added thereto. The solution was then stirred at 0 C for 1 hour, and at room temperature for another 2 hours. The reaction solution was concentrated in vacuo, and then the residue was washed with diethyl ether. The filtrate was poured to aqueous saturated sodium bicarbonate, followed by extraction with diethyl ether. The organic layer was washed sequentially with water and saturated brine, then dried with anhydrous magnesium sulfate, and concentrated in vacuo to yield the subject compound (7) (15.5 g, 62%) as a white powder. |
| 54% |
With tin(II) bromide; sodium hydroxide; In water; at 3.3 - 20℃; for 0.966667h; |
A solution of 3-hydroxy-2-nitropyridine (176.0 g, 1.256 mol) in aqueous sodiumhydroxide (74.0 mL of 50% NaOH in 1.94 L water, 1.40 mol) was cooled at 3.3 C whiledibromantin (198.5 g, 0.694 mol) was added portion-wise over 58 minutes maintaining reaction temperature at or below 4 C. The reaction mixture was then allowed to warm to room temperature overnight. The reaction was quenched with acetic acid (80.0 mL, 1.34 mol), and the resulting slurry was stirred at room temperature for 4 h. The solids werecollected by filtration, washed with water (3 x 300 mL), and then vacuum-dried (35C) overnight to give 148.3 g (54%) of 2-bromo-5-hydroxy-6-nitropyridine as a yellow solid with a purity of 97.8% (LC). |
| 54.1% |
With N-Bromosuccinimide; In N,N-dimethyl-formamide; at 0 - 20℃; |
A solution of 2-nitropyridin-3-ol (15 g, 104 mmol) in DMF (189 mL) was cooled to 0C then N- bromosuccinimide (24 g, 135 mmol) was added gradually over 25 minutes. The solution was stirred at 0C for an additional 15 minutes and then the mixture was allowed to warm to RT, and stirred over night. The reaction mixture was concentrated in vacuo and purified by column chromatography using 100% CH2CI2 to afford 6-bromo-2-nitro-pyridin-3-ol (13.67 g, 56.2 mmol, 54.1 % yield) as a yellow solid. MS ES+ (m/z): 219.1 [(M+H)+]. |
| 53% |
|
Compound I-1 (5 g, 35.7 mmol) was added to a clean and dry reaction flask,Dissolved in 50 mL of methanol,After replacing the nitrogen three times,Sodium methoxide (2.89 g, 53.5 mmol)In methanol (15 mL) was added dropwise to the reaction system,The reaction was stirred at room temperature for 30 min.The reaction was then cooled to 0 C,Bromine (6.3 g, 39.4 mmol) was added dropwise,The temperature of the reaction system was controlled at 0-5 CUnder the conditions of reaction 4h;(CH2Cl2: CH3OH = 25: 1), the reaction was quenched with a small amount of 10% aqueous sodium sulfite solution, the reaction system was cooled to -15C, and the yellow solid was stirred,After filtration, the filter cake was washed with ice methanol (2 x 5 mL), dried,A yellow solid was the target product I-2 (4.2 g, 53%). |
| 53% |
|
Under an atmosphere of nitrogen, a solution of CH3ONa (2.89 g,53.5 mmol) in CH3OH (15 mL) was added dropwise to a solution of2-nitropyridin-3-ol (16) (5 g, 35.7 mmol) in CH3OH (50 mL) and themixture was stirred at RT for 30 min. After the reaction systemcooling to 0 C, Br2 (6.3 g, 39.4 mmol) was added dropwise withstirring. After 16 was consumed, the mixture was quenched byadding a solution of 10% Na2SO3 and then cooled to 15 C. Yellowsolid was precipitated, filtered and washed with cold CH3OH. Thetitle compound was obtained as a yellow solid (4.2 g, 53%). 1H NMR(400 MHz, DMSO) d 7.85 (d, J 8.64 Hz, 1H), 7.66 (d, J 8.64 Hz,1H); MS (M H): m/z 216.97. |
| 28% |
|
At 0 C, Br2 was slowly added to a mixture of 2-nitropyridin-3-ol ( 1 ; 80.0 g, 570 mmol) and NaOCH3 (30.8 g, 570 mmol) in methanol (600 mL) and stirred at this temperature for 30 m in. AcOH (1.5 mL) was added to the mixture and stirred again for 1 0 min. The crude reaction mixture was then concentrated in vacuo to afford a yellow solid, which was triturated in mixed petroleum ether/EtOAc to give 6-bromo-2-nitropyridin-3-ol (2; 35.0 g, 28%). M S (ESI) calcd for C5H3BrN203 (m/z): 2 17.93. |
