Urban, R.; Schnider, O. published an article in 1964, the title of the article was Aminomethoxypyridines and corresponding sulfanilamides.Electric Literature of 90764-84-4 And the article contains the following content:
A number of 2-, 3-, and 4-sulfanilamidopyridines containing substituents in the pyridine ring, particularly all still unknown monomethoxy derivatives, were prepared for pharmacol. evaluation. To 10 g. Na in 185 mL. absolute MeOH was added 20 g. 2-amino-4-chloropyridine and a little Cu powder, the whole heated 12 h. at 150° in a sealed tube, cooled, diluted with H2O, filtered, and evaporated, the residue dissolved in H2O, and the product extracted with Et2O to give 10.6 g. 2-amino-4-methoxypyridine, m. 115-16° (C6H6). 2-Chloro-4-nitropyridine (16 g.), 32 g. Fe powder, and 500 mL. AcOH heated gradually with stirring until the reaction became brisk, when the reaction subsided the mixture heated 1 h. at 100°, cooled, and worked up gave 10.4 g. 4-amino-2-chloropyridine (I), m. 87-9° (C6H6-petr. ether). To 5.0 g. Na in 90 mL. absolute MeOH was added 10 g. I and a little Cu powder and the mixture heated 10 h. at 150° in a sealed tube, and worked up to give 5.4 g. 4-amino-2-methoxypyridine, m. 88-9° (C6H6-petr. ether, sublimation at 60°/0.1 mm.); Ac derivative m. 96-7° (C6H6). 5-Hydroxy-2-phenylazopyridine (II) in 400 mL. tert-BuOH added dropwise during 4 h. to 11 g. CH2N2 in 1.7 l. Et2O at – 15 to -10° with stirring, the solution allowed to reach room temperature and evaporated, the residue dissolved in C6H6, the solution worked up, and the partially crystalline product chromatographed on Al2O3 (activity II) with C6H6 gave 14.8 g. 5-MeO analog (III) of II, m. 72-3° (petr. ether). III (10 g.) in 220 mL. MeOH and 55 mL. 3N HCl hydrogenated over 10 g. 10% Pd-C (the calculated amount H was absorbed in 8 h.) and the solution filtered, concentrated, and worked up gave 4.1 g. 2-amino-5-methoxypyridine, b10 128-30°, m. 36-8°; Ac derivative (IV) m. 102-3° (C6H6-petr. ether); HCl salt m. 145-6° (MeOH-Et2O). Ac2O (2.9 mL.) added dropwise to 2.5 g. 2-amino-3-methoxypyridine (V) in 5.0 mL. anhydrous C5H5N at below 0° with stirring and worked up gave 2.9 g. Ac derivative of V, m. 102-3° (C6H6-petr. ether, C6H6 or EtOAc), mixed m.p. (with IV) 70°. 5-Bromonicotinic acid NH4 salt (270 g.) in 2 1. 25% aqueous NH3 heated 10 h. at 180° with 100 g. CuO in an autoclave, the filtered solution concentrated and treated with aqueous Cu(OAc)2, the precipitated Cu salt filtered and dissolved in dilute HCl, the solution treated with H2S, filtered, and evaporated, the residue dissolved in dilute aqueous NaOH, and the solution neutralized with dilute HCl gave 104 g. 5-aminonicotinic acid (VI), m. 295-6° (decomposition) (H2O). VI (20 g.) suspended in 400 mL. absolute MeOH saturated with HCl with ice-cooling, and the resulting solution refluxed 0.5 h. while continuously introducing HCl and cooled gave (in 2 crops) 23.8 g. Me 5-hydroxynicotinate-HCl (VII.-HCl), m. 194-6° (decomposition); 73% VII m. 192-3° (H2O). VII (8.0 g.) in 200 mL. tert-BuOH added dropwise during 6 h. to 3.5 g. CH2N2 in 350 mL. Et2O at – 15 to – 10° with stirring, the solution stirred several hrs. with cooling, allowed to reach room temperature, filtered, and concentrated, the residue dissolved in alc.