4-乙酰基-1-苄基哌啶

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: The title compound was prepared using a procedure similar to that described in Example 13 Step C from 1-benzyl-4-acetylpiperidine and methyl 4-t-butoxyphenylacetate in 87% yield. 1H NMR (500 MHz) δ 7.30˜7.35 (m, 4H), 7.24˜7.29 (m, 1H), 7.12˜7.15 (m, 2H), 6.95˜6.97 (m, 2H), 3.57 (s, 2H), 3.50 (s, 2H), 2.91˜2.95 (m, 2H), 2.15 (tt, 3.9 & 11.8 Hz, 1H), 1.95˜2.01 (m, 2H), 1.75˜1.80 (m, 2H), 1.63˜1.72 (m, 2H), 1.36 (s, 9H).

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: The title compound was prepared in 67% yield from 2.18 g 1-benzyl-4-acetylpiperidine from the last step, 5.58 g methyl 3,4-difluorophenylacetate from Fisher esterification, and 0.8 g 60% NaH in 15 mL anhydrous THF using a procedure similar to that described in Example 1, Step A Method B. RF: 0.28 (15% EtOAc in hexanes). 1H NMR (500 MHz, CDCl3): δ7.32˜7.35 (m, 4H), 7.26˜7.30 (m, 1H), 7.06˜7.15 (m, 3H), 6.95˜6.98 (m, 1H), 5.47 (s, 1H), 3.57 (s, 2H), 3.54 (br s, 2H), 2.96 (br d, 11.5 Hz, 2H), 2.17˜2.21 (m, 1H), 2.02˜2.10 (m, 2H), 1.70˜1.83 (m, 4H).

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A solution of 47.32 g 1-benzyl-N-methyl-N-methoxy-piperidine-4-carboxamide in 1.5 L anhydrous ether in a 2-L 3-neck round-bottom flask fitted with a nitrogen bubbler, an overhead stirrer, and an addition funnel was cooled with an ice-acetone bath, and was treated with 270 mL of a 1.53M solution of methylmagnesium bromide in 1:3 THF:toluene with stirring over 70 minutes. After stirring in an ice bath for additional two hours, the mixture was quenched with 15 mL EtOAc, stirred for 10 minutes, and then poured into 2 L of ice water. After adjusting the pH to 8˜9, the layers were separated. The mixture was extracted with 4×250 mL ether, the combined ether solution was washed with 300 mL each of water and saturated brine, and then dried over Na2SO4. Removal of solvent under reduced pressure gave 40.68 g of crude product. This material was purified by flash chromatography on silica gel eluting with 25%˜40% EtOAc in hexanes with 1% Et3N to give 39.533 g of the title compound as a yellowish liquid. RF: 0.20 (20% EtOAc in hexanes with 1% (v/v) Et3N). 1H NMR (500 MHz, CDCl3): δ7.32˜7.35 (m, 4H), 7.25˜7.30 (m, 1H), 3.53 (s, 2H), 2.91˜2.95 (m, 2H), 2.28˜2.34 (m, 1H), 2.16 (s, 3H), 2.01˜2.07 (m, 2H), 1.83˜1.88 (m, 2H), 1.66˜1.74 (m, 2H). was cooled with an ice-acetone bath the mixture was quenched with 15 mL EtOAc stirred for 10 minutes poured into 2 L of ice water the layers were separated The mixture was extracted with 4×250 mL ether the combined ether solution was washed with 300 mL each of water and saturated brine dried over Na2SO4 Removal of solvent under reduced pressure gave 40.68 g of crude product This material was purified by flash chromatography on silica gel eluting with 25%˜40% EtOAc in hexanes with 1% Et3N

