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With sulfuric acid; nitric acid; at 85℃;Cooling with ice;
a) 5-Fluoro-3-nitropyridin-2-ol A mixture of concentrated sulphuric acid (1 mL) and fuming nitric acid (1 mL) was added dropwise to a stirred, cooled (ice-bath) mixture of 5-fluoropyridin-2-ol (1.20 g, 10.6 mmol) and concentrated sulphuric acid (2.7 mL). The mixture was warmed to ambient temperature and then to 85 C. After 2 hours, the mixture was cooled and poured onto ice-water. The precipitate was filtered and dried to give the title compound (0.72 g, 43%) as a yellow solid. LRMS (m/z): 157 (M-1)+. 1H NMR delta (300 MHz, DMSO-d6): 8.28 (s, 1H), 8.67 (s, 1H).
43%
With sulfuric acid; nitric acid; at 85℃; for 2h;Cooling with ice;
5-Fluoro-2-methoxypyridin-3 -amine a) 5-Fluoro-3-nitropyridin-2-olA mixture of concentrated sulphuric acid (1 mL) and fuming nitric acid (1 mL) was added dropwise to a stirred, cooled (ice-bath) mixture of 5-fluoropyridin-2-ol (1 .20 g, 10.6 mmol) and concentrated sulphuric acid (2.7 mL). The mixture was warmed to ambient temperature and then heated to 85 C. After 2 hours, the mixture was cooled and poured onto ice-water. The precipitate was filtered and dried to give the title compound (0.72 g, 43%) as a yellow solid.LRMS (m/z): 157 (M-1 )+.1H NMR delta (300 MHz, DMSO-d6): 8.28 (s, 1 H), 8.67 (s, 1 H).
40%
With sulfuric acid; nitric acid; at 28 - 65℃; for 2.75h;
To a solution of 5-fluoro-2-hydroxypyridine (200 mg, 1.77 mmol) in concentrated sulfuric acid (900 mul) was added, dropwise over 15 minutes, a premixed solution of concentrated sulfuric acid (900 mul) and fuming nitric acid (170 mul). The internal temperature rose by up to 280C. The reaction mixture was then heated at 650C for 2.5 hours. The cooled mixture was poured onto ice-water, and the pH of the mixture was adjusted to 2.5 with sodium carbonate. It was then extracted with ethyl acetate (2 x 25 ml). The aqueous layer was concentrated and extracted again with a mixture of tetrahydrofuran (25 ml) and ethyl acetate (25 ml). The organic layers were combined, dried over magnesium sulfate, filtered and concentrated under reduced pressure to yield the title compound (112 mg, 40%) as a solid. 1H NMR (400MHz, DMSO-D6): delta 8.22 (dd, 1 H), 8.60 (dd, 1 H); LRMS APCI" m/z 157 [M-H]'.
With sulfuric acid; nitric acid; In water; at 65 - 80℃; for 1h;
The solid from above containing (4-80) was divided in 4 batches and treated with H2SO4 and fuming HNO3 as shown below. The amounts used were: Compound 4-80 was dissolved in sulfuric acid (the larger amounts indicated above) at rt and then heated to 65 C. A preformed solution of fuming nitric acid and sulfuric acid (the smaller amount indicated above) was added dropwise. The temperature was kept between 65 C. and 80 C. (rxn is exothermic and although the bath is at 65 C., temperature goes higher, usually 75, sometimes 80 C.). After the addition was complete, the reaction mixture was heated at 65 C. for an additional hr. The reaction mixture was then cooled to rt and poured in a flask containing ice) (20 g of ice/gr compound, evolution of gas occurred). A solid precipitated out and it was collected by filtration (1HNM? showed 4-80 and something else (discarded)). [1493] The aqueous layer was extracted with AcOEt several times (3-5) and concentrated on a rotary evaporator under vacuum to afford a solid that was triturated with ether to afford 5-80 as a bright yellow solid. A total of 117 g of desired product was collected in the first crop (27% yield from diazonium salt). A portion did not crystallize: this oil was triturated with MeOH and Et2O to afford 3.6 g of 5-80; another precipitation from the mother liquid afforded an additional 6.23 g of the desired product 5-80 [1494] Total:117.0+3.6+6.23 =126.83. 30.4%). Yield for 3 steps (decomposition of diazonium salt; deprotection and nitration). [1495] Analytical data from Notebook: 53877-115: 1HNMR(delta, MeOD): 8.56-8.27 (dd, J=7.5, 3.3 Hz, 1H), 8.01 (d, J=3.3 Hz, 1H); LC/MS(M+1)+=158.9; rt=0.15 min. [1496] Note: A portion of the aqueous acidic solution was taken and neutralized with Na2CO3 until effervescence stopped and then it was extracted with AcOEtA different product was obtained. No desired product in these extracts.
