1-Piperidinecarboxylicacid,4-hydroxy-2-methyl-,1,1-dimethylethylester,(2S,4S)-(9CI)

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

実験手順: With stirring, a solution of 2 ml (0.012 mol) of diethyl azodicarboxylate (93%) in 10 ml of toluene is added dropwise at 5°-10° C. to a suspension of 2.15 g (0.01 mol) of cis-N-BOC-2-methyl-4-hydroxypiperidine (cf. Example 1b), 2.0 g (0.012 mol) of 4-nitrobenzoic acid and 3.15 g (0.012 mol) of triphenylphosphine in 30 ml of toluene. The reaction mixture is further stirred for 15 hours at room temperature and then filtered to remove precipitated diethyl hydrazinedicarboxylate. The filtrate is then concentrated under vacuum and the oily residue is purified by flash chromatography over silica gel using ethyl acetate:hexane (1:5). Concentration of the fractions containing the product gives the title compound as a crystalline residue which melts at 106°-108° C. The reaction mixture is further stirred for 15 hours at room temperature filtered to remove precipitated diethyl hydrazinedicarboxylate The filtrate is then concentrated under vacuum the oily residue is purified by flash chromatography over silica gel Concentration of the fractions containing the product

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

実験手順: A solution of 14.6 g (0.04876 mol) of cis-N-BOC-2-methyl-4-[(tetrahydropyran-2-yl)oxy]piperidine in 120 ml of methanol is treated with 20 g of cationic exchanger Dowex® 50 WX8 (H+ form; 50-100 mesh (50 mesh corresponds to a granular size of c. 300 μm, 100 mesh to c. 150 μm); cationic exchanger based on a styrene/divinylbenzene polymer containing sulfonyl groups; registered trademark of Dow Chemicals Co., USA)), and the mixture is stirred for 22 hours at room temperature. After filtration, washing the ion exchanger with methanol and concentrating the filtrate under vacuum, the title compound is obtained in the form of a viscous oil, Rf =0.16 (silica gel/ethyl acetate:hexane (1:2)). containing sulfonyl groups After filtration washing the ion exchanger with methanol concentrating the filtrate under vacuum

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

実験手順: Triethylamine (0.49 mL, 3.49 mmol) was added to a 0° C. solution of (rac)-tert-butyl (cis)-4-hydroxy-2-methylpiperidine-1-carboxylate (250 mg, 1.16 mmol) and methanesulfonyl chloride (0.14 mL, 1.74 mmol) in dichloromethane (4.5 mL). The resulting mixture was warmed to room temperature and stirred overnight. The reaction was quenched by the addition of saturated aqueous sodium bicarbonate (10 mL) and dichloromethane (10 mL) was added. The organic layer was separated and washed with 1M aqueous citric acid (10 mL) and brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified via column chromatography on silica gel (Biotage 50 g column, gradient elution with 20-30% ethyl acetate in hexanes) to afford (rac)-tert-butyl (cis)-2-methyl-4-((methylsulfonyl)oxy)piperidine-1-carboxylate (315 mg, 92%) as a colorless oil that slowly solidified to a white solid upon standing. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.17 (d, J=7.04 Hz, 3H), 1.38 (s, 9H), 1.63-1.76 (m, 1H), 1.85-1.90 (m, 3H), 2.96-3.06 (m, 1H), 3.18 (s, 3H), 3.72-3.78 (m, 1H), 4.16-4.24 (m, 1H), 4.93-4.98 (m, 1H). The reaction was quenched by the addition of saturated aqueous sodium bicarbonate (10 mL) and dichloromethane (10 mL) was added The organic layer was separated washed with 1M aqueous citric acid (10 mL) and brine (10 mL) dried over anhydrous sodium sulfate filtered concentrated in vacuo The residue was purified via column chromatography on silica gel (Biotage 50 g column, gradient elution with 20-30% ethyl acetate in hexanes)