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A solution of 47.32 g 1-benzyl-N-methyl-N-methoxy-piperidine-4-carboxamide in 1.5 L anhydrous ether in a 2-L 3-neck round-bottom flask fitted with a nitrogen bubbler, an overhead stirrer, and an addition funnel was cooled with an ice-acetone bath, and was treated with 270 mL of a 1.53M solution of methylmagnesium bromide in 1:3 THF:toluene with stirring over 70 minutes. After stirring in an ice bath for additional two hours, the mixture was quenched with 15 mL EtOAc, stirred for 10 minutes, and then poured into 2 L of ice water. After adjusting the pH to 8˜9, the layers were separated. The mixture was extracted with 4×250 mL ether, the combined ether solution was washed with 300 mL each of water and saturated brine, and then dried over Na2SO4. Removal of solvent under reduced pressure gave 40.68 g of crude product. This material was purified by flash chromatography on silica gel eluting with 25%˜40% EtOAc in hexanes with 1% Et3N to give 39.533 g of the title compound as a yellowish liquid. RF: 0.20 (20% EtOAc in hexanes with 1% (v/v) Et3N). 1H NMR (500 MHz, CDCl3): δ7.32˜7.35 (m, 4H), 7.25˜7.30 (m, 1H), 3.53 (s, 2H), 2.91˜2.95 (m, 2H), 2.28˜2.34 (m, 1H), 2.16 (s, 3H), 2.01˜2.07 (m, 2H), 1.83˜1.88 (m, 2H), 1.66˜1.74 (m, 2H). was cooled with an ice-acetone bath the mixture was quenched with 15 mL EtOAc stirred for 10 minutes poured into 2 L of ice water the layers were separated The mixture was extracted with 4×250 mL ether the combined ether solution was washed with 300 mL each of water and saturated brine dried over Na2SO4 Removal of solvent under reduced pressure gave 40.68 g of crude product This material was purified by flash chromatography on silica gel eluting with 25%˜40% EtOAc in hexanes with 1% Et3N

反应条件: temp:27.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a stirred solution of 1-benzyl-N-methoxy-N-methylpiperidine-4-carboxamide (11.5 g, 44 mmol) in diethyl ether (150 mL) at 0° C. was added methyl magnesium bromide (15.7 g, 132 mmol), drop-wise over 10 min. The resulting mixture was stirred at 25-30° C. for 2 h. After completion of the reaction, the mixture was treated with EtOAc and saturated NH4Cl solution. The separated organic layer was washed with brine and dried over anhydrous sodium sulfate and concentrated under vacuum to afford 1-(1-benzylpiperidin-4-yl)ethanone product. [M+1]=218.1 After completion of the reaction The separated organic layer was washed with brine dried over anhydrous sodium sulfate concentrated under vacuum

反应条件: temp:27.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a stirred solution of 1-benzyl-N-methoxy-N-methylpiperidine-4-carboxamide (11.5 g, 44 mmol) in diethyl ether (150 mL) at 0° C. was added methyl magnesium bromide (15.7 g, 132 mmol), drop-wise over 10 min. The resulting mixture was stirred at 25-30° C. for 2 h. After completion of the reaction, the mixture was treated with EtOAc and saturated NH4Cl solution. The separated organic layer was washed with brine and dried over anhydrous sodium sulfate and concentrated under vacuum to afford 1-(1-benzylpiperidin-4-yl)ethanone product. [M+1]=218.1 After completion of the reaction The separated organic layer was washed with brine dried over anhydrous sodium sulfate concentrated under vacuum

反应条件: temp:27.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a stirred solution of 1-benzyl-N-methoxy-N-methylpiperidine-4-carboxamide (11.5 g, 44 mmol) in diethyl ether (150 mL) at 0° C. was added methyl magnesium bromide (15.7 g, 132 mmol), drop-wise over 10 min. The resulting mixture was stirred at 25-30° C. for 2 h. After completion of the reaction, the mixture was treated with EtOAc and saturated NH4Cl solution. The separated organic layer was washed with brine and dried over anhydrous sodium sulfate and concentrated under vacuum to afford 1-(1-benzylpiperidin-4-yl)ethanone product. [M+1]=218.1 After completion of the reaction The separated organic layer was washed with brine dried over anhydrous sodium sulfate concentrated under vacuum

反应条件: temp:27.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a stirred solution of 1-benzyl-N-methoxy-N-methylpiperidine-4-carboxamide (11.5 g, 44 mmol) in diethyl ether (150 mL) at 0° C. was added methyl magnesium bromide (15.7 g, 132 mmol), drop-wise over 10 min. The resulting mixture was stirred at 25-30° C. for 2 h. After completion of the reaction, the mixture was treated with EtOAc and saturated NH4Cl solution. The separated organic layer was washed with brine and dried over anhydrous sodium sulfate and concentrated under vacuum to afford 1-(1-benzylpiperidin-4-yl)ethanone product. [M+1]=218.1 After completion of the reaction The separated organic layer was washed with brine dried over anhydrous sodium sulfate concentrated under vacuum