With sulfuric acid; nitric acid; at 20 - 80℃; for 1h;
Intermediate 3 was dissolved in sulfuric acid (the larger amounts indicated above) at rt and then heated to 65 C. A preformed solution of fuming nitric acid and sulfuric acid (the smaller amount indicated above) was added dropwise. The temperature was kept between 65 C. and 80 C. (rxn is exothermic and although the bath is at 65 C., temperature goes higher, usually 75, sometimes 80 C.). After the addition was complete, the reaction mixture was heated at 65 C. for an additional hr. The reaction mixture was then cooled to rt and poured in a flask containing ice) (20 g of ice/gr compound, evolution of gas occurred). A solid precipitated out and it was collected by filtration (1HNM? showed intermediate 4 and something else (discarded)). The aqueous layer was extracted with AcOEt several times (3-5) and concentrated on a rotary evaporator under vacuum to afford a solid that was triturated with ether to afford intermediate 4 as a bright yellow solid. A total of 117 g of desired product was collected in the first crop (27% yield from diazonium salt). A portion did not crystallize: this oil was triturated with MeOH and Et2O to afford 3.6 g of intermediate 4; another precipitation from the mother liquid afforded an additional 6.23 g of the desired product intermediate 4. Total: 117.0+3.6+6.23=126.83. 30.4%). Yield for 3 steps (decomposition of diazonium salt; deprotection and nitration). Analytical data from Notebook: 53877-115: 1HNMR(delta, MeOD): 8.56-8.27 (dd, J=7.5, 3.3 Hz, 1H), 8.01 (d, J=3.3 Hz, 1H); LC/MS(M+1)+=158.9; rt=0.15 min.
With sulfuric acid; nitric acid; In water; at 65 - 80℃;
Compound 4-80 was dissolved in sulfuric acid (the larger amounts indicated above) at rt and then heated to 65 C. A preformed solution of fuming nitric acid and sulfuric acid (the smaller amount indicated above) was added dropwise. The temperature was kept between 65 C. and 80 C. (rxn is exothermic and although the bath is at 65 C., temperature goes higher, usually 75, sometimes 80 C.). After the addition was complete, the reaction mixture was heated at 65 C. for an additional hr. The reaction mixture was then cooled to rt and poured in a flask containing ice) (20 g of ice/gr compound, evolution of gas occurred). A solid precipitated out and it was collected by filtration (1HNM showed 4-80 and something else (discarded)). The aqueous layer was extracted with AcOEt several times (3-5) and concentrated on a rotary evaporator under vacuum to afford a solid that was triturated with ether to afford 5-80 as a bright yellow solid. A total of 117 g of desired product was collected in the first crop (27% yield from diazonium salt). A portion did not crystallize: this oil was triturated with MeOH and Et2O to afford 3.6 g of 5-80; another precipitation from the mother liquid afforded an additional 6.23 g of the desired product 5-80. Total: 117.0+3.6+6.23=126.83. 30.4%). Yield for 3 steps (decomposition of diazonium salt; deprotection and nitration). Analytical data from Notebook: 53877-115: 1HNMR(delta, MeOD): 8.56-8.27 (dd, J=7.5, 3.3 Hz, 1H), 8.01 (d, J=3.3 Hz, 1H); LC/MS(M+1)+=158.9; rt=0.15 min. Note: A portion of the aqueous acidic solution was taken and neutralized with Na2CO3 until effervescence stopped and then it was extracted with AcOEt A different product was obtained. No desired product in these extracts.
With benzyltrimethylammonium chloride; trichlorophosphate; In acetonitrile; at 80℃; for 6h;
a) Synthesis of 2-chloro-5-fluoro-3-nitro-pyridine 5-fluoro-3-nitro-pyridin-2-ol (2 g, 12.7 mmol) and benzyltrimethyl ammonium chloride (1.17 g, 6.35 mmol) were dissolved in acetonitrile, and phosphorus oxychloride (3.5 ml, 38.1 mmol) was added thereto and stirred at 80 C. for 6 hours. The reaction mixture was cooled and poured into ice water to quench the reaction, and extracted with dichloromethane. The combined organic layer was washed with saturated saline solution, dried over anhydrous sodium sulfate (Na2SO4), filtered and evaporated under reduced pressure. The residue was purified by column chromatography on silica eluding with a solvent of dichloromethane:methanol=30:1. The fractions containing the product were collected and evaporated to obtain yellow liquid (1.57 g, 70%). 1H-NMR (CDCl3, 300 MHz); delta=8.56 (d, J=2.7 Hz, 1H), 8.40 (dd, J=6.5 Hz, 2.7 Hz, 1H). MS (ESI); 176.9 (M++1).
69%
With tetraethylammonium chloride; trichlorophosphate; In acetonitrile; at 90℃; for 24h;
PREPARATION 53 2-Chloro-5-fluoro-3-nitropyridine 5-Fluoro-3-nitro-pyridin-2-ol (1.00 g, 5.33 mmol) was dissolved in acetonitrile (40 mL) and tetraethylammonium chloride (2.10g, 12.65 mmol) was added. The mixture became clear, phosphorous oxytrichloride (1.94 g, 12.65 mmol) was added at room temperature and the mixture was heated at 90 oC for 24h. The reaction mixture was evaporated to dryness; the residue was taken up with water (100 mL) and extracted with ethyl acetate (2x100 mL). The organic layer was dried with sodium sulfate, filtered and evaporated to dryness. A yellow solid (0.90 g, 69%) was isolated, pure enough to perform the next synthetic step. LRMS (m/z): 177 (M+1)+
41%
With trichlorophosphate;N,N-dimethyl-formamide; at 110℃; for 18h;
A mixture of the pyridine of preparation 55 (105 mg, 0.66 mmol), phosphorus oxychloride (1 ml) and Lambda/,Lambda/-dimethyIformamide (10 mul, catalytic) was heated at 11O0C for 18 hours. The cooled reaction mixture was then concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel using dichloromethane/acetonitrile as eluant (100:0 to 50:50 v/v) to yield the title compound (48 mg, 41%) as a solid. 1H NMR (400MHz, CDCI3): delta 8.03 (dd, 1 H), 8.55 (d, 1 H).
With trichlorophosphate; In 1,2-dimethoxyethane; at 110℃; for 5h;
In Step B, compound zz2' (500 mg, 3.16 mmol) was dissolved in phosphorous oxychloride (1.7 mL, 18.9 mmol) and dimethoxyethane at room temperature. The reaction was heated to 110 C. for 5 hours. The excess phosphorous oxychloride was then removed by concentrating the reaction mixture in vacuo. The residue was chromatographed on silica gel, eluted with chloroform (100%) to afford 176 mg of product zz3'.
With tetraethylammonium chloride; trichlorophosphate; In acetonitrile; at 20 - 90℃; for 24h;
5-Fluoro-3-nitro-pyridin-2-ol (1 .00 g, 5.33 mmol) was dissolved in acetonitrile (40 mL) and tetraethylammonium chloride (2.1 Og, 12.65 mmol) was added. The mixture became clear, phosphorous oxytrichloride (1 .94 g, 12.65 mmol) was added at room temperature and the mixture was heated at 90 C for 24h. The reaction mixture was evaporated to dryness; the residue was taken up with water (100 mL) and extracted with ethyl acetate (2x100 mL). The organic layer was dried with sodium sulphate, filtered and evaporated to dryness. A yellow solid (0.90 g, 69%) was isolated, pure enough to perform the next synthetic step.LRMS (m/z): 177 (M+1 )+
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