Bernstein, Jack; Stearns, Barbara; Shaw, Elliott; Lott, W. A. published an article in 1947, the title of the article was Derivatives of 2,6-diaminopyridine.Related Products of 51566-22-4 And the article contains the following content:
Since 2,6-diaminopyridine (I) showed an appreciable antiparasitic activity when tested against Plasmodium lophurae in ducklings, various derivatives of I have been prepared to determine if further substitution in the mol. would increase the antiparasitic activity of the parent compound I (66 g.) in 300 cc. dioxane, treated dropwise with 23.5 g. AcCl in 50 cc. dioxane (0.5 h.) at 25-30° and stirred 2 addnl. hrs., gives 40% of the 2-Ac derivative (II), m. 156-7°; 2-butyryl derivative m. 152-3°, 25%; 2-salicyloyl derivative (prepared from o-AcOC6H4COCl and purified by precipitation from dilute HCl with dilute NaOH) m. 178-9°, 44%; 2-[phenyl(acetoxy)acetyl] derivative (as HCl salt with 1 mol. H2O) m. 151-3°, 23%. N,N’-Bis(6-amino-2-pyridyl)adipamide m. 228-9°, 72%; N,N’-bis(6-amino-2-pyridyl)sebacamide m. 152-5°, 55%. 1,3-Bis(6-amino-2-pyridyl)urea does not melt, 71%. (CH2CO)2O (30 g.) in 200 cc. dioxane, treated slowly with 33 g. I in 200 cc. dioxane and heated 3 h. on the steam bath, gives 57% N-(6-amino-2-pyridyl)succinamic acid, m. 174-5° (decomposition). I (46 g.) and 222 cc. AcCH2CO2Et, heated 15 min. at 160° and the product in EtOH treated with alc. HCl, give 40% 2,6-bis(acetylacetamido)pyridine-HCl, m. 195-8°; the filtrate yields 10% of the 2-acetylacetamido derivative, m. 146-7°. I (22 g.) and 22.6 g. NCCH2CO2Et, heated 2 h. at 165°, give 85% 2-amino-6-cyanoacetamidopyridine, m. 152-3°. 2-Acetamido-6-carbethoxyacetamidopyridine m. 150-1.5°, 41%. I (282 g.) and 290 g. HOCH2CO2H, fused 15 h. at 120° under reduced pressure, give 35% 2,6-bis(glycolylamino)pyridine, m. 220-1°. I (33 g.) in 200 cc. absolute EtOH containing 6.9 g. Na and 43 g. Et2NCH2CO2Et, refluxed 2 h., give 55% 2,6-bis(diethylaminoacetamido)pyridine, m. 109.5-10.5°. I (22 g.) and 27 g. AcNHCOCl, ground in a mortar and 35 cc. C5H5N added, give 19% 2,6-bis(acetamidoacetamido)pyridine, m. 260-1°. MeC(:NH)NH2.HCl (24.6 g.) in 100 cc. absolute EtOH, added to 22 g. I in 150 cc. absolute EtOH, stirred 3 h., and allowed to stand overnight at room temperature, give 38% N-(6-amino-2-pyridyl)acetamidine-HCl, m. 246-7° (decomposition). I (396 g.) in 8 l. H2O, treated dropwise with 195 g. ClCO2Et (3 h.), gives 76% 2-amino-6-carbethoxyaminopyridine (III), m. 109-12°. I (33 g.) in 500 cc. H2O, 200 cc. N HCl, and 300 g. ice, treated dropwise with 33 g. ClCO2Et, stirred 2 h., 200 cc. N HCl added, and the mixture allowed to stand overnight at 10°, gives 55% 2,6-bis(carbethoxyamino)pyridine, m. 132.5-3.5°, and 12 g. III. III (21.6 g.) in 120 cc. 3 N EtOH-NH3, heated 12 h. at 110°, gives 75% 2-amino-6-ureidopyridine, m. 175-6° (decomposition). I (48 g.) and 48 g. CO(NH2)2, heated 36 h. at 130°, give 49% 2,6-diureidopyridine, does not melt below 300° (purified by extraction with 