* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Stage #1: With n-butyllithium In tetrahydrofuran; hexanes at -90℃; Stage #2: With water In tetrahydrofuran; hexanes at -90℃;
Step 36-2.; To a solution of T96-2 (8.0 g, 31.3 mmol) in THF (307 mL) at -90° C. was added slowly a solution of n-BuLi (1.15 M in hexanes, 71 mL). The mixture was stirred for 40 min, then water (10 eq) was added and the mixture warmed to room temperature. The solvent was removed under reduced pressure and the resulting residue purified by flash chromatography (acetone:MeOH, 10:1) to give 3.22 g (60percent) of T 96-3.
Reference:
[1] Synthesis, 2001, # 14, p. 2175 - 2179
3
[ 25813-25-6 ]
[ 74-88-4 ]
[ 2683-35-4 ]
Reference:
[1] Yakugaku Zasshi, 1952, vol. 72, p. 274[2] Chem.Abstr., 1953, p. 6416
4
[ 25813-25-6 ]
[ 13626-17-0 ]
Yield
Reaction Conditions
Operation in experiment
99%
With N-ethyl-N,N-diisopropylamine; trichlorophosphate In acetonitrile for 17 h; Cooling with ice; Reflux
Compound (M-41) (10.0 g, 39.5 mmol) was suspended in acetonitrile (50 mL), DIPEA (15 mL, 87 mmol) wasadded at room temperature, phosphoryl chloride (7.4 mL, 79 mmol) was added under ice-cooling, and the mixture wasstirred with heating under reflux for 17 hr. The mixture was allowed to cool, and the reaction mixture was added dropwiseto ice water, and neutralized with sodium carbonate (11.6 g, 138 mmol). Thereafter, the mixture was extracted with ethylacetate, and the organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The solventwas evaporated under reduced pressure to give a chloro compound (yield 10.6 g, 99percent) as a brown solid. The chlorocompound (10.6 g, 39.1 mmol) was dissolved in THF (70 mL), sodium methoxide (28percent methanol solution, 14 mL, 59mmol) was added, and the mixture was stirred at 60°C for 30 min. The mixture was allowed to cool, water was addedto the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successivelywith water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reducedpressure to give compound (VII-46) (yield 9.21 g, 88percent) as a yellow solid
91%
at 70℃; for 3 h; Inert atmosphere
In a round-bottom flask, equipped with a stirrer, thermometer and reflux condenser, mix under nitrogen in the specified order: 120 mL of phosphoryl chloride and 38 g (150 mmol) of BCD-BTK-104-9. Stir the reaction mass at 70 °C for 3 hours, cool it to 40 °C, and pour on ice, while stirring vigorously. Filter the precipitate, wash with water, and dry under vacuum at 40 °C. Yield: 36.7 g (91percent).
75%
at 140℃; for 2.5 h; Inert atmosphere; Schlenk technique
3,5-dibromopyridin-4-ol (239) (1.00 g, 3.95 mmols) was combined with phosphoryl chloride (921.45 µl, 9.89 mmols) in a pressure stable vessel. The vessel was closed and the solution heated to 140 °C under stirring for 2.5 h. Afterwards the reation vessel was cooled down to rt and the reaction solution combined with ice cold water (75 mL). The aqueous layer was extracted with EtOAc (5 x 15 mL) and the combined organic layers were dried over anhydrous magnesium sulfate. The product was dried in vacuo. Purification of the crude was performed by silica gel column chromatography (1percent EtOAc/n‑pentane) to obtain the product (805 mg, 2.97 mmols, 75percent) as a white solid. Rf: 0.32 (5percent EtOAc/PE). 1H NMR (500 MHz, CDCl3) δ = 8.63 (s, 2H). 13C NMR (126 MHz, CDCl3) δ = 150.97, 144.13, 121.93. GC-MS: tR = 4.59 min; m/z = 268.8, 270.8, 272.8, 274.8 [M]+. HRMS (ESI): calculated for C5H3N 79Br235Cl: m/z = 269.83153 [M+H]+, found: m/z = 269.83155 [M+H]+. calculated for C5H3N 79Br237Cl: m/z = 271.82858 [M+H]+, found: m/z = 271.82878 [M+H]+. calculated for C5H3N 79Br 81Br 37Cl: m/z = 273.82653 [M+H]+, found: m/z = 273.82597 [M+H]+. calculated for C5H3N 81Br235Cl: m/z = 275.82449 [M+H]+, found: m/z = 275.82316 [M+H]+.