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

実験手順: Triethylamine (0.49 mL, 3.49 mmol) was added to a 0° C. solution of (rac)-tert-butyl (cis)-4-hydroxy-2-methylpiperidine-1-carboxylate (250 mg, 1.16 mmol) and methanesulfonyl chloride (0.14 mL, 1.74 mmol) in dichloromethane (4.5 mL). The resulting mixture was warmed to room temperature and stirred overnight. The reaction was quenched by the addition of saturated aqueous sodium bicarbonate (10 mL) and dichloromethane (10 mL) was added. The organic layer was separated and washed with 1M aqueous citric acid (10 mL) and brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified via column chromatography on silica gel (Biotage 50 g column, gradient elution with 20-30% ethyl acetate in hexanes) to afford (rac)-tert-butyl (cis)-2-methyl-4-((methylsulfonyl)oxy)piperidine-1-carboxylate (315 mg, 92%) as a colorless oil that slowly solidified to a white solid upon standing. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.17 (d, J=7.04 Hz, 3H), 1.38 (s, 9H), 1.63-1.76 (m, 1H), 1.85-1.90 (m, 3H), 2.96-3.06 (m, 1H), 3.18 (s, 3H), 3.72-3.78 (m, 1H), 4.16-4.24 (m, 1H), 4.93-4.98 (m, 1H). The reaction was quenched by the addition of saturated aqueous sodium bicarbonate (10 mL) and dichloromethane (10 mL) was added The organic layer was separated washed with 1M aqueous citric acid (10 mL) and brine (10 mL) dried over anhydrous sodium sulfate filtered concentrated in vacuo The residue was purified via column chromatography on silica gel (Biotage 50 g column, gradient elution with 20-30% ethyl acetate in hexanes)

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

実験手順: Following the procedure found in Plettenburg, Oliver et. Al (PCT Int. Appl., 2007012421), sodium borohydride (213 mg, 5.6 mmol) was added portion-wise to a solution of tert-butyl 2-methyl-4-oxopiperidine-1-carboxylate (1.0 g, 4.7 mmol) in ethanol (10 mL). The mixture was stirred at room temperature for 2 h. The solution was concentrated in vacuo and then partitioned between water (40 mL) and ethyl acetate (40 mL). The aqueous layer was extracted twice with ethyl acetate (40 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified via column chromatography on silica gel (Biotage 50 g column, gradient elution with 40-50% ethyl acetate in hexanes) to afford (rac)-tert-butyl (cis)-4-hydroxy-2-methylpiperidine-1-carboxylate (367 mg, 36%) and (rac)-tert-butyl (trans)-4-hydroxy-2-methylpiperidine-1-carboxylate (205 mg, 20%) as white solids. The solution was concentrated in vacuo partitioned between water (40 mL) and ethyl acetate (40 mL) The aqueous layer was extracted twice with ethyl acetate (40 mL) The combined organic layers were washed with brine (20 mL) dried over anhydrous sodium sulfate filtered concentrated in vacuo The residue was purified via column chromatography on silica gel (Biotage 50 g column, gradient elution with 40-50% ethyl acetate in hexanes)

反応条件: temp:65.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Add sodium hydride (95%, 0.318 g) to a solution of 4-hydroxy-cis-2-methyl-piperidine-1-carboxylic acid tert-butyl ester isomer 2 (preparation 3, 2.465 g) in DMSO (100 mL) and heat in an oil bath at 65° C. After 30 min., add 2,6-dichloropyridine (1.864 g) and beat at 100° C. After 4 hr., partition between ethyl acetate-hexane (1:4) and saturated aqueous NaCl aqueous NaCl, dry over anhydrous sodium sulfate, evaporate and purify on a 35 g silica gel column eluting with ethyl acetate-hexane (1:39) to give the title compound (3.26 g). 1H NMR (CDCl3): 7.50 (t, 1H), 6.87 (d, 1H), 6.61 (d, 1H), 5.38 (m, 1H), 4.35 (m, 1H), 3.89 (m, 1H), 3.22 (m, 1H), 1.93 (m, 3H), 1.75 (m, 1H), 1.46 (s, 9H), 1.26 (d, 3H). beat at 100° C After 4 hr , partition between ethyl acetate-hexane (1:4) and saturated aqueous NaCl aqueous NaCl dry over anhydrous sodium sulfate evaporate purify on a 35 g silica gel column eluting with ethyl acetate-hexane (1:39)

