Popp, Frank D.; McEwen, Wm. E. published an article in 1958, the title of the article was Approaches to the synthesis of emetine from Reissert compounds.Reference of 4-Bromo-5-ethyl-2-methylpyridine And the article contains the following content:
2-Methyl-4-nitro-5-ethylpyridine 1-oxide (94 g.) and 325 cc. PBr3 yielded by the method of Lee and Swan (C.A. 50, 13918g) 53% 2-methyl-4-bromo-5-ethylpyridine (I), b0.9 55-7°. EtBr added slowly with stirring to 36.48 g. Mg and 75 cc. dry Et2O, the mixture treated after the initial reaction had subsided with 108.5 g. I and 99.4 g. EtBr in 300 cc. dry Et2O at such a rate as to maintain gentle reflux, refluxed 2 hrs., the Et2O distilled, the residue diluted with 375 cc. dry C6H6, cooled, treated with 222.3 g. HC(OEt)3, refluxed 2 hrs., kept 15 hrs. at room temperature, treated with 500 cc. aqueous NH4Cl, the aqueous layer extracted with Et2O, the Et2O layer extracted with 1 l. N H2SO4 in portions, the acidic extract basified with aqueous NaHCO3, extracted with Et2O, and the extract worked up yielded 44.36 g. di-Et acetal (II) of 2-methyl-5-ethyl-4-pyridinecarboxaldehyde (III), b3 109-14°; picrate, m. 139-40° (EtOH) (all m.ps. are corrected). II (11.15 g.) in 90 cc. 10% HCl refluxed 2 hrs. under N, kept 16 hrs. at room temperature, basified with aqueous Na2CO3, extracted with CHCl3, and the extract worked up gave 6.57 g. III, b1 64-8°; oxime, m. 143-4° (EtOH). 3-Ethyl-4-methylpyridine was converted by the method of Berson and Cohen (C.A. 50, 9405i) to 69% 1-oxide (IV), b3 142-9°; picrate, m. 141.5-2.5° (EtOH). IV (186 g.) added slowly to 380 cc. warm Ac2O, refluxed 4 hrs., and evaporated gave 154 g. (3-ethyl-4-pyridyl)methanol acetate (V), b2.5 108-15°; picrate, m. 137-8° (EtOH). V (44.7 g.), 25 cc. 30% H2O2, and 115 g. glacial AcOH heated 4 hrs. on the steam bath, treated again with 21 cc. H2O2, heated 4 hrs., kept 36 hrs. at room temperature, evaporated in vacuo, the residue treated with 125 cc. Ac2O, heated 5.5 hrs. on the steam bath, concentrated in vacuo, treated with 175 cc. 6N HCl, refluxed 2 hrs., concentrated in vacuo, neutralized with aqueous NaOH, extracted with Et2O, and the extract worked up gave 10.2 g. 3-ethyl-4-pyridinecarboxaldehyde (VI), b2.5 71-5°; oxime, m. 146.5-8.5° (EtOH). VI (11.25 g.) and 52 cc. 13.5% alc. HBr kept 88 hrs. at room temperature, diluted with a large volume of C6H6, dried azeotropically during 24 hrs., evaporated, the residue basified with aqueous K2CO3, and the product isolated with Et2O gave 9.47 g. di-Et acetal (VIII) of VI, b1.9 100-2°; picrate, m. 115-16° (EtOH). 2-(p-Anisoyl)-6,7-dimethoxy-1,2-dihydroisoquinaldonitrile (VIII) (8.75 g.) in 45 cc. dry dioxane and 15 cc. dry Et2O treated at -20° under N slowly with stirring with PhLi (from 4.40 g. PhBr) in Et2O, then slowly with 3.38 g. VI, stirred 20 min. at -20° and 7 hrs. at room temperature, washed with H2O, 0.5N HCl, and H2O, distilled, and the gummy residue crystallized from EtOH gave 0.20 g. 6,7-dimethoxyisoquinaldonitrile (IX), m. 198.4-9.0° (EtOH); the HCl extract basified with aqueous NaOH, extracted with Et2O, the extract evaporated, and the gummy residue treated with EtOH gave 3.31 g. 1-(6,7-dimethoxyisoquinolyl)-4-(3-ethyl-4-pyridyl)carbinyl β-anisate (X), m. 248.2-8.7° (EtOH); the EtOH filtrate refluxed 2 hrs. with 2.8 g. KOH in 20 cc. H2O, the EtOH evaporated in vacuo, the aqueous residue extracted with Et2O, the precipitate filtered off, the extract evaporated, and the combined solids recrystallized from EtOH gave 1.57 g. 1-(6,7-dimethoxyisoquinolyl)-4-(3-ethyl-4-pyridyl)carbinol (XI), m. 168-9° (EtOH); the aqueous filtrate acidified gave 0.93 g. p-MeOC6H4CO2H. IX (0.02 g.) and 4.0 g. polyphosphoric acid heated 1 hr. on the steam bath, diluted with 10 cc. iced H2O, and neutralized with aqueous KOH gave 0.02 g. 6,7-dimethoxyisoquinaldamide, m. 169-70° (EtOH). 