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With methanol; sodium tetrahydroborate In dichloromethane at 0 - 20℃; for 18 h;
To a solution of 5-chloro-nicotinic acid methyl ester (17.2 g, 101 mmol) in methanol (230 mL) and DCM (230 mL) at 0° C. was added sodium borohydride (16.4 g, 434 mmol). The reaction mixture was stirred at room temperature for 18 hours. After completion, the reaction mixture was concentrated under reduced pressure, diluted with water (300 mL) and extracted with AcOEt (3×300 mL). The combined organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was then purified by silica gel chromatography to afford (5-chloro-pyridin-3-yl)-methanol (7.8 g, 54percent). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.45-8.52 (m, 2H), 7.83 (s, 1H), 5.45 (t, J=5.8 Hz, 1H), 4.55 (t, J=5.7 Hz, 2H). MS m/z 144.1
Stage #1: With triethylamine In tetrahydrofuran at 0 - 20℃; Stage #2: With lithium aluminium tetrahydride In tetrahydrofuran for 0.5 h;
A. (5-Chloro-pyridin-3-yl)-methanol To a solution of 5-chloro-nicotinic acid (2 g, 12.7 mmol) and TEA (1.52 g, 15 mmol) in THF (30 mL) was added slowly methyl chloroformate (1.42 g, 15 mmol) at 0° C. The resulting mixture was stirred at room temperature overnight. The reaction was diluted with ethyl acetate, washed with saturated ammonia chloride and dried over anhydrous sodium sulfate. The organic layer was concentrated to give the crude product (2.8 g, crude), which was dissolved in THF (40 mL) and cooled to -78° C. Lithium aluminium hydride (570 mg, 15 mmol) was added portion-wise. The resulting mixture was stirred for 30 min. The reaction was quenched with aqueous sodium hydroxide and extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated to give the crude product, which was purified by silica gel column chromatography (30percent ethyl acetate in petroleum ether) to afford the title compound (1.4 g, 9.72 mmol, 76percent yield). MS (ESI) m/z 144.1 [M+H]+.
With diborane In tetrahydrofuran at 0 - 20℃; for 72 h; Inert atmosphere
1.3.2 (5-Chloropyridin-3-yl)methanol (AOH-2) 5-Chloronicotinic acid (1 g, 6.35 mmol) was dissolved in dry THF (20 mL) in a N2flushed flask and 1 M BH3in THF (25.4 mL, 25.4 mmol) was added via a syringe at 0°C. The mixture was stirred at RT for 72 h. The reaction mixture was cooled in an ice bath and aqueous saturated K2C03(50 mL) was added cautiously. The organic solvent was removed in vacuo and the residue was extracted withEtOAc (2x 50 mL). The combined organic layers were washed with saturated aqueous NaHC03(2x 25 mL) and brine (2x 25 mL) before drying on Na2S04and concentration in vacuo to give a colorless oil. The product was purified using column chromatography (silica, heptane/EtOAc, 1 :1 ) to give the desired product (285 mg, 31 percent) as a yellow oil which partially solidified upon standing.
With methanol; sodium tetrahydroborate; In dichloromethane; at 0 - 20℃; for 18h;
To a solution of 5-chloro-nicotinic acid methyl ester (17.2 g, 101 mmol) in methanol (230 mL) and DCM (230 mL) at 0 C. was added sodium borohydride (16.4 g, 434 mmol). The reaction mixture was stirred at room temperature for 18 hours. After completion, the reaction mixture was concentrated under reduced pressure, diluted with water (300 mL) and extracted with AcOEt (3×300 mL). The combined organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was then purified by silica gel chromatography to afford (5-chloro-pyridin-3-yl)-methanol (7.8 g, 54%). 1H NMR (400 MHz, DMSO-d6) delta ppm 8.45-8.52 (m, 2H), 7.83 (s, 1H), 5.45 (t, J=5.8 Hz, 1H), 4.55 (t, J=5.7 Hz, 2H). MS m/z 144.1
With methanol; sodium tetrahydroborate; In dichloromethane; at 20℃; for 18h;
Sodium borohydride (790 mg, 20.9 mmol) was added to a solution of crude methyl 5-chloronicotinate (-6.35 mmol) in methanol (10 mL) and CH2CI2 (10 mL). After 18 h at room temperature, the reaction mixture was concentrated in vacuo. Water (50 mL) was added and the mixture was extracted with CH2CI2 (3x50 mL).The organic phase was dried (MgStheta4), filtered and concentrated in vacuo. . Purification of the crude residue by chromatography on 40 g silica gel (hexanes ? EtOAc, gradient) afforded 510 mg (56% over two steps) of(5-chloropyridin-3-yl)methanol.
With methanesulfonyl chloride; triethylamine; In dichloromethane; at 0 - 20℃; for 18h;
Triethylamine (1.75 mL, 12.6 mmol) and methanesulfonyl chloride (0.69 mL, 8.9 mmol) were added to a solution of <strong>[22620-34-4](5-chloropyridin-3-yl)methanol</strong> (510 mg, 3.6 mmol) in CH2CI2 (3.5 mL) at 0 oC and the reaction was allowed to warm to room temperature. After 18 h at room temperature, the reaction was partitioned between water (50 mL) and CH2CI2 (50 mL). The phases were separated and the organic phase was extracted withCH2CI2 (20 mL). The combined organic phase was dried (MgStheta4), filtered and concentrated in vacuo.Purification of the crude residue by chromatography on 12 g silica gel (hexanes ? EtOAc, gradient) afforded300 mg (52%) of 3-chloro-5-(chloromethyl)pyridine.
With diborane; In tetrahydrofuran; at 0 - 20℃; for 72h;Inert atmosphere;
1.3.2 (5-Chloropyridin-3-yl)methanol (AOH-2)5-Chloronicotinic acid (1 g, 6.35 mmol) was dissolved in dry THF (20 mL) in a N2flushed flask and 1 M BH3in THF (25.4 mL, 25.4 mmol) was added via a syringe at 0C. The mixture was stirred at RT for 72 h. The reaction mixture was cooled in an ice bath and aqueous saturated K2C03(50 mL) was added cautiously. The organic solvent was removed in vacuo and the residue was extracted withEtOAc (2x 50 mL). The combined organic layers were washed with saturated aqueous NaHC03(2x 25 mL) and brine (2x 25 mL) before drying on Na2S04and concentration in vacuo to give a colorless oil. The product was purified using column chromatography (silica, heptane/EtOAc, 1 :1 ) to give the desired product (285 mg, 31 %) as a yellow oil which partially solidified upon standing.
A. (5-Chloro-pyridin-3-yl)-methanol To a solution of 5-chloro-nicotinic acid (2 g, 12.7 mmol) and TEA (1.52 g, 15 mmol) in THF (30 mL) was added slowly methyl chloroformate (1.42 g, 15 mmol) at 0 C. The resulting mixture was stirred at room temperature overnight. The reaction was diluted with ethyl acetate, washed with saturated ammonia chloride and dried over anhydrous sodium sulfate. The organic layer was concentrated to give the crude product (2.8 g, crude), which was dissolved in THF (40 mL) and cooled to -78 C. Lithium aluminium hydride (570 mg, 15 mmol) was added portion-wise. The resulting mixture was stirred for 30 min. The reaction was quenched with aqueous sodium hydroxide and extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated to give the crude product, which was purified by silica gel column chromatography (30% ethyl acetate in petroleum ether) to afford the title compound (1.4 g, 9.72 mmol, 76% yield). MS (ESI) m/z 144.1 [M+H]+.
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