反応条件: temp:65.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Combine 4-hydroxy-cis-2-methyl-piperidine-1-carboxylic acid tert-butyl ester isomer 2 (preparation 3, 0.986 g) in DMF (10 mL) and add to a suspension of sodium hydride (95%, 0.127 g) in DMF (10 mL) and heat in an oil bath at 65° C. After 30 min., add 1-bromo-3-fluoro-benzene (0.96 g) and heat at 65° C. After 18 hr., partition between ethyl acetate-hexane (1:4) and saturated aqueous NaCl, dry over anhydrous sodium sulfate, evaporate and purify on a 35 g silica gel column eluting with ethyl acetate-hexane (1:9) to give the title compound as a colorless oil (0.759 g). 1H NMR (CDCl3): 7.13 (dd, 1H), 7.05 (ddd, 1H), 7.04 (m, 1H), 6.81 (ddd, 1H), 4.63 (m, 1H), 4.35 (m, 1H), 3.88 (m, 1H), 3.23 (m, 1H), 1.90 (m, 3H), 1.73 (m, 1H), 1.46 (s, 9H), 1.27 (d, J=7.0 Hz, 3H). heat at 65° C After 18 hr , partition between ethyl acetate-hexane (1:4) and saturated aqueous NaCl dry over anhydrous sodium sulfate evaporate purify on a 35 g silica gel column eluting with ethyl acetate-hexane (1:9)

反応条件: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Dissolve 4-hydroxy-cis-2-methyl-piperidine-1-carboxylic acid tert-butyl ester isomer 1 (preparation 2, 2.53 g, 11.75 mmol) in 1-methyl-2-pyrrolidinone (50 mL) and treat with 95% sodium hydride (0.33 g, 12.93 mmol), stir and heat at 70° C. After 1 hr., add 1-bromo-3-fluoro-benzene (1.44 mL, 12.93 mmol), stir and heat at 100° C. After 16 hr., cool to ambient temperature and quench with water (100 mL). Extract with 4:1 hexane:ethyl acetate (2×100 mL). Combine the organic layers and wash with aqueous NaCl solution (75 mL), dry over sodium sulfate, filter and concentrate. Purify residue by silica gel flash chromatography eluting with 4:1 hexanes:ethyl acetate to obtain the title compound (2.47 g, 57%). 1H NMR (CDCl3): 7.15 (m, 1H), 7.05 (m, 2H), 6.8 (dd, 1H), 4.6 (m, 1H), 4.35 (m, 1H), 3.9 (m, 1H), 3.25 (m, 1H), 1.9 (m, 3H), 1.75 (m, 1H), 1.5 (s, 9H), 1.3 (d, 3H). Dissolve stir heat at 100° C After 16 hr , cool to ambient temperature quench with water (100 mL) Extract with 4:1 hexane Combine the organic layers and wash with aqueous NaCl solution (75 mL) dry over sodium sulfate filter concentrate Purify residue by silica gel flash chromatography eluting with 4:1 hexanes

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

実験手順: With stirring, a solution of 2 ml (0.012 mol) of diethyl azodicarboxylate (93%) in 10 ml of toluene is added dropwise at 5°-10° C. to a suspension of 2.15 g (0.01 mol) of cis-N-BOC-2-methyl-4-hydroxypiperidine (cf. Example 1b), 2.0 g (0.012 mol) of 4-nitrobenzoic acid and 3.15 g (0.012 mol) of triphenylphosphine in 30 ml of toluene. The reaction mixture is further stirred for 15 hours at room temperature and then filtered to remove precipitated diethyl hydrazinedicarboxylate. The filtrate is then concentrated under vacuum and the oily residue is purified by flash chromatography over silica gel using ethyl acetate:hexane (1:5). Concentration of the fractions containing the product gives the title compound as a crystalline residue which melts at 106°-108° C. The reaction mixture is further stirred for 15 hours at room temperature filtered to remove precipitated diethyl hydrazinedicarboxylate The filtrate is then concentrated under vacuum the oily residue is purified by flash chromatography over silica gel Concentration of the fractions containing the product