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: The title compound was prepared using a procedure similar to that described in Example 13 Step C from 1-benzyl-4-acetylpiperidine and methyl 4-t-butoxyphenylacetate in 87% yield. 1H NMR (500 MHz) δ 7.30˜7.35 (m, 4H), 7.24˜7.29 (m, 1H), 7.12˜7.15 (m, 2H), 6.95˜6.97 (m, 2H), 3.57 (s, 2H), 3.50 (s, 2H), 2.91˜2.95 (m, 2H), 2.15 (tt, 3.9 & 11.8 Hz, 1H), 1.95˜2.01 (m, 2H), 1.75˜1.80 (m, 2H), 1.63˜1.72 (m, 2H), 1.36 (s, 9H).

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: The title compound was prepared in 67% yield from 2.18 g 1-benzyl-4-acetylpiperidine from the last step, 5.58 g methyl 3,4-difluorophenylacetate from Fisher esterification, and 0.8 g 60% NaH in 15 mL anhydrous THF using a procedure similar to that described in Example 1, Step A Method B. RF: 0.28 (15% EtOAc in hexanes). 1H NMR (500 MHz, CDCl3): δ7.32˜7.35 (m, 4H), 7.26˜7.30 (m, 1H), 7.06˜7.15 (m, 3H), 6.95˜6.98 (m, 1H), 5.47 (s, 1H), 3.57 (s, 2H), 3.54 (br s, 2H), 2.96 (br d, 11.5 Hz, 2H), 2.17˜2.21 (m, 1H), 2.02˜2.10 (m, 2H), 1.70˜1.83 (m, 4H).

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A solution of 47.32 g 1-benzyl-N-methyl-N-methoxy-piperidine-4-carboxamide in 1.5 L anhydrous ether in a 2-L 3-neck round-bottom flask fitted with a nitrogen bubbler, an overhead stirrer, and an addition funnel was cooled with an ice-acetone bath, and was treated with 270 mL of a 1.53M solution of methylmagnesium bromide in 1:3 THF:toluene with stirring over 70 minutes. After stirring in an ice bath for additional two hours, the mixture was quenched with 15 mL EtOAc, stirred for 10 minutes, and then poured into 2 L of ice water. After adjusting the pH to 8˜9, the layers were separated. The mixture was extracted with 4×250 mL ether, the combined ether solution was washed with 300 mL each of water and saturated brine, and then dried over Na2SO4. Removal of solvent under reduced pressure gave 40.68 g of crude product. This material was purified by flash chromatography on silica gel eluting with 25%˜40% EtOAc in hexanes with 1% Et3N to give 39.533 g of the title compound as a yellowish liquid. RF: 0.20 (20% EtOAc in hexanes with 1% (v/v) Et3N). 1H NMR (500 MHz, CDCl3): δ7.32˜7.35 (m, 4H), 7.25˜7.30 (m, 1H), 3.53 (s, 2H), 2.91˜2.95 (m, 2H), 2.28˜2.34 (m, 1H), 2.16 (s, 3H), 2.01˜2.07 (m, 2H), 1.83˜1.88 (m, 2H), 1.66˜1.74 (m, 2H). was cooled with an ice-acetone bath the mixture was quenched with 15 mL EtOAc stirred for 10 minutes poured into 2 L of ice water the layers were separated The mixture was extracted with 4×250 mL ether the combined ether solution was washed with 300 mL each of water and saturated brine dried over Na2SO4 Removal of solvent under reduced pressure gave 40.68 g of crude product This material was purified by flash chromatography on silica gel eluting with 25%˜40% EtOAc in hexanes with 1% Et3N

反应条件: temp:27.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a stirred solution of 1-benzyl-N-methoxy-N-methylpiperidine-4-carboxamide (11.5 g, 44 mmol) in diethyl ether (150 mL) at 0° C. was added methyl magnesium bromide (15.7 g, 132 mmol), drop-wise over 10 min. The resulting mixture was stirred at 25-30° C. for 2 h. After completion of the reaction, the mixture was treated with EtOAc and saturated NH4Cl solution. The separated organic layer was washed with brine and dried over anhydrous sodium sulfate and concentrated under vacuum to afford 1-(1-benzylpiperidin-4-yl)ethanone product. [M+1]=218.1 After completion of the reaction The separated organic layer was washed with brine dried over anhydrous sodium sulfate concentrated under vacuum