300 cc. 3% HCl and crystallization of the residue from H2O). I (12 g.) in 1500 cc. C6H6, treated dropwise with 17.9 g. p-EtOC6H4NCO in 75 cc. C6H6, gives 86% 2-(p-ethoxyphenylureido)-6-aminopyridine, m. 168-9°; 2-(2-nitro-4-methoxyphenylureido)-6-aminopyridine m. 208-10°, 73%; reduction over Pt oxide gives 50% of the corresponding 2-(2-amino-4-methylphenylureido) derivative, m. 182-4°. I (154 g.) and 200 g. of the HCl salt of I, heated 12 h. at 190°, give 60% bis(6-amino-2-pyridyl)amine, m. 172-3° (the HCl salt does not melt). 2,6-Dibromopyridine (IV) (38 g.) and 160 cc. 25% aqueous MeNH2, heated 8 h. at 190°, give 59% 2,6-bis(methylamino)pyridine, m. 70-1°; this results in 20% yield from 27.6 g. 2-amino-6-bromopyridine (V) and 110 cc. 25% aqueous MeNH2 on heating 30 h. at 190°. V (80 g.) and 200 cc. EtNH2, heated 36 h. at 170-80°, give 81% 2-amino-6-(diethylamino)pyridine (VI), b4.5 122-3°, m. 34-5° (HCl salt, m. 143-4°). IV (45 g.) and 27.8 g. Et2NH in 100 cc. absolute EtOH, heated 8 h. at 170-80°, give 85% 2-bromo-6-(diethylamino)pyridine (VII), b4 97-9°; VII does not react with NH4OH (d. 0.9) at 170-80° (8 h.); 11 g. VII and 35 cc. 5 N EtOH-NH3, heated 25 h. at 170°, also did not react; 18.8 g. VII in 100 cc. NH4OH (d. 0.9) containing 1 g. CuSO4.5H2O, heated 30 h. at 140-5°, gives 44% VI. IV (35.6 g.) and 100 cc. Et2NH containing 4 cc. 25% CuSO4.5H2O, heated 30 h. at 160°, give 76% 2,6-bis(diethylamino)pyridine, b3 120-2° (HCl salt, m. 120-2°). 2-Amino-6-(3-diethylaminopropylamino)pyridine-HCl m. 65-75°, 53%; 2-acetamido-6-(4-diethylamino-1-methylbutylamino)pyridine m. 106-8° (51%). 2-Acetamido-6-(3-keto-1-methylbutylideneamino)-pyridine, 2,6-AcNHC5H3N(N:CMeCH2Ac), m. 146-7.5°, 40%. 2-Acetamido-6-(2,5-dimethyl-1-pyrryl)pyridine m. 147.5-8.5°, 54%. 2-Methoxy-6,9-dichloroacridine (11.2 g.) in 50 g. PhOH, warmed on the steam bath, treated with 11 g. I, and heated 3 h., gives 61% 2-methoxy-6-chloro-9-(6-amino-2-pyridylamino)acridine, yellow, m. 232-3°. II (30.2 g.), added in small portions to 100 cc. HNO3 (d. 1.5) at -5° to -2° and stirred an addnl. 30 min., gives 65% of the Ac derivative, decompose violently at 193°, of 2-nitramino-6-aminopyridine (VIII), darkens at 240-50° (hydrolysis by refluxing 1 h. with N NaOH); reduction of 15.4 g. VIII in 300 cc. 10% NaOH at 0-2° with 31 g. Zn gives 69% 2-hydrazino-6-aminopyridine, pale yellow, m. 93-4°; warmed 2 h. on the steam bath with AcCH2CO2Et (N atm.), there results 44% 1- (6-amino-2-pyridyl)-3-methyl-5-pyrazolone, m. 188-9.5°. 3-Methylpyridine (80 g.), 160 g. PhNMe2, and 144 g. NaNH2, heated 10 h. at 130-50° and 6 h. at 170-200°, give 4% 2,6-diamino-3-methylpyridine, m. 149-50°. 2,6-Dihydroxy-4-methylpyridine (9 g.) and 30 g. PBr3, heated 4.5 h. at 180°, give 36% 2,6-dibromo-4-methylpyridine, m. 74-5°; heated with NH4OH (d. 0.9) 27 h. at 195°, there results 71% 2,6-diamino-4-methylpyridine, m. 87-8°, which on sublimation m. 109-11° but reverts to the lower m.p. on standing. 