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

実験手順: A solution of 14.6 g (0.04876 mol) of cis-N-BOC-2-methyl-4-[(tetrahydropyran-2-yl)oxy]piperidine in 120 ml of methanol is treated with 20 g of cationic exchanger Dowex® 50 WX8 (H+ form; 50-100 mesh (50 mesh corresponds to a granular size of c. 300 μm, 100 mesh to c. 150 μm); cationic exchanger based on a styrene/divinylbenzene polymer containing sulfonyl groups; registered trademark of Dow Chemicals Co., USA)), and the mixture is stirred for 22 hours at room temperature. After filtration, washing the ion exchanger with methanol and concentrating the filtrate under vacuum, the title compound is obtained in the form of a viscous oil, Rf =0.16 (silica gel/ethyl acetate:hexane (1:2)). containing sulfonyl groups After filtration washing the ion exchanger with methanol concentrating the filtrate under vacuum

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

実験手順: Triethylamine (0.49 mL, 3.49 mmol) was added to a 0° C. solution of (rac)-tert-butyl (cis)-4-hydroxy-2-methylpiperidine-1-carboxylate (250 mg, 1.16 mmol) and methanesulfonyl chloride (0.14 mL, 1.74 mmol) in dichloromethane (4.5 mL). The resulting mixture was warmed to room temperature and stirred overnight. The reaction was quenched by the addition of saturated aqueous sodium bicarbonate (10 mL) and dichloromethane (10 mL) was added. The organic layer was separated and washed with 1M aqueous citric acid (10 mL) and brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified via column chromatography on silica gel (Biotage 50 g column, gradient elution with 20-30% ethyl acetate in hexanes) to afford (rac)-tert-butyl (cis)-2-methyl-4-((methylsulfonyl)oxy)piperidine-1-carboxylate (315 mg, 92%) as a colorless oil that slowly solidified to a white solid upon standing. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.17 (d, J=7.04 Hz, 3H), 1.38 (s, 9H), 1.63-1.76 (m, 1H), 1.85-1.90 (m, 3H), 2.96-3.06 (m, 1H), 3.18 (s, 3H), 3.72-3.78 (m, 1H), 4.16-4.24 (m, 1H), 4.93-4.98 (m, 1H). The reaction was quenched by the addition of saturated aqueous sodium bicarbonate (10 mL) and dichloromethane (10 mL) was added The organic layer was separated washed with 1M aqueous citric acid (10 mL) and brine (10 mL) dried over anhydrous sodium sulfate filtered concentrated in vacuo The residue was purified via column chromatography on silica gel (Biotage 50 g column, gradient elution with 20-30% ethyl acetate in hexanes)

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

実験手順: Following the procedure found in Plettenburg, Oliver et. Al (PCT Int. Appl., 2007012421), sodium borohydride (213 mg, 5.6 mmol) was added portion-wise to a solution of tert-butyl 2-methyl-4-oxopiperidine-1-carboxylate (1.0 g, 4.7 mmol) in ethanol (10 mL). The mixture was stirred at room temperature for 2 h. The solution was concentrated in vacuo and then partitioned between water (40 mL) and ethyl acetate (40 mL). The aqueous layer was extracted twice with ethyl acetate (40 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified via column chromatography on silica gel (Biotage 50 g column, gradient elution with 40-50% ethyl acetate in hexanes) to afford (rac)-tert-butyl (cis)-4-hydroxy-2-methylpiperidine-1-carboxylate (367 mg, 36%) and (rac)-tert-butyl (trans)-4-hydroxy-2-methylpiperidine-1-carboxylate (205 mg, 20%) as white solids. The solution was concentrated in vacuo partitioned between water (40 mL) and ethyl acetate (40 mL) The aqueous layer was extracted twice with ethyl acetate (40 mL) The combined organic layers were washed with brine (20 mL) dried over anhydrous sodium sulfate filtered concentrated in vacuo The residue was purified via column chromatography on silica gel (Biotage 50 g column, gradient elution with 40-50% ethyl acetate in hexanes)