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59.2 Step-2 Methyl 6-chloro-5-methylpyridine-2-carboxylate
Into a 100-mL round-bottom flask, was placed 2-(methoxycarbonyl)-5-methylpyridine 1-oxide (10 g, 59.82 mmol, 1 equiv) and chloroform (50 mL), followed by the addition of phosphoroyl trichloride (42.2 mL, 9 equiv) dropwise with stirring. The resulting solution was stirred overnight at 80° C. in an oil bath. The resulting mixture was concentrated under vacuum and then quenched with water (20 mL). The pH value of the solution was adjusted to 7 with K2CO3 (10% in water) and extracted with EtOAc (3*20 mL). The combined organic layers were washed with H2O (3*20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (Gradient 0-10% MeOH/CH2Cl2) to afford the title compound as a yellow solid (7 g, 57% yield). 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 7.96-8.02 (m, 2H), 3.88 (s, 1H), 2.41-2.51 (m, 3H). MS: (ES, m/z): 186 [M+H]+.
39%
With trichlorophosphate for 3h; Reflux;
20.4
Intermediate 20-4: Methyl 6-chloro-5-methylpyridine-2-carboxylateA solution of Intermediate 20-5 (1.67g, 9.99mmol) in POCl3 (15 mL) was heated to reflux for 3 h. After cooling to RT the reaction mixture was added to an ice-water solution, basified with IM NaOH (aq) and extracted with DCM (3 x 30 mL). Organic layers were combined, passed through a phase separator and evaporated. The crude product was purified by flash chromatography using EtOAc (15 %) in heptane as eluent. Pure fractions were evaporated to dryness to afford the title compound (0.73 g, 39 %). 1H NMR (400 MHz, CDCl3) δ 2.44 (s, 3H), 3.97 (s, 3H), 7.67 (d, IH), 7.96 (d, IH); m/z 186 (M+H)+.
methyl 6-chloro-5-methylpyridine-2-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
21.44%; 58.3%
Phosphorus oxychloride (21ml, 229.40 mmol) was added dropwise to a stirred solution of 2-(methoxycarbonyl)-5-methylpyridine 1 -oxide (4.2 g, 25.13 mmol) dissolved in chloroform (16 ml) over a period of 5 minutes. The resulting solution was stirred at 800C overnight. The mixture was cooled to room temperature and was added dropwise to a ice cold 10% aqueous solution OfK3CO3. K2CO3 solid was then added to ajust the pH to 7 and the aqueous phase extracted with dichloromethane (3 x 10 ml). The combined organic phases were washed with brine, dried over magnesium sulfate and concentrated to afford the crude product which was purified by flash chromatography on silica gel eluting with 15 to 30% ethyl acetate in petroleum ether. The solvent was evaporated to dryness to afford methyl 6-chloro-5-methylpicolinate (2.72 g, 58.3 %) as a white solid and methyl 4-chloro- 5-methylpicolinate (1.000 g, 21.44 %) as a white solid. NMR Spectrum (CDC13): 2.47 (s, 3H), 3.99 (s, 3H), 7.70 (d, IH), 7.99 (d, IH)
10
Sodium borohydride (1.005 g, 26.56 mmol) was added to a stirred solution of methyl 6- chloro-5-methylpicolinate (2.9 g, 15.62 mmol) dissolved in ethanol (35 ml) at 20 0C and the resulting suspension stirred overnight. The reaction mixture was concentrated to dryness, poured into brine and extracted with ethyl acetate (3 x 50 ml). The combined organic phases were washed with brine, dried over magnesium sulfate and concentrated to afford the crude product (6-chloro-5-methylpyridin-2-yl)methanol (2.400 g, 97 %) as a clear colorless oil .Mass Spectrum: M+H+ 158. NMR Spectrum (CDC13): 2.38 (s, 3H), 2.95 (bs, IH), 4.71 (s, 2H), 7.15 (d, IH), 7.55 (d, IH)
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium dihydrogenphosphate In 1,2-dimethoxyethane; ethanol; water at 140℃; for 0.833333h; Inert atmosphere; Microwave irradiation;
With N-Bromosuccinimide; dibenzoyl peroxide In tetrachloromethane at 80℃; Inert atmosphere;
59.3 Step-3 Methyl 5-(bromomethyl)-6-chloropyridine-2-carboxylate
Into a 100-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed methyl 6-chloro-5-methylpyridine-2-carboxylate (4.2 g, 22.63 mmol, 1 equiv), benzoyl peroxide (549.9 mg, 2.27 mmol, 0.1 equiv), NBS (4.04 g, 22.70 mmol, 1 equiv) and CCl4 (35 mL). The resulting mixture was stirred overnight at 80° C. in an oil bath. The reaction was concentrated under vacuum and quenched with water (20 mL), then extracted with EtOAc (3*30 mL). The combined organic layers were washed with H2O (3*20 mL), and dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (Gradient 0-10% MeOH/CH2Cl2) to afford the title compound as a yellow solid (2.5 g, 38% yield). MS: (ES, m/z): 265 [M+H]+.
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