Reference:
[1] Patent: EP3351533, 2018, A1, . Location in patent: Paragraph 0676; 0678
[2] Patent: WO2018/92047, 2018, A1, . Location in patent: Page/Page column 94-95
[3] Tetrahedron, 2018, vol. 74, # 35, p. 4531 - 4537
[4] Justus Liebigs Annalen der Chemie, 1932, vol. 4942, p. 284,299
5
[ 626-64-2 ]
[ 25813-25-6 ]
Yield
Reaction Conditions
Operation in experiment
100%
With N-Bromosuccinimide In tetrachloromethane at 20℃; for 24 h;
Step 36-1.; To a solution of 4-hydroxypyridine (T96-1, 7.0 g, 74 mmol) in CCl4 (360 mL) at rt was added NBS (26.2 g, 0.147 mol). The solution was stirred for 24 h in the dark (covered with aluminum foil). The mixture was concentrated under reduced pressure and the resulting residue triturated with MeOH, then with acetone to give 18.9 g (100percent) of T96-2.
88%
With N-Bromosuccinimide In tetrachloromethane at 25℃; for 30 h; Inert atmosphere
In a round-bottom flask, equipped with a stirrer, thermometer and reflux condenser, mix under nitrogen in the specified order: 500 mL of tetrachloromethane, 23.75 g (250 mmol) of 4-hydroxypyridine, and 89 g (500 mmol) of N-bromosuccinimide. Stir at 25 °C for 30 hours. Filter the precipitate, wash with 50 mL of tetrachloromethane; stir the precipitate in a mixture of 500 mL of acetone and 150 mL of methanol for 15 minutes. Filter the suspension; stir the precipitate in a mixture of 400 mL of acetone and 400 mL of dichloromethane for 15 minutes. Filter the suspension; mix the precipitate vigorously in 400 mL of acetonitrile for 20 minutes. Filter the suspension; dry the precipitate under vacuum at 40 °C. Yield: 56 g (88percent).
86%
With N-Bromosuccinimide In tetrachloromethane at 20℃; for 24 h;
4-Pyridinol (M-40) (20.0 g, 210 mmol) was suspended in carbon tetrachloride (400 mL), NBS (77.0 g, 431mmol) was added, and the mixture was stirred under shading at room temperature for 24 hr. The solvent was evaporatedunder reduced pressure, and the residue was suspended in acetone (400 mL)/methanol (120 mL), and the mixture wasstirred at room temperature for 30 min. The precipitated solid was collected by filtration and suspended in acetonitrile(1.0 L), and the suspension was stirred at room temperature for 1 hr. The solid were collected by filtration, and driedunder reduced pressure to give compound (M-41) (yield 46.0 g, 86percent) as a white solid
86%
With N-Bromosuccinimide In tetrachloromethane at 20℃; for 24 h;
4-pyridinol (M-40) (20.0 g, 210 mmol)Was suspended in carbon tetrachloride (400 mL)NBS (77.0 g, 431 mmol) was added and, under light shielding,And the mixture was stirred at room temperature for 24 hours.After distilling off the solvent under reduced pressure,The residue was suspended in acetone (400 mL) / methanol (120 mL) and stirred at room temperature for 30 minutes.The precipitated solid was collected by filtration,This was suspended in acetonitrile (1.0 L)And the mixture was stirred at room temperature for 1 hour. After collecting the solid by filtration,After drying under reduced pressure, the compound (M-41)(Yield 46.0 g, yield 86percent)As a white solidIt was.
68%
With N-Bromosuccinimide In tetrachloromethane at 20℃; for 24 h; Darkness
To a stirring solution of pyridine-4-ol (5g, 52.6 mmol) in CC14 (100 mL) at room temperature was added N-bromosuccinimide (18.72g, 105 mmol). The reaction mixture was allowed to stir under cover of darkness for 24 hours. The solvent was removed under reduced pressure, and the obtained solid was dissolved with acetone (100 mL) and MeOH (30 mL) and stirred for 5 min. The resulting slurry was filtered and the solid was rinsed with excess acetone/CH2Cl2. The solid material was vigorously stirred with acetonitrile, and filtered to yield Intermediate 31A (9.04g, 35.7 mmol, 68percent yield) as an off-white solid. MS (ES): m/z=253.8 [M+H]+. 3/4 NMR (400 MHz, MeOD) δ ppm 8.30 (2 H, s).
