ethyl (3S)-piperidine-3-carboxylate

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

実験手順: To 13.0 g of ethyl (3S)-3-piperidinecarboxylate D(−)-tartarate which was synthesized following the method of P. Magnus, et al. [J. Org. Chem. Vol. 56, 1166-1170 (1991)], 3N aqueous sodium hydroxide solution was added to render the former basic, followed by extraction with chloroform and drying over anhydrous magnesium sulfate. Distilling the solvent off under reduced pressure, 7.50 g of the title compound was obtained. followed by extraction with chloroform drying over anhydrous magnesium sulfate Distilling the solvent off under reduced pressure

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

実験手順: Ethyl (S)-Piperidine-3-carboxylate (25 g, 159.02 mmol) in anhydrous DCM (500 mL) was cooled down to 0° C. and treated with Et3N. A solution of isovaleryl chloride (23.27 mL, 190.08 mmol, 1.2 eq.) in anhydrous DCM (200 mL) was added dropwise at 0° C. The resulting reaction mixture was kept on the cooling bath and allowed to warm up slowly to room temperature. After 6 hrs the reaction was washed subsequently with aqueous HCl solution (2M), saturated NaHCO3, brine, dried over Na2SO4, filtered, concentrated under vacuum and purified by filtration over a short silica gel column using EtOAc as solvent. The solvent was removed under vacuum to yield the desired product as pale yellow oil (37.4 g, 154.97 mmol, 97.5%) that was used in the next step without further purification. 1H NMR (400 MHz, DMSO-d6, 20° C.) δ0.88 (pseudo d, J=6.4 Hz, 6H), 1.13-1.23 (m, 3H), 1.26-1.45 (m, 1H), 1.47-1.75 (m, 2H), 1.82-2.03 (m, 2H), 2.10-2.28 (m, 2H), 2.28-2.39 (m, 0.5H), 2.45-2.56 (m, 0.5H), 2.84 (dd, J=10.0, 12.8 Hz, 0.5H), 2.97-3.11 (m, 1H), 3.38 (dd, J=8.8, 13.6 Hz, 0.5H), 3.63-3.83 (m, 1.5H), 4.00-4.14 (m, 2H), 4.26-4.36 (dm, 0.5H). MS 242 (MH). The resulting reaction mixture After 6 hrs the reaction was washed subsequently with aqueous HCl solution (2M), saturated NaHCO3, brine dried over Na2SO4 filtered concentrated under vacuum purified by filtration over a short silica gel column The solvent was removed under vacuum

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

実験手順: To 13.0 g of ethyl (3S)-3-piperidinecarboxylate D(−)-tartarate which was synthesized following the method of P. Magnus, et al. [J. Org. Chem. Vol. 56, 1166-1170 (1991)], 3N aqueous sodium hydroxide solution was added to render the former basic, followed by extraction with chloroform and drying over anhydrous magnesium sulfate. Distilling the solvent off under reduced pressure, 7.50 g of the title compound was obtained. followed by extraction with chloroform drying over anhydrous magnesium sulfate Distilling the solvent off under reduced pressure

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

実験手順: To 13.0 g of ethyl (3S)-3-piperidinecarboxylate D(−)-tartarate which was synthesized following the method of P. Magnus, et al. [J. Org. Chem. Vol. 56, 1166-1170 (1991)], 3N aqueous sodium hydroxide solution was added to render the former basic, followed by extraction with chloroform and drying over anhydrous magnesium sulfate. Distilling the solvent off under reduced pressure, 7.50 g of the title compound was obtained. followed by extraction with chloroform drying over anhydrous magnesium sulfate Distilling the solvent off under reduced pressure

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

実験手順: Prepared from 5-(5-Trifluoromethyl-4-methyl-isoxazol-3-yl)-thiophene-2-carboxylic acid and (S)-(+)-nipecotic acid, ethyl ester (TCI America, Portland Oreg., USA) by the method described in Example 2 Method B. Colorless solid (415 mg, 91%). 1H NMR (CDCl3) 1.19 (t, J=7.0, 3H), 1.50-1.60 (m, 1H), 1.66-1.82 (m, 2H), 2.02-2.12 (m, 1H), 2.29 (d, J=1.4, 3H), 2.46-2.56 (m, 1H), 3.13 (t, J=11.0, 1H), 3.28 (br s, 1H), 4.08 (q, J 7.0, 3H), 4.10 (obs m, 1H), 4.34 (br s, 1H), 7.28 (d, J=4.0, 1H), 7.39 (d, J=3.5, 1H). 19F NMR −63.12. LC/MS 6.74 min, [M+1]+ 417. LC/MS 6.74 min, [M+1]+ 417