|
With N-Bromosuccinimide; In N,N-dimethyl-formamide; at 0 - 20℃; for 20h; |
3-Hydroxy-2-nitropyridine (100 g, 0.714 mole) was dissolved in DMF (1 L), the solution was cooled to 0 0C, and /V-bromosuccinimide (165 g, 0.927 mole) was added portionwise over 5 hr. The mixture was then stirred at RT for 15 hr and concentrated in vacuo. The residue was taken up in Et2O (500 ml.) and the mixture was stirred for 30 min. The precipitate was removed by suction filtration, and the filtrate was concentrated in vacuo to afford the title compound (180 g): MS (ES) m/e 219.0 (M + H)+. This material was used without further purification. |
|
|
A. 6-Bromo-2-nitro-pyridin-3-ol. To a solution of 3-hydroxy-2-nitropyridine (20 g, 140 mmol) in CH3OH (400 mL) was added a solution of 25% NaOCH3 in CH3OH (33.0 mL, 153 mmol). After stirring at RT for 30 min, the reaction mixture was cooled to 0 C. and Br2 (7.2 mL, 140 mmol) added slowly. The mixture was stirred for 30 min, and then was quenched with glacial acetic acid (2.5 mL). The solvent was removed under reduced pressure. A portion of the crude material was purified on SiO2 (50% EtOAc/hexanes) to provide the title compound as a white solid. MS (ESI): exact mass calculated for C5H3BrN2O3, 217.93; m/z not found. 1H NMR (400 MHz, CDCl3): 10.24 (s, 1H), 7.74 (d, J=8.6, 1H), 7.54 (d, J=8.6, 1H). |
|
|
To a stirred solution of 3-hydroxy-2-nitropyridine (l Og, 71.4 mmol) in MeOH (200 mL) was added sodium methoxide (19.8 mL, 71.4 mmol, 3.6 M solution in MeOH) and the resulting mixture was allowed to stir at room temperature for 30 min. The reaction mixture was then cooled to 0 C and bromine (3.7 mL, 71.4 mmol) was added slowly over a period of 30 min. After the reaction was deemed to be complete by LC-MS, the mixture was quenched with glacial acetic acid (1.3 mL) and the volatiles were removed in vacuo. The crude residue thus obtained was azeotroped with heptane to afford 6-bromo-2- nitropyridin-3-ol as a brown solid. |
|
|
Intermediate I3-Oxo-3,4-dihydro-2H-pyrido[3 -b][l,4]oxazine-6-carbaldehyde1.1 I.2To a solution of LI (140 g) in methanol (2.5 L) was added a solution of sodium methoxide [prepared from sodium (24.2 g) and methanol (215 mL)] at room temperature. The mixture was stirred at the same temperature for 30 minutes. Bromine (51.4 mL) was added dropwise to the mixture at 0 C, the mixture was stirred at the same temperature for 2 hours. After quenching the reaction by adding acetic acid (18 mL), the mixture was concentrated in vacuo to give 1.2, which was used for the next step without further purification. |
|
With bromine; sodium methylate; In methanol; at 0℃; for 2h; |
Step 1 : Preparation of 6-bromo-3-methoxy-2-nitropyridine To a stirred solution of 3-hydroxy-2-nitropyridine (50.0 g, 0.34 mol) in MeOH (1 L) was added 30% NaOMe in MeOH (83 mL). The solution was stirred at rt for 30 min then cooled to 0C and Br2 (18 mL, 0.35 mol) was added dropwise maintaining this temperature. The reaction was then stirred at 0C for 2 h before the addition of glacial acetic acid (10 mL). Concentration in vacuo gave crude material (1 19 g), to which was added acetone (2 L) and K2C03 (153 g, 0.8 mol) followed by iodomethane (85.5 mL, 1.4 mol). After stiring at 40C for 4 h the reaction was cooled to rt and filtered. After concentration of the filtrate in vacuo purification by flash chromatography eluting with 3:1 heptane-EtOAc yielded the title compound (14.4 g, 61.8 mmol). 1H NMR: (400 MHz, CDCI3) delta: 3.96 (s, 3H), 7.42 (d, J=8.7, 1 H), 7.68 (d, J=8.7, 1 H) |
