| 89% |
With thionyl chloride;N,N-dimethyl-formamide; In dichloromethane; at 0 - 20℃; for 4h; |
5-chloro-2(chloromethyl)pyridine; [00372] To a 0 C solution of 5-chloropicolinic acid (3.00 g, 19.0 mmol) indichloromethane (20 mL) was added sulfurous dichloride (2.78 mL, 38.1 mmol), after which the reaction was warmed to room temperature and stirred at that temperature for 4 hours. The reaction was then concentrated to dryness, then reconstituted in dichloromethane (5 mL). Methanol (10 mL) was added to the reaction mixture, and the reaction was allowed to stir at room temperature for 12 hours, after which it was then diluted with water, extracted with ethyl acetate (3 x 50 mL), washed with water, then washed with saturated sodium bicarbonate solution, dried (magnesium sulfate), filtered and concentrated. Purification was achieved by silica gel chromatography (ISCO 80g) using 0 to 80% ethyl acetate in hexanes to afford methyl 5-chloropicolinate was as an off-white solid (2.75 g, 15.2 mmol, 80% yield ).[00373] To a 0 C solution of methyl 5-chloropicolinate (2.70 g, 15.7 mmol) in methanol (50 mL) was added sodium borohydride (1.79 g, 47.2 mmol), after which the reaction was warmed to room temperature and stirred at that temperature for 4 hours. The reaction mixture was then concentrated to a residue which was treated with 1M hydrochloric acid solution (15 mL), extracted with ethyl acetate (3 x 100 mL), washed with water, then washed with saturated sodium bicarbonate solution, dried (magnesium sulfate), filtered and concentrated. Purification was achieved by silica gel chromatography (ISCO 80g) using 0 to 60% ethyl acetate in hexanes to afford (5-chloropyridin-2-yl)methanol was as an off-white solid (2.15 g, 14.9 mmol, 95% yield).[00374] To a 0 C solution of (5-chloropyridin-2-yl)methanol (2.10 g, 14.6 mmol) in dichloromethane (10 mL) was added sulfurous dichloride (1.60 mL, 21.9 mmol) followed by N,N-dimethylformamide (50 μ), after which the reaction was warmed to room temperature and stirred at that temperature for 4 hours. The reaction mixture was then concentrated to a residue which was reconstituted in water (15 mL), ethyl acetate (15 mL), and saturated sodium bicarbonate solution (15 mL). The organic layers were separated and washed with saturated sodium chloride solution, dried (magnesium sulfate), filtered and concentrated. Purification was achieved by silica gel chromatography (ISCO 40g) using 0 to 50% ethyl acetate in hexanes to afford 5-chloro-2(chloromethyl)pyridine as an light brown oil (2.11 g, 13.0 mmol, 89% yield). |
| 78% |
|
To a mixture of (5-chloro-pyridine-2-yl)-methanol (706 mg, 4.92 mmol) described in Manufacturing Example 63-1-1 and dichloromethane (70 mL) was added thionyl chloride (539 μL, 7.38 mmol), which was stirred for 1 hour at room temperature. Saturated aqueous sodium hydrogencarbonate solution was added to the reaction mixture, which was then extracted with dichloromethane. The organic layer was separated, washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure to obtain the title compound (620.0 mg, 78%). 1H-NMR Spectrum (CDCl3) δ (ppm): 4.66 (2H, s), 7.45 (1H, d, J=8.0 Hz), 7.71 (1H, dd, J=2.8, 8.0 Hz), 8.54 (1H, d, J=2.8 Hz). |
|
With thionyl chloride;N,N-dimethyl-formamide; In dichloromethane; at 0 - 20℃; for 1h; |
C. Preparation of 5-chloro-2-(chloromethyl)pyridine To a stirring solution of (5-chloropyridin-2-yl)methanol (840 mg, 5.8 mmol) in dichloromethane (10 mL) at 0 C. under argon was added thionyl chloride (0.64 mL, 8.77 mmol), followed by 4 drops of DMF (white precipitate formed). The reaction mixture was allowed to stir at room temperature for 1 h. The reaction mixture was concentrated to a white solid. The solid thus obtained was cooled in an ice bath before EtOAc (20 mL) and water (20 mL) and then 10% aqueous Na2CO3 solution (20 mL) were added. The organic layer was separated, washed with saturated aqueous NaCl, dried (MgSO4), filtered and concentrated to obtain 840 mg of the title compound as a light brown gum. HPLC/MS: retention time=2.392 min, [M+H]30 =162. |
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