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

実験手順: (S)-ethyl nipecotate (309.1 mg; 1.97 mmol) was dissolved in anhydrous methanol (8 ml) and commercially available benzaldehyde (200 μl; 1.97 mmol) was added, followed by sodium cyanoborohydride (234 mg; 3.72 mmol). This mixture was allowed to stir at ambient temperature for 23 hours and was then diluted with dichloromethane. The dichloromethane was washed with water, then washed with saturated sodium chloride solution, dried with anhydrous potassium carbonate, and evaporated under reduced pressure at ambient temperature. The crude product was purified by chromatography on silica eluting with 50% ethyl acetate/50% hexane, giving (S)-ethyl 1-benzyl-3-piperidinecarboxylate (192.7 mg) as a colorless oil. MS mi/z (positive ion) 248 (MH+; 100). The dichloromethane was washed with water washed with saturated sodium chloride solution dried with anhydrous potassium carbonate evaporated under reduced pressure at ambient temperature The crude product was purified by chromatography on silica eluting with 50% ethyl acetate/50% hexane

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

実験手順: (S)-ethyl nipecotate (309.1 mg; 1.97 mmol) was dissolved in anhydrous methanol (8 ml) and commercially available benzaldehyde (200 μl; 1.97 mmol) was added, followed by sodium cyanoborohydride (234 mg; 3.72 mmol). This mixture was allowed to stir at ambient temperature for 23 hours and was then diluted with dichloromethane. The dichloromethane was washed with water, then washed with saturated sodium chloride solution, dried with anhydrous potassium carbonate, and evaporated under reduced pressure at ambient temperature. The crude product was purified by chromatography on silica eluting with 50% ethyl acetate/50% hexane, giving (S)-ethyl 1-benzyl-3-piperidinecarboxylate (192.7 mg) as a colorless oil. MS mi/z (positive ion) 248 (MH+; 100). The dichloromethane was washed with water washed with saturated sodium chloride solution dried with anhydrous potassium carbonate evaporated under reduced pressure at ambient temperature The crude product was purified by chromatography on silica eluting with 50% ethyl acetate/50% hexane

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

実験手順: This reaction was run in the same manner as ethyl 1-(3-thiophenecarbonyl)-3-piperidinecarboxylate, starting with commercially available 2-phenylpropionic acid (265 μl; 1.94 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (371.3 mg; 1.94 mmol) and (S)-ethyl nipecotate (300 μl; 1.94 mmol). Crude product was purified by chromatography on silica eluting with 25% ethyl acetate/75% hexane, giving (S)±ethyl 1-(2-phenylpropionyl)-3-piperidinecarboxylate (268.9 mg) as a colorless oil. MS m/z (positive ion) 290 (MH+; 100), 142 (55), 115 (50). Crude product was purified by chromatography on silica eluting with 25% ethyl acetate/75% hexane

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

実験手順: This reaction was run in the same manner as ethyl 1-(3-thiophenecarbonyl)-3-piperidinecarboxylate, starting with commercially available 4-(2-thienyl)butyric acid (280 μl; 1.93 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (367.7 mg; 1.92 mmol) and (S)-ethyl nipecotate (300 μl; 1.94 mmol). The crude product was purified by chromatography on silica eluting with 30% ethyl acetatel70% hexane to 40% ethyl acetate/60% hexane in a single step gradient, giving (S)-ethyl 1-(2-thienylpropyl)-3-piperidinecarboxylate (181.7 mg) as a colorless oil. MS m/z (positive ion) 411 (MH++Et3N; 40), 332 (M+Na+; 30), 310 (MH+; 100), 101 (Et3NH+; 30). The crude product was purified by chromatography on silica eluting with 30% ethyl acetatel70% hexane to 40% ethyl acetate/60% hexane in a single step gradient

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

実験手順: The reaction was run in the same manner as ethyl 1-benzoyl-3-piperidinecarboxylate, starting with commercially available (S)-ethyl nipecotate (203 mg; 1.29 mmol; Chemi SpA; Italy) and benzoyl chloride (150 μl; 1.29 mmol). The crude product was distilled at 200° C./0.1 torr, giving (S)-ethyl 1-benzoyl-3-piperidinecarboxylate (171.7 mg) as a colorless oil. MS m/z (positive ion) 545 (dimer+Na+; 15), 523 (dimer+; 10), 284 (M+Na+; 25), 262 (MH+; 100). The crude product was distilled at 200° C./0.1 torr

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

実験手順: The reaction was run in the same manner as ethyl 1-benzoyl-3-piperidinecarboxylate, starting with commercially available (S)-ethyl nipecotate (203 mg; 1.29 mmol; Chemi SpA; Italy) and benzoyl chloride (150 μl; 1.29 mmol). The crude product was distilled at 200° C./0.1 torr, giving (S)-ethyl 1-benzoyl-3-piperidinecarboxylate (171.7 mg) as a colorless oil. MS m/z (positive ion) 545 (dimer+Na+; 15), 523 (dimer+; 10), 284 (M+Na+; 25), 262 (MH+; 100). The crude product was distilled at 200° C./0.1 torr

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

実験手順: To 13.0 g of ethyl (3S)-3-piperidinecarboxylate D(−)-tartarate which was synthesized following the method of P. Magnus, et al. [J. Org. Chem. Vol. 56, 1166-1170 (1991)], 3N aqueous sodium hydroxide solution was added to render the former basic, followed by extraction with chloroform and drying over anhydrous magnesium sulfate. Distilling the solvent off under reduced pressure, 7.50 g of the title compound was obtained. followed by extraction with chloroform drying over anhydrous magnesium sulfate Distilling the solvent off under reduced pressure