Reference:
[1] Synthesis, 2001, # 14, p. 2175 - 2179
7
[ 110-89-4 ]
[ 25813-25-6 ]
Reference:
[1] Chemische Berichte, 1879, vol. 12, p. 988
8
[ 1124-33-0 ]
[ 25813-25-6 ]
Reference:
[1] Recueil des Travaux Chimiques des Pays-Bas, 1951, vol. 70, p. 581,587
9
[ 108-96-3 ]
[ 25813-25-6 ]
Reference:
[1] Gazzetta Chimica Italiana, 1948, vol. 78, p. 873,876
10
[ 694-59-7 ]
[ 25813-25-6 ]
Reference:
[1] Recueil des Travaux Chimiques des Pays-Bas, 1951, vol. 70, p. 581,587
11
[ 25813-25-6 ]
[ 124-41-4 ]
[ 25813-24-5 ]
Yield
Reaction Conditions
Operation in experiment
88%
Stage #1: With N-ethyl-N,N-diisopropylamine; trichlorophosphate In acetonitrile at 20℃; for 17 h; Cooling with ice; Reflux Stage #2: at 60℃; for 0.5 h;
Compound (M-41) (10.0 g, 39.5 mmol)Was suspended in acetonitrile (50 mL)DIPEA (15 mL, 87 mmol) was added at room temperature,Phosphoryl chloride (7.4 mL, 79 mmol)Was added under cooling with ice, and the mixture was stirred under heating reflux for 17 hours. After allowing to cool, the reaction solution was added dropwise to ice water,And neutralized with sodium carbonate (11.6 g, 138 mmol).Thereafter, the mixture was extracted with ethyl acetate,The organic layer was washed with saturated brine,And dried over anhydrous sodium sulfate.The solvent was distilled off under reduced pressure,Chloro compound (yield 10.6 g, yield 99percent)As a brown solid.Chloro form (10.6 g, 39.1 mmol)Was dissolved in THF (70 mL)Sodium methoxide (28percent methanol solution,14 mL, 59 mmol) was added,Followed by stirring at 60 ° C. for 30 minutes. After cooling down,Water was added to the reaction solution, and the mixture was extracted with ethyl acetate.The organic layer was washed successively with water and saturated brine,And dried over anhydrous sodium sulfate.The solvent was distilled off under reduced pressure,Compound (VII-46) (yield 9.21 g, yield 88percent)As a yellow solid.
Reference:
[1] Patent: JP2018/145180, 2018, A, . Location in patent: Paragraph 0633; 0634; 635
With N-ethyl-N,N-diisopropylamine; trichlorophosphate; In acetonitrile; for 17h;Cooling with ice; Reflux;
Compound (M-41) (10.0 g, 39.5 mmol) was suspended in acetonitrile (50 mL), DIPEA (15 mL, 87 mmol) wasadded at room temperature, phosphoryl chloride (7.4 mL, 79 mmol) was added under ice-cooling, and the mixture wasstirred with heating under reflux for 17 hr. The mixture was allowed to cool, and the reaction mixture was added dropwiseto ice water, and neutralized with sodium carbonate (11.6 g, 138 mmol). Thereafter, the mixture was extracted with ethylacetate, and the organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The solventwas evaporated under reduced pressure to give a chloro compound (yield 10.6 g, 99%) as a brown solid. The chlorocompound (10.6 g, 39.1 mmol) was dissolved in THF (70 mL), sodium methoxide (28% methanol solution, 14 mL, 59mmol) was added, and the mixture was stirred at 60C for 30 min. The mixture was allowed to cool, water was addedto the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successivelywith water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reducedpressure to give compound (VII-46) (yield 9.21 g, 88%) as a yellow solid
91%
With trichlorophosphate; at 70℃; for 3h;Inert atmosphere;
In a round-bottom flask, equipped with a stirrer, thermometer and reflux condenser, mix under nitrogen in the specified order: 120 mL of phosphoryl chloride and 38 g (150 mmol) of BCD-BTK-104-9. Stir the reaction mass at 70 C for 3 hours, cool it to 40 C, and pour on ice, while stirring vigorously. Filter the precipitate, wash with water, and dry under vacuum at 40 C. Yield: 36.7 g (91%).
