4-Chloro-5-nitro-2-hydroxypyridine

Ammonia (74.0 mL, 3418.64 mmol) was condensed into THF (170 mL) cooled to -78 11.7 Ammonia gas (100 mL) was condensed into THF (300 mL) at -78°C in a cardice/acetone bath. Potassium tert- butoxide (395 mmol, 44.25 g) was then added portion-wise with stirring. After 5 minutes, the cardice bath was lowered so only the bottom quarter of the flask was immersed and stirring was continued for a further 20 minutes. Concurrently, tert-butyl hydroperoxide (158 mmol, 26.3 mL) was added to a suspension of 4-chloro-3- nitropyridine (158 mmol, 25 g) in THF (100 mL) cooled in an ice/water bath. This mixture was stirred for 45 minutes then transferred to a dropping funnel and added drop-wise over 1.25 hours to the ammonia solution (0797) prepared above. The mixture was stirred for a further 3 hours then saturated aqueous ammonium chloride solution (35 mL) was added carefully. The mixture was allowed to warm to room temperature overnight allowing the ammonia to vent to atmosphere. The solvents were then removed under reduced pressure and the residue triturated with ice-cold saturated aqueous ammonium chloride solution (50 mL) . The resulting solid was collected by filtration, washed with ice-cold water (2 x 50 mL) then dried under suction prior to further drying by azeotroping with toluene (5 x 100 mL) then in a vacuum oven at 40°C overnight to give the title compound as a brown solid (24.96 g, 90percent) .Step 2. 4-Chloro-2-hydroxy-5-nitropyridine THF (500 mL) was cooled to-78 °C and anhydrous NH3 (-200 mL) was condensed into the THF. Potassium t-butoxid (71.0 g, 630 mmol) was added and the mixture was allowed to warm to--35 OC. The product from Step 1 (40.0 g, 250 mmol) was cooled to 0 °C in THF (200 mL) and a solution of t-BuOOH (5 M in decane, 50 mL, 250 mmol) was added over 5 min. This solution was then added dropwise to the KOt-Bu solution prepared above over 1 h, then stirred for 2 h at-35 °C and then carefully quenched with-50 mL of sat. NH4C1 solution. The mixture was allowed to vent and warm to rt overnight, then the organics were concentrated and the residue made acidic with NH4Cl solution and filtered. The solid was washed with cold H20 and dried to give the title compound as a dark brown solid (35 g, 80 percent).Step 2. 4-Chloro-2-hydroxy-5-nitropyridine THF (500 mL) was cooled to-78 °C and anhydrous NH3 (-200 mL) was condensed into the THF. Potassium t-butoxid (71.0 g, 630 mmol) was added and the mixture was allowed to warm to--35 OC. The product from Step 1 (40.0 g, 250 mmol) was cooled to 0 °C in THF (200 mL) and a solution of t-BuOOH (5 M in decane, 50 mL, 250 mmol) was added over 5 min. This solution was then added dropwise to the KOt-Bu solution prepared above over 1 h, then stirred for 2 h at-35 °C and then carefully quenched with-50 mL of sat. NH4C1 solution. The mixture was allowed to vent and warm to rt overnight, then the organics were concentrated and the residue made acidic with NH4Cl solution and filtered. The solid was washed with cold H20 and dried to give the title compound as a dark brown solid (35 g, 80 percent).Into a 1 L 4-necked round-bottom flask purged and maintained with nitrogen, was added tetrahydrofuran (200 mL). Ammonia gas was bubbled into the solution at -70 °C to afford a saturated solution of ammonia. To the mixture was added t-BuOK (53.1 g, 0.473 mol) at -70 °C, providing solution (I). Into another 5 L 4-necked round-bottom flask purged and maintained with nitrogen, was added a solution of 4-chloro-3-nitropyridine (30.0 g, 0.189 mol) in tetrahydrofuran (200 mL). To the mixture was added i-BuOOH (53.1 g, 0.473 mol) at 0 °C to afford a solution (II) Solution (II) was added dropwise into Solution (I) at -70 °C, the resulting solution was stirred at - 40 °C for 2 hours. The reaction mixture was quenched by addition of saturated aqueous ammonium chloride and concentrated under vacuum. The residue was triturated with water, and the solids were collected by filtration, washed with THF (50 mL) and dried under vacuum to afford 4-chloro-5-nitropyridin-2-ol (13.0 g, 39.0 percent) as a yellow solid. LCMS (ESI): R(4b) 4-chloro-5-nitropyridin-2-ol Ammonia gas was bubbled against tetrahydrofuran (60 mL) at −78° C. for 1.5 hr, potassium tert-butoxide (8.88 g, 78.8 mmol) was added, and the mixture was heated to −35° C. 4-Chloro-3-nitropyridine (5.00 g, 31.5 mmol) produced in Example 4 (4a) was dissolved in tetrahydrofuran (25 mL) and, under ice-cooling, 5.5 M tert-butylhydrogen peroxide/decane solution (31.0 mL, 171 mmol) was added. This solution was added dropwise to the ammonia solution prepared earlier over 1 hr, and the mixture was stirred at the same temperature for 1.5 hr. To the reaction mixture was added saturated ammonium chloride water to separate the mixture into two layers. The organic layer was evaporated under reduced pressure, saturated aqueous ammonium chloride was added and the precipitate was collected by filtration and washed with water to give the title object compound as a pale-brown powder (670 mg). The filtrate was extracted twice with ethyl acetate, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the precipitated powder was collected by filtration with hexane to give the title object compound as a pale-brown powder (1.18 g, total yield 34percent).

Molecular Weight:174.54
XLogP3:0.1
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:3
Exact Mass:173.9832197
Monoisotopic Mass:173.9832197
Topological Polar Surface Area:74.9
Heavy Atom Count:11
Complexity:276
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes