Category: dioxole. The protonation of heteroatoms in aromatic heterocycles can be divided into two categories: lone pairs of electrons are in the aromatic ring conjugated system; and lone pairs of electrons do not participate. Compound: Methyl 5-fluoro-3-pyridinecarboxylate, is researched, Molecular C7H6FNO2, CAS is 455-70-9, about Preparation of 5-fluoronicotinic acid and 5-fluoronicotinamide. Author is Hawkins, G. F.; Roe, Arthur.
2-Amino-3-methylpyridine (50 g.) in 240 ml. concentrated H2SO4, cooled to 5°, was slowly treated with a mixture of 35 ml. each of concentrated H2SO4 and concentrated HNO3, with the temperature kept below 10°, and allowed to warm up to 30° overnight. [If the solution was then poured over cracked ice, neutralized, and filtered, the nitro derivative (I) could be obtained, but it was preferred not to isolate I.] To the solution, kept below 40° and stirred, was slowly added 35 ml. concentrated HNO3, approx. 50 ml. of the mixture (A) added to 100 ml. H2O, and heated to 120°. The balance of (A) was added in 50-ml. portions when gas evolution ceased, the mixture was cooled by the addition of 1 kg. ice, and the precipitate filtered off (46 g.); an addnl. 5 g. could be obtained by addition of 10 g. NaNO2 to the filtrate, and another 6 g. was obtainable by neutralizing the filtrate from the NaNO2 treatment. The combined products were dissolved in the min. amount of dilute NaOH, stirred with C, and filtered, giving 51 g. (71.5%) of fairly pure 2-hydroxy-3-methyl-5-nitropyridine (II), greenish yellow, m. 228.5-9.5°, after crystallizations from H2O and decolorization. II was also prepared by adding 15 ml. fuming HNO3 and 20 ml. concentrated H2SO4 to 20 g. 2-hydroxy-3-methylpyridine in 40 ml. concentrated H2SO4 at a temperature below 40°, allowing to warm up to 50° during 2.5 hrs., pouring over cracked ice, and filtering, washing, and drying the precipitate over P2O5, giving 13.5 g. cream-colored II, m. 228.5-9.5°. II (83 g.) and 400 ml. POCl3 were refluxed 6 hrs., the excess POCl3 distilled off, the residue poured over cracked ice, filtered, the filtrate neutralized with NaOH solution, extracted twice with 100-ml. portions of Et2O, the precipitate also dissolved in the Et2O solution, a lower liquid layer removed, and the solution dried over CaO; distillation yielded 81.5 g. (87.6%) 2-chloro-3-methyl-5-nitropyridine (III), m. 47-8°, b18 145.5°. III was also prepared from I by diazotization in concentrated HCl, in 32% yield with II as a by-product. To 24 g. III was added 100 ml. AcOH, 14 g. AcONa, and 5 g. Pd-charcoal catalyst, the mixture reduced with H at 15-25 lb. pressure (even after heating, only 80% of the theoretical H was absorbed), the hot solution filtered, evaporated to dryness, concentrated NaOH added, the mixture heated 30 min., extracted, after cooling, with three 75-g. portions of Et2O, and the extracts dried over NaOH and distilled, giving 9 g. (51%) 3-methyl-5-aminopyridine (IV), m. 57-9°, b21 153°. To 12 g. IV in 50 ml. 42% HBF4 and 75 ml. EtOH at -10° was added EtONO, at a temperature kept below -5°, until no more precipitation occurred, the solution poured into 75 ml. absolute EtOH and 100 ml. Et2O, at -70°, the solution filtered, the precipitate washed twice with cold absolute EtOH, twice with cold absolute Et2O, and twice with cold, dry petr. ether (30-60°), placed, with 75 ml. cold, dry petr. ether, in a 500-ml. flask with a condenser, the solution warmed slightly to initiate decomposition, the reaction then controlled by cooling, the mixture refluxed 0.5 hr., the solvent decanted, the petr. ether washed twice with 50 ml. dilute HCl, the extracts returned to the flask, warmed to remove petr. ether, made slightly alk., and distilled, giving, after drying, 7.4 g. (60%) 3-methyl-5-fluoropyridine (V). To 8.5 g. V and 600 ml. H2O in a flask with a reflux condenser was added 8 g. KMnO4, then more in small amounts as it reacted, to a total of 26 g. in 3 hrs., unreacted V removed by distillation, the residue filtered off hot, washed with hot H2O, the filtrate and washings evaporated to 150 ml., HCl added to complete precipitation, the solid filtered off, the filtrate evaporated to 50 ml., and more HCl added, precipitating more solid, and the combined precipitates (6.4 g.; 77.3%), recrystallized from H2O, giving 5-fluoronicotinic acid (VI), m. 195-7°. VI (3 g.) in 50 ml. SOCl2 was refluxed 12 hrs. and the excess solvent distilled off in vacuo, giving 1.5 ml. of liquid, b18 82°; this (acid chloride) with anhydrous NH3 gave, after 2 recrystallizations from H2O, 1.1 g. 5-fluoronicotinamide (VII), m. 173-5°. From 45 g. 3-bromoquinoline by the method of Graf, et al. (C.A. 28, 269.7) (oxidation and heating), was obtained 16.5 g. 5-bromonicotinic acid (VIII). VIII (14.5 g.), by the method of Meyer and G. (C.A. 23, 837), gave 6.5 g. 5-aminonicotinic acid (IX). IX (6.5 g.) with CH2N2 gave 3 g. Me 5-aminonicotinate (X), m. 135-7°. VII could not be prepared by diazotization of IX or X (the modified Schiemann reaction (R. and H., C.A. 42, 171e)). However, 2.7 g. X in 50 ml. 95% EtOH was treated with 25 ml. of 30% fluosilicic acid, the precipitated salt filtered off and suspended in 50 ml. AcOH, then EtONO passed in, at 32° or lower, until the salt dissolved, the solution cooled in ice, and 75 ml. dry Et2O added to precipitate the diazonium fluosilicate, which, when filtered off, washed once with absolute EtOH and twice with absolute Et2O in a CO2 atm., and dried over P2O5, m. 89° (violent decomposition). The salt suspended in dry PhMe, heated until it decomposed, and the PhMe layer distilled, gave 0.4 g. Me 5-fluoronicotinate (XI), b26 101-2°, m. 46-50°. XI in 50% MeOH with NH3 gave VII, m. 173-5°. Oxidation of 3-fluoroquinoline with KMnO4 or with concentrated HNO3 did not give VI.
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Reference:
1,3-Benzodioxole – Wikipedia,
Dioxole | C3H4O2 – PubChem