|
With phenyltrimethylammonium tribromide; triethylamine; In tetrahydrofuran; at -40℃; for 1h; |
A solution of phenyl trimethyl ammonium tribromide (8.45 g, 22.3 mmol) in THF (68 mL) was added dropwise to a stirred solution of 2-nitropyridin-3-ol (3.00 g, 21.4 mmol) and triethylamine (4.33 g, 5.97 mL, 42.8 mmol) in THF (91 mL) at -40 C. The addition was done over a period of 5 minutes and the reaction mixture was kept at -40 C. for 1 h. 1N HCl and aq. Na2S2O3 were added and the aq. phase was extracted with dichloromethane. The combined organic phase was washed with brine, dried over MgSO4, filtered and the filtrate evaporated under reduced pressure. The residue was purified by silica gel column chromatography eluted with 30 to 100% EtOAc/Hexanes to afford the title compound as a yellow solid. |
|
|
To a solution of D2 (140 g, 1.00 mol) in methanol (2.5 L) was added a solution of sodium methoxide [prepared from Na (24.2 g) and methanol (215 mL)] at room temperature. The mixture was stirred at the same temperature for 30 min. Bromine (51.4 mL, 1.00 mol) was added drop wise to the mixture at 0 C and the mixture was stirred at the 0 C temperature for 2 hours. The reaction was quenched with acetic acid (18 mL) and the mixture was concentrated under reduced pressure to give D3, which was used for the next step without further purification. |
|
With N-Bromosuccinimide; In N,N-dimethyl-formamide; at 0 - 26℃; |
To a solution of 4,6-dichloro-5-metho 2-nitropyridin-3-ol (20g, 0.142mol) in DMF(400ml), N- bromosuccinimide (32.52g, 0.187mol) was added portion wise over a period of 5 hours at 0C. The reaction mixture was stirred for room temperature for 12h. After completion of the reaction, the reaction mixture was concentrated in vacuo. The residue was taken up in the Ether and the mixture was stirred for 30min. The precipitate was removed by filtration and the filtrate was concentrated in vacuo to get 6-bromo-2-nitropyridin-3-ol, la (40g, 46%) as a mixture of mono and di bromo compound. The crude LCMS showed 46% of expected mono-bromo compound, this material was used as such for next step without further purification. LCMS Calculated for C5H3BrN203, 218.99, Observed = 219.2. |
| 22.00 g |
|
To a solution of A-25 (10 g, 71.38 mmol) in methanol (200 mL) was added CH3ONa (3.85 g, 71.38 mmol) slowly at 15 C. The resulting solution was stirred at 15 C for 30 min. Then Br2 (11.41 g, 71.38 mmol) was added to the solution dropwise 0 C and the mixture was stirred at 15 C for 16 hours. The reaction solution was quenched with glacial AcOH (1.25 mL) and concentrated to give the crude product of A-26 (22.00 g, crude) as a solid. The crude product was used in the next step without further purification. LCMS Rt = 0.54 mins using Method B, MS ESI calcd. for C5H4BrN203 [M+H]+ 218.9, found 219.1. |
|
With N-Bromosuccinimide; In N,N-dimethyl-formamide; at 0 - 25℃; |
To a solution of 2-nitropyridin-3-ol (20 g, 0.142 mol) in DMF (400 ml), N- bromosuccinimide (32.52 g, 0.187 mol) was added portion wise over a period of 5 hours at 0C. The reaction mixture was stirred for room temperature for l2h. After completion of the reaction, the reaction mixture was concentrated in vacuo. The residue was taken up in the ether and the mixture was stirred for 30min. The precipitate was removed by filtration and the filtrate was concentrated in vacuo to get 6-bromo-2-nitropyridin-3-ol, Ilia (40 g, 46%) as a mixture of mono and di bromo compound. The crude LCMS showed 46% of expected mono-bromo compound, this material was used as such for next step without further purification. LC-MS Calc for C5H3BrN203: 218.99; Obs.: 219.2. |
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