75%
With trichlorophosphate; at 140℃; for 2.5h;Inert atmosphere; Schlenk technique;
3,5-dibromopyridin-4-ol (239) (1.00 g, 3.95 mmols) was combined with phosphoryl chloride (921.45 mul, 9.89 mmols) in a pressure stable vessel. The vessel was closed and the solution heated to 140 C under stirring for 2.5 h. Afterwards the reation vessel was cooled down to rt and the reaction solution combined with ice cold water (75 mL). The aqueous layer was extracted with EtOAc (5 x 15 mL) and the combined organic layers were dried over anhydrous magnesium sulfate. The product was dried in vacuo. Purification of the crude was performed by silica gel column chromatography (1% EtOAc/n-pentane) to obtain the product (805 mg, 2.97 mmols, 75%) as a white solid. Rf: 0.32 (5% EtOAc/PE). 1H NMR (500 MHz, CDCl3) delta = 8.63 (s, 2H). 13C NMR (126 MHz, CDCl3) delta = 150.97, 144.13, 121.93. GC-MS: tR = 4.59 min; m/z = 268.8, 270.8, 272.8, 274.8 [M ]+. HRMS (ESI): calculated for C5H3N 79Br2 35Cl: m/z = 269.83153 [M+H]+, found: m/z = 269.83155 [M+H]+. calculated for C5H3N 79Br2 37Cl: m/z = 271.82858 [M+H]+, found: m/z = 271.82878 [M+H]+. calculated for C5H3N 79Br 81Br 37Cl: m/z = 273.82653 [M+H]+, found: m/z = 273.82597 [M+H]+. calculated for C5H3N 81Br2 35Cl: m/z = 275.82449 [M+H]+, found: m/z = 275.82316 [M+H]+.
With phosphorus pentabromide; at 180℃; for 3h;sealed tube;
A vessel was charged with a mixture of Intermediate 31A (3.08 g, 12.18 mmol) and phosphorous pentabromide (2.5 g, 5.81 mmol). The vessel was sealed and heated to 180 C for 3 hours. Upon cooling, the reaction mixture was diluted with water (10 mL) and filtered. The solid material was washed with successive quantities of water until the filtrate was a neutral pH. Intermediate 3 IB was obtained as a grey solid (3.7 g, 11.60 mmol, 95% yield). MS (ES): m/z=317.7 [M+H]+. ¾ NMR (400 MHz, MeOD) delta ppm 8.71 (2 H, s).
With N-Bromosuccinimide; In tetrachloromethane; at 20℃; for 24h;
Step 36-1.; To a solution of <strong>[626-64-2]4-hydroxypyridine</strong> (T96-1, 7.0 g, 74 mmol) in CCl4 (360 mL) at rt was added NBS (26.2 g, 0.147 mol). The solution was stirred for 24 h in the dark (covered with aluminum foil). The mixture was concentrated under reduced pressure and the resulting residue triturated with MeOH, then with acetone to give 18.9 g (100%) of T96-2.
88%
With N-Bromosuccinimide; In tetrachloromethane; at 25℃; for 30h;Inert atmosphere;
In a round-bottom flask, equipped with a stirrer, thermometer and reflux condenser, mix under nitrogen in the specified order: 500 mL of tetrachloromethane, 23.75 g (250 mmol) of <strong>[626-64-2]4-hydroxypyridine</strong>, and 89 g (500 mmol) of N-bromosuccinimide. Stir at 25 C for 30 hours. Filter the precipitate, wash with 50 mL of tetrachloromethane; stir the precipitate in a mixture of 500 mL of acetone and 150 mL of methanol for 15 minutes. Filter the suspension; stir the precipitate in a mixture of 400 mL of acetone and 400 mL of dichloromethane for 15 minutes. Filter the suspension; mix the precipitate vigorously in 400 mL of acetonitrile for 20 minutes. Filter the suspension; dry the precipitate under vacuum at 40 C. Yield: 56 g (88%).
