Methyl 4-oxopiperidine-3-carboxylate hydrochloride

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

実験手順: PTSA (24.7, 130 mmol) and ethylene glycol (24.8 mL, 439 mmol) were added to methyl-4-oxo-3-piperidine carboxylate hydrochloride (90) (25.1 g, 130 mmol) in benzene (52 mL, 2.5 M). The solution was stirred and heated to reflux overnight. H2O was removed using a Dean Stark trap. When the reaction was judged complete by TLC, 5% aqueous NaHCO3 and CH2Cl2 were added, and the organic layer was removed. The aqueous layer was extracted with CH2Cl2 (5×), and the combined organics were dried over sodium sulfate, filtered and concentrated in vacuo, and purified by silica gel chromatography with 20:1 CH2Cl2:2N NH3 in EtOH to provide 91 (16.7 g, 64%). 1H NMR (CDCl3) 3.82-3.70 (4H, m), 3.48 (3H, s), 3.00-2.50 (4H, m), 2.43 (1H, t), 1.76 (1H, m), 1.30 (1H, m) ppm. 13C NMR (CDCl3): 171.83, 106.57, 64.34, 64.17, 51.36, 48.91, 46.54, 43.69, 33.97 ppm. heated to reflux overnight H2O was removed were added the organic layer was removed The aqueous layer was extracted with CH2Cl2 (5×) the combined organics were dried over sodium sulfate filtered concentrated in vacuo purified by silica gel chromatography with 20:1 CH2Cl2

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

実験手順: PTSA (24.7, 130 mmol) and ethylene glycol (24.8 mL, 439 mmol) were added to methyl-4-oxo-3-piperidine carboxylate hydrochloride (90) (25.1 g, 130 mmol) in benzene (52 mL, 2.5 M). The solution was stirred and heated to reflux overnight. H2O was removed using a Dean Stark trap. When the reaction was judged complete by TLC, 5% aqueous NaHCO3 and CH2Cl2 were added, and the organic layer was removed. The aqueous layer was extracted with CH2Cl2 (5×), and the combined organics were dried over sodium sulfate, filtered and concentrated in vacuo, and purified by silica gel chromatography with 20:1 CH2Cl2:2N NH3 in EtOH to provide 91 (16.7 g, 64%). 1H NMR (CDCl3) 3.82-3.70 (4H, m), 3.48 (3H, s), 3.00-2.50 (4H, m), 2.43 (1H, t), 1.76 (1H, m), 1.30 (1H, m) ppm. 13C NMR (CDCl3): 171.83, 106.57, 64.34, 64.17, 51.36, 48.91, 46.54, 43.69, 33.97 ppm. heated to reflux overnight H2O was removed were added the organic layer was removed The aqueous layer was extracted with CH2Cl2 (5×) the combined organics were dried over sodium sulfate filtered concentrated in vacuo purified by silica gel chromatography with 20:1 CH2Cl2

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

実験手順: 1.94 g of methyl 4-oxo-3-piperidinecarboxylate hydrochloride, 1.68 g of sodium hydrogencarbonate and 1.67 g of ethyl bromoacetate were dissolved in a mixed solvent comprising 32 ml of water and 8 ml of diethyl ether and stirred at room temperature overnight. 50 ml of ethyl acetate was added to the reaction liquid, and the organic layer was separated by liquid-liquid separation. This was dried with sodium sulfate and concentrated. The resulting residue was purified by silica gel column chromatography (using a gradient eluent of chloroform to chloroform/methanol=100/1) to obtain 1.5 g of ethyl 3-methoxycarbonyl-4-oxo-1-piperidineacetate as an oily substance. the organic layer was separated by liquid-liquid separation This was dried with sodium sulfate concentrated The resulting residue was purified by silica gel column chromatography (

