benzyl 2-methyl-4-oxo-2,3-dihydropyridine-1-carboxylate

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of phenylmethyl 2-methyl-4-oxo-3,4-dihydropyridine-1(2H)-carboxylate (J. Bioorg. Med. Chem. 2007, 1106-1116) (2.4 g, 9.78 mmol) in THF (35 mL) was added dropwise a 1M solution of lithium bis(trimethylsilyl)amide in THF (11 mL) at −78° C. The solution was warmed up to 0° C., stirred at this temperature for 1 h, then cooled again to −78° C. 3-Fluorobenzaldehyde (1.3 mL, 12.7 mmol) was added in one portion. The reaction was stirred for 4 h while allowing it to slowly warm up to 0° C. Then, saturated ammonium chloride (20 mL) was added, and the layers were separated. The aqueous layer was extracted with ethyl acetate (2×20 mL) and the combined organic layers were washed with saturated sodium chloride (50 mL), dried over sodium sulfate, filtered and concentrated. Column chromatography on silica (gradient 20 to 100% ethyl acetate in hexanes) afforded phenylmethyl 3-[(3-fluorophenyl)(hydroxy)methyl]-2-methyl-4-oxo-3,4-dihydropyridine-1(2H)-carboxylate (2.4 g, 66% yield) as mixture of diastereomers. MS (EI) for C21H20FNO4: 370.1 (MH+). cooled again to −78° C The reaction was stirred for 4 h to slowly warm up to 0° C the layers were separated The aqueous layer was extracted with ethyl acetate (2×20 mL) the combined organic layers were washed with saturated sodium chloride (50 mL) dried over sodium sulfate filtered concentrated

反応条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of phenylmethyl 2-methyl-4-oxo-3,4-dihydropyridine-1(2H)-carboxylate (J. Bioorg. Med. Chem. 2007, 1106-1116) (2.4 g, 9.78 mmol) in THF (35 mL) was added dropwise a 1M solution of lithium bis(trimethylsilyl)amide in THF (11 mL) at −78° C. The solution was warmed up to 0° C., stirred at this temperature for 1 h, then cooled again to −78° C. 3-Fluorobenzaldehyde (1.3 mL, 12.7 mmol) was added in one portion. The reaction was stirred for 4 h while allowing it to slowly warm up to 0° C. Then, saturated ammonium chloride (20 mL) was added, and the layers were separated. The aqueous layer was extracted with ethyl acetate (2×20 mL) and the combined organic layers were washed with saturated sodium chloride (50 mL), dried over sodium sulfate, filtered and concentrated. Column chromatography on silica (gradient 20 to 100% ethyl acetate in hexanes) afforded phenylmethyl 3-[(3-fluorophenyl)(hydroxy)methyl]-2-methyl-4-oxo-3,4-dihydropyridine-1(2H)-carboxylate (2.4 g, 66% yield) as mixture of diastereomers. MS (EI) for C21H20FNO4: 370.1 (MH+). cooled again to −78° C The reaction was stirred for 4 h to slowly warm up to 0° C the layers were separated The aqueous layer was extracted with ethyl acetate (2×20 mL) the combined organic layers were washed with saturated sodium chloride (50 mL) dried over sodium sulfate filtered concentrated

反応条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of phenylmethyl 2-methyl-4-oxo-3,4-dihydropyridine-1(2H)-carboxylate (J. Bioorg. Med. Chem. 2007, 1106-1116) (2.4 g, 9.78 mmol) in THF (35 mL) was added dropwise a 1M solution of lithium bis(trimethylsilyl)amide in THF (11 mL) at −78° C. The solution was warmed up to 0° C., stirred at this temperature for 1 h, then cooled again to −78° C. 3-Fluorobenzaldehyde (1.3 mL, 12.7 mmol) was added in one portion. The reaction was stirred for 4 h while allowing it to slowly warm up to 0° C. Then, saturated ammonium chloride (20 mL) was added, and the layers were separated. The aqueous layer was extracted with ethyl acetate (2×20 mL) and the combined organic layers were washed with saturated sodium chloride (50 mL), dried over sodium sulfate, filtered and concentrated. Column chromatography on silica (gradient 20 to 100% ethyl acetate in hexanes) afforded phenylmethyl 3-[(3-fluorophenyl)(hydroxy)methyl]-2-methyl-4-oxo-3,4-dihydropyridine-1(2H)-carboxylate (2.4 g, 66% yield) as mixture of diastereomers. MS (EI) for C21H20FNO4: 370.1 (MH+). cooled again to −78° C The reaction was stirred for 4 h to slowly warm up to 0° C the layers were separated The aqueous layer was extracted with ethyl acetate (2×20 mL) the combined organic layers were washed with saturated sodium chloride (50 mL) dried over sodium sulfate filtered concentrated