-HCl, and the solution evaporated gave, after crystallization from MeOH-Et2O, 9.5 g. Me 5-methoxynicotinate-HCl (VIII.HCl), which in aqueous solution passed through a column of Amberlite IR-45 and the effluent evaporated gave 5.0 g. VIII, m. 61-2° (sublimation at 40°/0.1 mm.), saponification giving 5-methoxynicotinic acid (IX), m. 228-9°. VIII (8.0 g.), 18 mL. 100% N2H4.H2O, and 25 mL. MeOH refluxed 6 h. and cooled gave 6.8 g. hydrazide (X) of IX, m. 157-8° (MeOH). X (19.4 g.) in 125 mL. N HCl treated dropwise with 12 g. KNO2 in 40 mL. H2O at 5° with stirring and ice-cooling, the precipitated azide filtered off, washed with a little H2O, dried over P2O5, and refluxed 1 h. in 200 mL. absolute EtOH, and the solution evaporated gave 20.8 g. 5-methoxy-3-pyridinecarbamic acid Me ester, m. 139-41°, which refluxed with 40 g. Ba(OH)2 in 400 mL. H2O, the solution cooled, saturated with CO2, filtered, and worked up gave 8.0 g. 3-amino-5-methoxypyridine, b15 166-8°, m. 64-5° (C6H6); Ac derivative m. 133-4° (C6H6, EtOAc); HCl salt m. 205-7° (decomposition). Nicotinic acid-HCl (280 g.) and 500 mL. SOCl2 refluxed 6 days and then heated 12 h. at 180° in an autoclave, the mixture added to H2O, heated to boiling, and filtered hot, the filtrate cooled, and the precipitate recrystallized from H2O with C gave 130 g. mixture of 5-chloro- (XI) and 5,6-dichloronicotinic acid, which refluxed 4 h. with 52 g. red P and 130 g. KI in 800 mL. 57% HI, the solution cooled, diluted with H2O, filtered, concentrated to small volume, and treated with an appropriate amount aqueous Na2CO3 gave 78 g. XI, m. 167-8° (H2O); Me ester m. 87-8°; hydrazide (XII) m. 176-8°. XII (20 g.) dissolved in 120 mL. N HCl by heating, the solution cooled in ice, treated dropwise with 12 g. KNO2 in 40 mL. H2O at 5° with stirring, the precipitated azide filtered off, washed with H2O, heated 0.5 h. on a water bath in 220 mL. 50% AcOH, cooled, made alk. with aqueous NaOH, and cooled, and the product isolated with Et2O gave 6.0 g. 3-amino-5-chloropyridine, m. 78-9° (sublimation at 60°/0.1 mm., C6H6-petr. ether). The above azide dried over P2O5 and refluxed 1 h. with 10 volumes absolute EtOH gave 5-chloro-3-pyridinecarbamic acid Et ester, m. 149-51° (MeOH, sublimation at 70°/0.1 mm.). Na (5 g.) in 60 mL. MeOH and 16.2 g. 4,6-dichloro-2-picoline heated 12 h. at 130-40° in a sealed tube, cooled, and diluted with Et2O, and the solution filtered and fractionated gave 11.8 g. 4,6-dimethoxy-2-picoline (XIII), b17 87-8°, n23D 1.5076, m. 19-20°. XIII (11.7 g.) in 350 mL. H2O heated on a water bath, 13 g. finely powd. KMnO4 added with stirring, when the violet color disappeared 12.5 g. KMnO4 and 70 mh H2O added, the mixture heated 2.5 h., cooled a little, the MnO2 filtered off and washed with hot H2O, the combined cooled filtrates extracted with Et2O (6 g. XIII recovered), acidified with HCl, and evaporated, the residue (XIV) extracted (Soxhlet) exhaustively with C6H6, and the extract evaporated gave 1.2 g. 4,6-dimethoxypicolinic acid (XV), m. 145-7° (C6H6, sublimation