2-Benzoyl-6,7-dimethoxy-1,2-dihydroisoquinaldonitrile (1.45 g.) and 6 cc. SOCl2 heated 3 hrs. on the steam bath, evaporated in vacuo, the residue diluted with 35 cc. H2O, basified with aqueous NaOH, and the precipitate filtered off yielded 0.8 g. IX, m. 198.4-9.0° (EtOH). X (2.96 g.), 0.95 g. KOH, 25 cc. EtOH, and 55 cc. H2O refluxed 5 hrs., the EtOH evaporated in vacuo, and the aqueous residue filtered off gave 2.01 g. XI; the aqueous filtrate acidified gave 98% p-MeOC5H4CO2H. XI (0.5 g.), 0.5 g. Na2Cr2O7, and 10 cc. 80% AcOH stirred 1 hr. at room temperature, basified with aqueous NaHCO3, and extracted with CHCl3 gave 0.44 g. 1-(6,7-dimethoxyisoquinolyl) 3-ethyl-4-pyridyl ketone, m. 152-3° (ligroine). VIII (13.31 g.) in 70 cc. dry dioxane and 60 cc. dry Et2O treated under N at -25° slowly with stirring with PhLi from 6.60 g. PhBr in Et2O, then slowly with 5.70 g. III, stirred 1 hr. at -20°, kept 15 hrs. at room temperature, extracted with N HCl, washed, and the organic layer evaporated gave 4.06 g. IX; the HCl extract basified with aqueous NaOH, extracted with Et2O, the extract evaporated, the gummy residue (13.1 g.) dissolved in EtOH, the solution treated with 4.5 g. KOH in 30 cc. H2O, refluxed 1.5 hrs., the EtOH distilled, the aqueous distillation residue extracted with Et2O, and the extract worked up gave 3.95 g. 1-(6,7-dimethoxyisoquinolyl)(2-methyl-5-ethyl-4-pyridyl)carbinol, m. 174-5° (EtOH). 4-Pyridinecarboxaldehyde (XII) (50.0 g.) and 185 cc. 11.5% alc. HCl kept 90 hrs. at room temperature, diluted with 450 cc. dry C6H6, distilled with the azeotropic removal of the EtOH and H2O, the distillation residue basified with aqueous K2CO3, extracted with Et2O, and the extract worked up yielded 37.0 g. di-Et acetal (XIV) of XII, b6 99-100°. XIV (9.06 g.) and 9.25 g. Ph(CH2)2Br in 35 cc. dry xylene heated 1 hr. on the steam bath, the xylene solution decanted from a gummy precipitate, allowed to stand several days, diluted with a small amount of EtOH and a large amount of Et2O to precipitate more gum, and the combined precipitates crystallized from Et2O-EtOH gave 12.8 g. 1-phenethyl-4-(diethoxymethyl)pyridinium bromide (XV) dihydrate, m. 65.6-6.5°, which turned to a gum when dried over H2SO4 in vacuo; XV picrate, m. 104.6-5.6°. XV.2H2O (2.50 g.) in 25 cc. H2O treated with 8.8 g. K3Fe(CN)6 in 25 cc. H2O, kept overnight, diluted with 25 cc. C6H6, treated slowly with stirring at room temperature with 4.0 g. NaOH in 40 cc. H2O, stirred 1 hr., the aqueous layer extracted with C6H6, and the extract worked up gave 0.95 g. 1-phenethyl-4-(diethoxymethyl)-2(4H)-pyridone (XVI), m. 84.0-4.5°. 3,4-(MeO)2C6H3(CH2)2OH and PBr3 yielded 63% 3,4-(MeO)2C6H3(CH2)2Br (XVIII), b1.5 122-9°, m. 42-8°. XIV (3.62 g.) and 4.90 g. XVII heated 20 min. on the steam bath, kept overnight, and the gummy product treated with a small amount of EtOH and a large amount of Et2O yielded 4.90 g. 3,4-(MeO)2C6H3(CH2)2 analog (XVIII) of XV, m. 79-81.5°; picrate, m. 115.2-16.0° (EtOH). XVIII (2.83 g.) gave similarly 1.35 g. gummy product which, treated in EtOH, with a few drops of H2SO4, then with 2,4-(O2N)2C6H3NHNH2 solution, gave the 2,4-dinitrophenylhydrazone of 1-(3,4-dimethoxyphenethyl)-4-formyl-2(1H)-pyridone (XVIIIa), m. 270.0-70.8° (hot EtOH and hot Me2CO). VII (5.50 g.) and 6.44 g. XVII gave in the usual manner 90% 1-(3,4-dimethoxyphenethyl)-3-ethyl-4-(diethoxymethyl)pyridinium bromide (XIX), m. 140-1°; picrate, m. 126.3-7.1° (EtOH). XIX (4.54 g.) treated in the usual manner with K3Fe(CN)6 and the crude gummy product (2.90 g.) treated with EtOH, a few drops of H2SO4, and 2,4-(O2N)2C6H3NHNH2 solution yielded the 2,4-dinitrophenylhydrazone of the 3-Et derivative of XVIIIa, orange crystals, m. 268-9° (hot EtOH and hot Me2CO). 2-Methyl-5-ethyl-4-pyridinecarboxaldehyde di-Et acetal (3.41 g.) and 3.75 g. XVII yielded in the usual manner 43% 1-(3,4-dimethoxyphenethyl)-2-methyl-4-(diethoxymethyl)-5-ethylpyridinium bromide, m. 150.5-2.0° (Et2O-EtOH). The experimental process involved the reaction of 4-Bromo-5-ethyl-2-methylpyridine(cas: 98488-99-4).Reference of 4-Bromo-5-ethyl-2-methylpyridine
4-Bromo-5-ethyl-2-methylpyridine(cas:98488-99-4) 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.Reference of 4-Bromo-5-ethyl-2-methylpyridine