反応条件: temp:5.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: An 80% sulfuric acid solution (80 ml) is stirred and cooled to 5° C. in an ice bath and 3-methylphenol (10.8 ml, 0.10 moles) is added, followed by methyl-4-oxo-3-piperidine carboxylate hydrochloride (20.0 g, 0.10 moles). The mixture is allowed to warm gradually to room temperature. After 48 hours the solution is poured into ice water (400 ml) and stirred until a crystalline precipitate forms. Concentrated ammonium hydroxide is added until the mixture is strongly basic. After one hour the precipitate is filtered off, rinsed with concentrated ammonium hydroxide, then water, and dried. Recrystallization from acetonitrile gave the product (4.5 g), mp 128°-130° C. to warm gradually to room temperature After one hour the precipitate is filtered off rinsed with concentrated ammonium hydroxide water, and dried Recrystallization from acetonitrile

反応条件: temp:5.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: An 80% sulfuric acid solution (80 ml) is stirred and cooled to 5° C. in an ice bath and 3-methylphenol (10.8 ml, 0.10 moles) is added, followed by methyl-4-oxo-3-piperidine carboxylate hydrochloride (20.0 g, 0.10 moles). The mixture is allowed to warm gradually to room temperature. After 48 hours the solution is poured into ice water (400 ml) and stirred until a crystalline precipitate forms. Concentrated ammonium hydroxide is added until the mixture is strongly basic. After one hour the precipitate is filtered off, rinsed with concentrated ammonium hydroxide, then water, and dried. Recrystallization from acetonitrile gave the product (4.5 g), mp 128°-130° C. to warm gradually to room temperature After one hour the precipitate is filtered off rinsed with concentrated ammonium hydroxide water, and dried Recrystallization from acetonitrile

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

実験手順: Prepared by the method described for Example 1 from 3-t-butylphenol (15 g, 0.1 moles) and methyl 4-oxo-3-piperidinecarboxylate hydrochloride (19.3 g, 0.1 moles). Recrystallization from ethyl acetate gave the product (14.7 g), mp 181°-186° C. Prepared by the method Recrystallization from ethyl acetate

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

実験手順: Prepared by the method described for Example 1 from 3-t-butylphenol (15 g, 0.1 moles) and methyl 4-oxo-3-piperidinecarboxylate hydrochloride (19.3 g, 0.1 moles). Recrystallization from ethyl acetate gave the product (14.7 g), mp 181°-186° C. Prepared by the method Recrystallization from ethyl acetate

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

実験手順: Prepared by the method described for Example 1 from 3-phenylphenol (17 g, 0.1 moles) and methyl 4-oxo-3-piperidinecarboxylate hydrochloride (19.3 g, 0.1 moles). The crude material is washed with water and dried to give the product (15 g), mp 250°-270° C. Prepared by the method The crude material is washed with water dried

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

実験手順: Prepared by the method described for Example 1 from 3-ethylphenol (12.2 g, 0.1 moles) and methyl 4-oxo-3-piperidinecarboxylate hydrochloride (19.3 g, 0.1 moles). The crude material is washed with water and dried to give the product (6.6 g), mp 80°-85° C. Prepared by the method The crude material is washed with water dried

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

実験手順: Prepared by the method described for Example 1 from 3-ethylphenol (12.2 g, 0.1 moles) and methyl 4-oxo-3-piperidinecarboxylate hydrochloride (19.3 g, 0.1 moles). The crude material is washed with water and dried to give the product (6.6 g), mp 80°-85° C. Prepared by the method The crude material is washed with water dried

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

実験手順: Prepared by the method described for Example 1 from 3-methoxyphenol (16 g, 0.126 moles) and methyl 4-oxo-3-piperidinecarboxylate hydrochloride (25 g, 0.129 moles). Recrystallization from ethanol gave the product (10.43 g), mp 179°-183° C. Prepared by the method Recrystallization from ethanol

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

実験手順: Prepared by the method described in Example 1 from 3,4-dimethylphenol (10.0 g, 0.082 moles) and methyl 4-oxo-3-piperdinecarboxylate hydrochloride (11.3 g, 0.058 moles). Recrystallization from 2-methoxyethanol yielded the product (11.2 g), mp 172°-l74° C. Prepared by the method Recrystallization from 2-methoxyethanol