at 90°/0.1 mm.). It was preferable not to isolate XV, but to convert XIV directly into the Me ester (XVI) of XV (20% yield). XV (1.2 g.) in 40 mL. absolute MeOH saturated with HCl with ice-cooling, the solution evaporated, the residue extracted with Et2O, and the extract worked up gave 1.1 g. XVI, m. 108-9° (C6H6, sublimation at 60°/0.1 mm.). Na (3.3 g.) in 50 mL. absolute MeOH refluxed 8 h. with 10.0 g. Me 4,6-dichloropicolinate and a little Cu powder, the filtered solution evaporated, and the residue extracted with Et2O gave 4.8 g. XVI, m. 106-8°. XVI (18 g.) in 100 mL. MeOH treated with 33 mL. 100% N2H4.H2O gave 17 g. hydrazide (XVII) of XV, m. 156-7° (MeOH). H2O (35 mL.) containing 8.0 g. KNO2 added dropwise during 1.5 h. to 15 g. XVII suspended in 80 mL. N HCl with stirring and ice-cooling, the precipitated azide filtered off, washed with a little H2O, dried over P2O5, and refluxed 1 h. in 160 mL. absolute EtOH, the solution filtered [1.9 g. insoluble fraction (A) recovered] and evaporated, the residual urethane compound (13 g.) refluxed 6 h. with 37 g. Ba(OH)2.8H2O in 150 mL. H2O, the cooled solution saturated with CO2, filtered, and evaporated, and the residue worked up gave 6.3 g. 2-amino-4,6-dimethoxypyridine, b12 145-7°, m. 69-70°; fraction A crystallized from HCONMe2-H2O or a large volume C6H6 gave bis(4,6-dimethoxypicolinoyl)hydrazine, m. 228-30°. From 15 g. hydrazide of 2,6-dimethoxyisonicotinic acid was prepared similarly 5.5 g. 4-amino-2,6-dimethoxypyridine, m. 82-3° (C6H6-petr. ether); the intermediate 2,6-dimethoxy-4-pyridinecarbamic acid Et ester m. 58-60°. Na (17.5 g.) in 350 mL. absolute MeOH and 35 g. 3-amino-2,6-dibromopyridine heated 15 h. at 130-5° in a sealed tube, the solution evaporated, and the residue dissolved in a little H2O and worked up gave 6.3 g. 3-amino-6-bromo-2-methoxypyridine (XVIIa), m. 78-9° (sublimation at 50°/0.1 mm., dilute MeOH) [86% Ac derivative (XVIII) m. 147-8° (EtOAc)], and 4.65 g. 3-amino-2,6-dimethoxypyridine, b10 116-17°, m. 43-5° [Ac derivative m. 85-7° (EtOAc, sublimation)]. XVIII (2.45 g.) in 65 mL. MeOH was hydrogenated over Pd-C in the presence of 4.0 g. NaOAc.3H2O (the calculated amount H was absorbed rapidly), the filtered solution evaporated, the residue extracted with Et2O, and the extract worked up to give 1.6 g. 3-acetamido-2-methoxypyridine, m. 88-9° (sublimation, C6H6-petr. ether). 2,4-Dichloro-6-methyl-3-nitropyridine (XIX) (20 g.) in 100 mL. MeOH added dropwise to 7.0 g. Na in 100 mL. absolute MeOH with stirring, the solution refluxed 8 h. and evaporated, the residue partitioned between H2O and C6H6, and the organic layer worked up gave 16 g. 2,4-dimethoxy-6-methyl-3-nitropyridine (XX), m. 105-7° (C6H6-petr. ether). XX (10 g.) in 100 mL. MeOH hydrogenated over 5 g. 5% Pd-C (the calculated amount H was absorbed in 3 h.) and the filtered solution fractionated gave 7.3 g. 3-amino analog of XX, b15 140-1°; HCl salt m. 163-4° (MeOH-Et2O). XIX (10 g.) in 70 mL. absolute MeOH added dropwise to 1.2 g. Na in 25 mL. absolute MeOH with stirring, the solution stirred several hrs. at room temperature, kept overnight, filtered, and evaporated, and the residue recrystallized from 3.5 l. H2O gave 7.6 g. 2(or 4)-chloro-4(or 2)-methoxy-6-methyl-3-nitropyridine (XXI), m. 103° (MeOH). XXI (10 g.) in 200 mL. MeOH hydrogenated over 3 g. 5% Pd-C (the calculated amount H was absorbed in 3-4 h.), the filtered solution evaporated, and the residue made alk. with aqueous NaOH and extracted continuously with C6H6 gave 3.8 g. 3-amino-2(or 4)-methoxy-6-methylpyridine, m. 74-5° (C6H6-petr. ether). 