86%
With N-Bromosuccinimide; In tetrachloromethane; at 20℃; for 24h;
4-Pyridinol (M-40) (20.0 g, 210 mmol) was suspended in carbon tetrachloride (400 mL), NBS (77.0 g, 431mmol) was added, and the mixture was stirred under shading at room temperature for 24 hr. The solvent was evaporatedunder reduced pressure, and the residue was suspended in acetone (400 mL)/methanol (120 mL), and the mixture wasstirred at room temperature for 30 min. The precipitated solid was collected by filtration and suspended in acetonitrile(1.0 L), and the suspension was stirred at room temperature for 1 hr. The solid were collected by filtration, and driedunder reduced pressure to give compound (M-41) (yield 46.0 g, 86%) as a white solid
86%
With N-Bromosuccinimide; In tetrachloromethane; at 20℃; for 24h;
4-pyridinol (M-40) (20.0 g, 210 mmol)Was suspended in carbon tetrachloride (400 mL)NBS (77.0 g, 431 mmol) was added and, under light shielding,And the mixture was stirred at room temperature for 24 hours.After distilling off the solvent under reduced pressure,The residue was suspended in acetone (400 mL) / methanol (120 mL) and stirred at room temperature for 30 minutes.The precipitated solid was collected by filtration,This was suspended in acetonitrile (1.0 L)And the mixture was stirred at room temperature for 1 hour. After collecting the solid by filtration,After drying under reduced pressure, the compound (M-41)(Yield 46.0 g, yield 86%)As a white solidIt was.
68%
With N-Bromosuccinimide; In tetrachloromethane; at 20℃; for 24h;Darkness;
To a stirring solution of pyridine-4-ol (5g, 52.6 mmol) in CC14 (100 mL) at room temperature was added N-bromosuccinimide (18.72g, 105 mmol). The reaction mixture was allowed to stir under cover of darkness for 24 hours. The solvent was removed under reduced pressure, and the obtained solid was dissolved with acetone (100 mL) and MeOH (30 mL) and stirred for 5 min. The resulting slurry was filtered and the solid was rinsed with excess acetone/CH2Cl2. The solid material was vigorously stirred with acetonitrile, and filtered to yield Intermediate 31A (9.04g, 35.7 mmol, 68% yield) as an off-white solid. MS (ES): m/z=253.8 [M+H]+. ¾ NMR (400 MHz, MeOD) delta ppm 8.30 (2 H, s).
With bromine; potassium hydroxide; In water; at 0℃; for 3h;
To a stirred solution of potassium hydroxide (2.35 g, 0.042 mol) in water (40 mL) was added <strong>[626-64-2]pyridin-4-ol</strong> ( 2.0 g, 0.021 mol) and mixture was cooled to 0 C. To the above solution bromine was added slowly at 0 C and stirred for 3 h. The reaction mixture was filtered and washed the solid with cold water, hexane and dried under vacuum to obtain the title compound. MS (M+l): 251.8.
Step 36-2.; To a solution of T96-2 (8.0 g, 31.3 mmol) in THF (307 mL) at -90 C. was added slowly a solution of n-BuLi (1.15 M in hexanes, 71 mL). The mixture was stirred for 40 min, then water (10 eq) was added and the mixture warmed to room temperature. The solvent was removed under reduced pressure and the resulting residue purified by flash chromatography (acetone:MeOH, 10:1) to give 3.22 g (60%) of T 96-3.