2,6-Diamino-3-iodopyridine (23.5 g.) in 25 cc. AcOH and 35 cc. Ac2O, heated 1 h. on the steam bath, gives 33% of the di-Ac derivative, m. 210-11°. I (38 g.) in 550 cc. H2O, treated with 93 g. iodine and 93 g. KI in 150 cc. H2O, the mixture stirred 8 h., and allowed to stand overnight at room temperature, gives 36% 2,6-diamino-3,5-diiodopyridine-HCl, m. 160-5°; the free base m. 209-10°. 3-Methoxypyridine (IX) (15.8 g.) in 100 cc. concentrated H2SO4, treated dropwise (with cooling) with 25 cc. HNO3 (d. 1.6) and warmed 6 h. on the steam bath, gives 12.2 g. 3-methoxy-2,6-dinitropyridine (X), m. 114-15°. IX (57 g.), added to 130 cc. concentrated H2SO4 at 5°, the mixture treated with 70 cc. HNO3 (d. 1.6), and heated 1 h. on the steam bath, yields 38 g. 2-nitro-3-methoxypyridine (XI), m. 73-5°; 5 g. XI in 15 cc. concentrated H2SO4, treated with 4 cc. HNO3 (d. 1.6), gives 4.4 g. X. Catalytic reduction (Pt oxide) of 16.8 g. X in 500 cc. AcOH and 250 cc. Ac2O at room temperature (4 h.) gives 60% 3-methoxy-2,6-diacetamidopyridine, m. 173.5-4.5°. 2,3,6-Triaminopyridine-2HCl in 200 cc. H2O and 25 g. Ac2 in 200 cc. H2O, boiled 4 min., yield 98% 2,3-dimethyl-6-aminopyrido[2,3]pyrazine, m. 227-8°; 6-aminopyrido[2,3]pyrazine m. 267°, 62%. 2,3,6-Triaminopyridine oxalate (80 g.) in 150 cc. (CO2Et)2, heated 90 min. at 185°, gives 68% 2,3-dihydroxy-6-aminopyrido[2,3]pyrazine, does not m. below 300°. Addition of 23.8 g. 2,6-diacetamido-3-nitropyridine to 100 g. SnCl2.2H2O in 150 cc. concentrated HCl gives 26% 2-methyl-5-amino-1-imidazo[b]pyridine-HCl; neither the base nor the salt melts. I (55 g.) and 194 g. KCNS in 1 l. 95% AcOH, treated dropwise at -5° to -10° with 26 cc. Br, give 24% 2,5-diaminopyrido[2,3-d]thiazole (XII), m. 138-9°; II likewise gives the 5-Ac derivative of XII, m. 184-5°. I (66 g.) in 2 l. AcOH, treated with 460 g. KCNS in 100 cc. H2O and then at 0-3° with 64 cc. Br, with stirring 1 h. at room temperature, yields 22% 2,6-diaminopyrido[2,3-d,6,5-d’]bisthiazole, does not melt below 300°. I (25 g.), 29 g. I.HCl, and 42 g. benzoin, heated 1 h. at 185°, yield 89% 2,3-diphenyl-6-amino-1-pyrrolo[2,3-b]pyridine, m. 234.5-5.5°. 2-Amino-6-(3-keto-1-methylbutylideneamino)pyridine (16 g.) in 100 cc. 85% H3PO4, warmed 1 h. on the steam bath, gives 84% 2,4-dimethyl-7-amino-1,8-naphthyridine, m. 216-18°; this results in 85% yield from 5 g. I and 5 cc. CH2Ac2 in 25 cc. 85% H3PO4 on warming 30 min. on the steam bath. 2,7-Dihydrazino-4-methyl-1,8-naphthyridine-2HCl-2H2O (23 g.) and 18 g. AcCH2CO2Et in 200 cc. 50% EtOH, heated 5 min. at 70°, give 84% 2,7-bis(3-methyl-5-keto-1-pyrazolyl)-4-methyl-1,8-naphthyridine, m. 260-2°. The most active of these compounds (II, XII, and the di-Ac derivative of I) are only 1/3 as active as quinine as antiparasitic agents for Plasmodium lophurae in ducklings. The experimental process involved the reaction of 3-Methylpyridine-2,6-diamine(cas: 51566-22-4).Related Products of 51566-22-4
The Article related to aminopyridines, malaria and other aspects.Related Products of 51566-22-4