2,4-Dichloro-6-methylpyridine (65 g.), 200 mL. absolute EtOH, and 200 g. liquid NH3 heated 24 h. at 150° in an autoclave, the solution cooled, filtered, and evaporated, the residue dissolved in H2O, the solution saturated with K2CO3 and extracted with hot C6H6, and the extract kept deposited 18 g. 4-amino-2-chloro-6-methylpyridine (XXII), m. 155-7° (C6H6, H2O); from the aqueous mother liquors of XXII was isolated 4.8 g. 2,4-diamino-6-methylpyridine, m. 117-18°; all the C6H6 mother liquors combined and evaporated, and the residue recrystallized from 50 volumes H2O gave 11.5 g. 2-amino-4-chloro-6-methylpyridine (XXIII), m. 108-9° (C6H6). XXIII (2.85 g.) in 130 mL. MeOH hydrogenated over Pd-C in the presence of NaOAc.3H2O (the calculated amount H was absorbed rapidly), the filtered solution evaporated, the residue dissolved in H2O, the solution made alk. with concentrated aqueous NaOH, and the product isolated with Et2O gave 1.45 g. 2-amino-6-methylpyridine, b15 105-6°, m. 41-2°; HCl salt m. 155-6°. From XXII was similarly prepared 4-amino-2-methylpyridine, m. 93-5° (C6H6-petr. ether). Na (4.8 g.) in 90 mL. MeOH heated 12 h. at 130-40° with 8.0 g. XXIII and a little Cu powder in a sealed tube, the solution cooled, filtered, and evaporated, and the residue sublimed at 100°/0.1 mm. gave 5.65 g. 4-MeO analog of XXIII, m. 141-2° (C6H6). XXII treated similarly, the crude product sublimed, and the impure sublimate chromatographed on Al2O3 (activity III) with C6H6 gave 5.1 g. 2-MeO analog of XXII, m. 98-9°. 4-AcNHC6H4SO2Cl (XXIIIa) (14.8 g.) added to 15.1 g. 4-amino-3-methoxypyridine (XXIV) in 50 mL. dioxane with stirring, the mixture heated 0.5 h. at 90-5°, added to H2O-MeOH, the solution concentrated to a small volume and diluted with H2O, the precipitate filtered off (from the mother liquor was isolated 9.75 g. unchanged XXIV) and dissolved in dilute aqueous NaOH, and the solution decolorized with bone black and treated with CO2 gave 11.3 g. 4-(4-acetylsulfanilamido)-3-methoxypyridine, m. 232-3° (MeOH). 4-O2NC6H4SO2Cl (7.2 g.) added portionwise to 6.0 g. XVIIa in 50 mL. anhydrous C5H5N with stirring, the solution heated 2.5 h. at 70°, cooled, and evaporated, the residue dissolved in H2O, the solution acidified with AcOH, the precipitate dissolved in dilute aqueous NaOH, and the solution treated with bond black, and saturated with CO2 gave 9.8 g. 6 – bromo – 2 – methoxy – 3 – (4 – nitrobenzenesulfonamido)pyridine (XXV), m. 165-7°. XXV (9.8 g.), 31 g. Fe powder, 1 mL. 20% HCl, and 100 mL. MeOH refluxed and stirred 9 h., the solution filtered hot, the filter cake washed with MeOH, the combined filtrates evaporated, the residue dissolved in dilute aqueous NaOH, the solution filtered and saturated with CO2, and the precipitate