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:-30.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 4-methoxypyridine (796 g, 7.29 mole) was stirred in 8 L of anhydrous THF in a 20 L reactor. The reactor was cooled to −30° C., then methylmagnesium bromide (5.1 L, 7.29 mole) was added as a 1.4M solution in 3:1 toluene/THF was added via cannula one 800 mL bottle at a time with 800 mls added over a 5 min time period. After the addition was complete and the reaction temperature was −30° C., benzyl chloroformate (1244 g, 7.29 mole) was added dropwise over a 60 min period via addition funnel. The warmest temperature reached was 16° C. After addition was complete the reaction was warmed to 25° C. and stirred for 1.5 hrs. The reaction was cooled to 0° C. and quenched with 4.0 L of 2 N HCl. 4 L of MTBE and brine was added and the layers separated. The temperature was now 25° C. The aqueous phase was extracted with 2×2 L of MTBE. The combined organics were washed with brine and dried over Na2SO4, filtered and concentrated to give the crude oil. Chromatography using a Varian Metaflash 150 long (15 cm×60 cm long 5 kilo silica) and eluting with 10-35% EtOAc/Heptanes gave the product as an oil. added over a 5 min time period After the addition was −30° C. reached was 16° C After addition was warmed to 25° C. The reaction was cooled to 0° C. quenched with 4.0 L of 2 N HCl 4 L of MTBE and brine was added the layers separated was now 25° C The aqueous phase was extracted with 2×2 L of MTBE The combined organics were washed with brine dried over Na2SO4 filtered concentrated to give the crude oil eluting with 10-35% EtOAc/Heptanes

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mixture of 1.1 g of the crude 2(R,S)-methyl-1(benzyloxycarbonyl)-2,3-dihydro-4-pyridone, 200 mL of ethyl acetate, 1 g of di-tert-butyldicarbonate and 1 g of 10% palladium on carbon was shaken under 55 psi of hydrogen for 24 h. The mixture was filtered, concentrated under reduced pressure, and purified by low pressure chromatography on silica gel eluting with 40% ethyl acetate in hexane. There was obtained first 0.20 g of (±)-1-(2,2-dimethylethoxycarbonyl)-2-methyl-4-oxopiperidine: 1H NMR (400 MHz, CDCl3) 4.65 (m, 1H), 4.2 (m, 1H), 3.3 (m, 1H), 2.65 (dd, 1H), 2.45 (m, 1H), 2.3 (m, 1H), 2.2 (dd, 1H), 1.45 (s, 9H), 1.14 (d, 3H). Later fractions gave 0.50 g of the (±)-1-(2,2-dimethylethoxycarbonyl)-2-methyl-4-hydroxypiperidine: 1H NMR (400 MHz, CDCl3) 4.3 (m, 1H), 4.15 (t, 1H), 3.8 (m, 1H), 3.25 (m, 1H), 2.15 (s, 1H), 2.8 (m, 1H), 1.65 (m, 3H), 1.42 (s, 3H), 1.25 (d, 3H). The mixture was filtered concentrated under reduced pressure purified by low pressure chromatography on silica gel eluting with 40% ethyl acetate in hexane

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: The methodology of D. L. Comins and J. D. Brown, Tetrahedron Letters, 1986, pp 4549-4552 was used: To a stirred solution of 2.5 g of 4-methoxypyridine in 75 mL of anhydrous tetrahydrofuran cooled to -23° C. under a nitrogen atmosphere was added 8 mL of 3M methylmagnesium chloride in tetrahydrofuran followed by 4 g of benzylchloroformate, keeping the internal temperature below -20° C. After stirring for 4 h at -25°±5° C., the reaction was quenched with 100 mL of 1N HCl and extracted with 5×100 mL portions of ether. The combined extracts were dried over MgSO4 and concentrated under reduced pressure. Further drying under vacuum gave 5.1 g of 2(R,S)-methyl-1-(benzyloxycarbonyl)-2,3-dihydro-4-pyridone as a greenish oil: TLC (25% EtOAc in hexane); 1H NMR (400 MHz, CDCl3) 7.75 (d, 1H), 7.4 (s, 5H), 5.30 (d, 1H), 5.26 (s, 2H), 4.7 (m, 1H), 2.82 (dd, 1H), 2.38 (d, 2H), 1.25 (t, 3H). the internal temperature below -20° C the reaction was quenched with 100 mL of 1N HCl extracted with 5×100 mL portions of ether The combined extracts were dried over MgSO4 concentrated under reduced pressure Further drying under vacuum

反応条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of phenylmethyl 2-methyl-4-oxo-3,4-dihydropyridine-1(2H)-carboxylate (J. Bioorg. Med. Chem. 2007, 1106-1116) (2.4 g, 9.78 mmol) in THF (35 mL) was added dropwise a 1M solution of lithium bis(trimethylsilyl)amide in THF (11 mL) at −78° C. The solution was warmed up to 0° C., stirred at this temperature for 1 h, then cooled again to −78° C. 3-Fluorobenzaldehyde (1.3 mL, 12.7 mmol) was added in one portion. The reaction was stirred for 4 h while allowing it to slowly warm up to 0° C. Then, saturated ammonium chloride (20 mL) was added, and the layers were separated. The aqueous layer was extracted with ethyl acetate (2×20 mL) and the combined organic layers were washed with saturated sodium chloride (50 mL), dried over sodium sulfate, filtered and concentrated. Column chromatography on silica (gradient 20 to 100% ethyl acetate in hexanes) afforded phenylmethyl 3-[(3-fluorophenyl)(hydroxy)methyl]-2-methyl-4-oxo-3,4-dihydropyridine-1(2H)-carboxylate (2.4 g, 66% yield) as mixture of diastereomers. MS (EI) for C21H20FNO4: 370.1 (MH+). cooled again to −78° C The reaction was stirred for 4 h to slowly warm up to 0° C the layers were separated The aqueous layer was extracted with ethyl acetate (2×20 mL) the combined organic layers were washed with saturated sodium chloride (50 mL) dried over sodium sulfate filtered concentrated