To a stirred solution of 3,5-dibromopyridin-4-ol (IN-11; 2.5 g, 0.00988 mol) in dry tetrahydrofuran (100 mL) at -100 C was added 1.6 M t-butyl lithium in hexane (15.6 mL, 0.0247 mol) drop wise under nitrogen atmosphere and stirred for 2 h at -100 C. The reaction mixture was quenched with water (1.77 g, 0.0988 mol) at -100 C and allows the reaction mixture to RT slowly. The reaction mixture was evaporated. The obtained crude was purified with silica gel chromatography by 0 -12% methanol in dichloromethane to afford the title compound. 1H NMR (400 MHz, DMSO-i¾) delta: 11.71 (s, 1 H), 8.15 (s, 1 H), 7.66-7.65 (d, J= 5.6 Hz, 1 H), 6.20-6.18 (d, J=6.4 Hz, 1 H). MS (M+l): 173.8
EXAMPLE 6; 5-Benzyl-N-(4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluorophenyl)-4-oxo-1,4-dihydropyridine-3-carboxamide; A) 3-Bromo-5-(hydroxy(phenyl)methyl)pyridin4-ol; To a heterogeneous mixture of <strong>[25813-25-6]3,5-dibromo-4-hydroxypyridine</strong> (2.53 g, 10 mmol, prepared following the procedure in Synthesis, 2001, No. 14, 2175-2179) in anhydrous THF (20 mL) at -78 C. under Ar-atm was added phenylmagnesium bromide solution (11 mL of 1 M solution in THF, 11 mmol). After stirring for 15 min. was added nBuLi solution (5.5 mL of 2 M solution in cyclohexane), and the reaction mixture was stirred for 15 minutes at -78 C. under Ar-atm. To this mixture benzaldehyde (2.15 mL, 21 mmol) was added and the reaction mixture was stirred for 2 h -78 C. under Ar-atm. The reaction mixture was quenched by adding HOAc (3 mL) and TFA (3 mL), concentrated and the residue was purified by flash column on silica gel eluting with hexane/EtOAc/MeOH//750:250:50 followed by hexane/EtOAc/MeOH/Et3N//460:460:50:10 to obtain the desired product (2.85 g, 91%) as a white solid. 1H NMR (CD3OD) delta8.13 (s, 1H), 8.04 (s, 1H), 7.41-7.20 (m, 5H), 5.94 (s, 1H); MS(ESI+) m/z 280, 282 (M+H)+.
A solution of methyllithium in ether (1 M, 4.8 ml) was added to a solution of <strong>[25813-25-6]3,5-dibromopyridin-4-ol</strong> (1200 mg) in THF (10 ml) at -78 C., and the mixture was stirred for 30 minutes. A solution of n-butyllithium in hexane (1.65 M, 6.0 ml) was added at -78 C., and the mixture was stirred for one hour. Dry ice was added at -78 C. and the mixture was stirred at 0 C. for 20 minutes, followed by addition of a 4 N aqueous hydrochloric acid solution. The precipitated solid was collected by filtration and washed with water to give a mixture of the title compound and <strong>[25813-25-6]3,5-dibromopyridin-4-ol</strong>.
Compound (M-41) (10.0 g, 39.5 mmol)Was suspended in acetonitrile (50 mL)DIPEA (15 mL, 87 mmol) was added at room temperature,Phosphoryl chloride (7.4 mL, 79 mmol)Was added under cooling with ice, and the mixture was stirred under heating reflux for 17 hours. After allowing to cool, the reaction solution was added dropwise to ice water,And neutralized with sodium carbonate (11.6 g, 138 mmol).Thereafter, the mixture was extracted with ethyl acetate,The organic layer was washed with saturated brine,And dried over anhydrous sodium sulfate.The solvent was distilled off under reduced pressure,Chloro compound (yield 10.6 g, yield 99%)As a brown solid.Chloro form (10.6 g, 39.1 mmol)Was dissolved in THF (70 mL)Sodium methoxide (28% methanol solution,14 mL, 59 mmol) was added,Followed by stirring at 60 C. for 30 minutes. After cooling down,Water was added to the reaction solution, and the mixture was extracted with ethyl acetate.The organic layer was washed successively with water and saturated brine,And dried over anhydrous sodium sulfate.The solvent was distilled off under reduced pressure,Compound (VII-46) (yield 9.21 g, yield 88%)As a yellow solid.
With potassium carbonate; In tetrahydrofuran; at 50 - 55℃; for 3h;
In a 500 ml four-necked flask equipped with a stirring, thermometer, and reflux condenser,130 grams of tetrahydrofuran,22.6 g (0.05 mol) of 3,3,5,5-tetrabromopiperidin-4-one obtained in Example 6,16.6 g of potassium carbonate,Stir the reaction at 50-55 C for 3 hours.Cool to 20-25 ,Filtered, the filter cake was washed with 20 g of solvent,Combine the filtrates and recover the solvent by distillation.11.5 g of 3,5-dibromo-4-hydroxypyridine was obtained as a white solid,Yield 90.9% (yield based on piperidin-4-one hydrochloride),The liquid purity was 99.2%.