worked up gave 5.5 g. 3-sulfanilamido analog of XXV, m. 172-3° (dilute MeOH). The appropriate aminopyridine (0.1 mol) in 100 mL. anhydrous C5H5N treated portionwise with 0.12 mol XXIIIa with stirring, the solution heated 2 h. at 70° or stirred 6 h. at room temperature and evaporated in vacuo, the residue treated with H2O, the precipitate filtered off, washed with H2O, and dissolved in dilute aqueous NaOH, and the solution treated with bone black and saturated with CO2 gave 63-90% N4-acetylsulfanilamidopyridines (XXVI), which were recrystallized from MeOH or dilute MeOH or HCONMe2-H2O. The appropriate XXVI (0.1 mol) in 120 mL. 2N NaOH refluxed 1 h., the solution cooled and acidified with AcOH, and the crude product purified gave 76-94% sulfanilamidopyrimidines, which were recrystallized from MeOH or dilute MeOH. The following 2-sulfanilamido compounds (XXVII) were prepared (Z, R, R1, R2, R3, % yield, m.p. given): Ac, OMe, H, H, H, 69, 212°; Ac, H, OMe, H, H, 63, 262-3°; Ac, H, H, OMe, H, 90, 228-30°; Ac, H, OMe, H, OMe, 90, 201-3°; Ac, H, OMe, H, Me, 58, 236-8°; H, OMe, H, H, H, 85, 214-15°; H, H, OMe, H, H, 76, 237-9°; H, H, H, OMe, H, 93, 200-1°; H, H, OMe, H, OMe, 92, 158-9°; H, H, OMe, H, Me, 72, 184-5°. Also prepared were the following 3-sulfanilamidopyridines (XXVIII) (same data given): Ac, OMe, H, H, H, 63, 194-5°; Ac, H, OMe, H, H, 73, 257-8°; Ac, H, H, OMe, H, 75, 253-4°; Ac, H, H, Br, H, 88, 250-1°; Ac, H, H, Cl, H, 72, 255-6°; Ac, OMe, H, H, OMe, 85, 193-5°; Ac, OMe, H, H, Br, 78, 210-11°; Ac, OMe, OMe, H, Me, 68, 236-7°; Ac, H (or OMe), OMe (or H), H, Me, 61, 228-9°; H, OMe, H, H, H, 82, 134-6°; H, H, OMe, H, H, 90, 222-3° (dilute HCONMe2); H, H, H, OMe, H, 85, 220-1°; H, H, H, Br, H, 92, 208-10°; H, H, H, Cl, H, 87, 208-9°; H, OMe, H, H, OMe, 94, 165-7°; H, OMe, H, H, Br, 61, 172-3°; H, OMe, OMe, H, Me, 90, 225-7°; H, H (or OMe), OMe (or H), H, Me, 90, 210-11°. Also prepared were the following 4-sulfanilamidopyridines (XXIX) (same data given): Ac, OMe, H, H, H, 72, 218-19°; Ac, H, OMe, H, H, 77, 232-3°; Ac, OMe, H, OMe, H, 84, 230-1°; Ac, OMe, H, Me, H, 81, 204-5°; H, OMe, H, H, H, 86, 151-2°; H, H, OMe, H, H, 89, 173-4° (hydrate); H, OMe, H, OMe, H, 84, 181-2°; H, OMe, H, Me, H, 71, 69-71° (methanolate). The monomethoxy-substituted 2- and 4-sulfanilamidopyridines and the 5-substituted 3-sulfanilamidopyridines had a strong chemotherapeutic action against various bacteria in the mouse and rat, but this action did not approach that of 6-sulfanilamido-2,4-dimethoxypyrimidine. The 3-sulfanilamidopyridines having an MeO group in the 2- or 4-position and all the disubstituted sulfanilamidopyridines were inactive or had little activity. The experimental process involved the reaction of 4,6-Dimethoxypicolinic acid(cas: 90764-84-4).Electric Literature of 90764-84-4
4,6-Dimethoxypicolinic acid(cas:90764-84-4) belongs to pyridine-derivatives. Several pyridine derivatives play important roles in biological systems. While its biosynthesis is not fully understood, nicotinic acid (vitamin B3) occurs in some bacteria, fungi, and mammals.Electric Literature of 90764-84-4
Referemce:
Pyridine – Wikipedia,
Pyridine | C5H5N – PubChem