ethyl 4-oxopiperidine-3-carboxylate;hydrochloride

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 18.8 g (0.2 m) of phenol and 20.7 g (0.1 m) of 3-carbethoxy-4-piperidone HCl was cooled in an ice bath and treated with 75 cc of 73% v/v H2SO4 in 1/2 hr. with stirring and protection from moisture. After stirring 4 days at room temperature the reaction was chilled and treated with an additional 10 g (0.106 m) of phenol. After 5 days a second 10 g portion of phenol was added. After stirring 6 days the reaction was treated with 100 g of ice and conc. NH4OH to pH 8-9. The resultant gum was stirred with 100 cc CHCl3 for 1/2 hr. and was filtered. The filtrate was evaporated and the resultant gum was triturated with pet ether followed by ethyl ether. The resultant solid was crystallized from 100 cc 3N HCl affording 2.3 g (10%) of product mp. 330°- 5° C. was cooled in an ice bath After stirring 4 days at room temperature the reaction was chilled After stirring 6 days the reaction and was filtered The filtrate was evaporated the resultant gum was triturated with pet ether The resultant solid was crystallized from 100 cc 3N HCl affording 2.3 g (10%) of product mp. 330°- 5° C.

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 18.8 g (0.2 m) of phenol and 20.7 g (0.1 m) of 3-carbethoxy-4-piperidone HCl was cooled in an ice bath and treated with 75 cc of 73% v/v H2SO4 in 1/2 hr. with stirring and protection from moisture. After stirring 4 days at room temperature the reaction was chilled and treated with an additional 10 g (0.106 m) of phenol. After 5 days a second 10 g portion of phenol was added. After stirring 6 days the reaction was treated with 100 g of ice and conc. NH4OH to pH 8-9. The resultant gum was stirred with 100 cc CHCl3 for 1/2 hr. and was filtered. The filtrate was evaporated and the resultant gum was triturated with pet ether followed by ethyl ether. The resultant solid was crystallized from 100 cc 3N HCl affording 2.3 g (10%) of product mp. 330°- 5° C. was cooled in an ice bath After stirring 4 days at room temperature the reaction was chilled After stirring 6 days the reaction and was filtered The filtrate was evaporated the resultant gum was triturated with pet ether The resultant solid was crystallized from 100 cc 3N HCl affording 2.3 g (10%) of product mp. 330°- 5° C.

Conditions: temp:140.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A suspension of 31.15 g (150 mmol) 3-Ethoxycarbonyl-4-piperidone hydrochloride was suspended in 400 ml hexamethyldisilazane and heated under reflux (140° C.) for 2.5 h. The solution was evaporated complete, the residue dissolved in 400 ml THF and treated with 34 g (150 mmol) of naphthalene-2-sulfonylchloride in 150 ml THF. The reaction was stirred 16 h at room temperature, evaporated, treated with 400 ml aqueous 10% NaCl, stirred for 10 min and extracted with EtOAc (3×400 ml). The organic phase was dried (Na2SO4) and evaporated and crystallized from Et2O at 5° C. to give 53.1 g (90%) of 4-hydroxy-1-(naphthalene-2-sulfonyl)-1,2,5,6-tetrahydro-pyridine-3-carboxylic acid ethyl ester, MS: 362 (MH+). heated The solution was evaporated complete the residue dissolved in 400 ml THF evaporated treated with 400 ml aqueous 10% NaCl stirred for 10 min extracted with EtOAc (3×400 ml) The organic phase was dried (Na2SO4) evaporated crystallized from Et2O at 5° C.

Conditions: temp:140.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A suspension of 31.15 g (150 mmol) 3-Ethoxycarbonyl-4-piperidone hydrochloride was suspended in 400 ml hexamethyldisilazane and heated under reflux (140° C.) for 2.5 h. The solution was evaporated complete, the residue dissolved in 400 ml THF and treated with 34 g (150 mmol) of naphthalene-2-sulfonylchloride in 150 ml THF. The reaction was stirred 16 h at room temperature, evaporated, treated with 400 ml aqueous 10% NaCl, stirred for 10 min and extracted with EtOAc (3×400 ml). The organic phase was dried (Na2SO4) and evaporated and crystallized from Et2O at 5° C. to give 53.1 g (90%) of 4-hydroxy-1-(naphthalene-2-sulfonyl)-1,2,5,6-tetrahydro-pyridine-3-carboxylic acid ethyl ester, MS: 362 (MH+). heated The solution was evaporated complete the residue dissolved in 400 ml THF evaporated treated with 400 ml aqueous 10% NaCl stirred for 10 min extracted with EtOAc (3×400 ml) The organic phase was dried (Na2SO4) evaporated crystallized from Et2O at 5° C.

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Prepared by the method described in Example 1 except that the 3,4-dimethoxyphenol (61.5 g, 0.40 moles) is added in one portion to an ice-cooled mixture of ethyl 4-oxo-3-piperidinecarboxylate hydrochloride (75 g, 0.36 moles) and 200 ml of 72% sulfuric acid. Recrystallization from acetonitrile yielded the product (71 g), mp 186°-188° C. Prepared by the method cooled Recrystallization from acetonitrile

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Prepared by the method described in Example 1 except that the 3,4-dimethoxyphenol (61.5 g, 0.40 moles) is added in one portion to an ice-cooled mixture of ethyl 4-oxo-3-piperidinecarboxylate hydrochloride (75 g, 0.36 moles) and 200 ml of 72% sulfuric acid. Recrystallization from acetonitrile yielded the product (71 g), mp 186°-188° C. Prepared by the method cooled Recrystallization from acetonitrile

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 18.8 g (0.2 m) of phenol and 20.7 g (0.1 m) of 3-carbethoxy-4-piperidone HCl was cooled in an ice bath and treated with 75 cc of 73% v/v H2SO4 in 1/2 hr. with stirring and protection from moisture. After stirring 4 days at room temperature the reaction was chilled and treated with an additional 10 g (0.106 m) of phenol. After 5 days a second 10 g portion of phenol was added. After stirring 6 days the reaction was treated with 100 g of ice and conc. NH4OH to pH 8-9. The resultant gum was stirred with 100 cc CHCl3 for 1/2 hr. and was filtered. The filtrate was evaporated and the resultant gum was triturated with pet ether followed by ethyl ether. The resultant solid was crystallized from 100 cc 3N HCl affording 2.3 g (10%) of product mp. 330° -5° C. was cooled in an ice bath After stirring 4 days at room temperature the reaction was chilled After stirring 6 days the reaction and was filtered The filtrate was evaporated the resultant gum was triturated with pet ether The resultant solid was crystallized from 100 cc 3N HCl affording 2.3 g (10%) of product mp. 330° -5° C.

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of ethyl 4-piperidone-3-carboxylate hydrochloride (5 g, 24.05 mmol) in THF (70 mL) and water (35 mL) at 0° C., was added triethylamine (8.7 mL, 62.5 mmol), followed by N-(benzyloxycarbonyloxy)succinimide (7.79 g, 31.27 mmol). The reaction mixture was stirred and allowed to warm to room temperature. After 3 hours the reaction mixture was diluted with water (50 mL) and ethyl acetate (100 mL) added. The aqueous phase was extracted into ethyl acetate (2×100 mL). The organic phases were combined, washed with brine (50 mL), dried (MgSO4), and the solvent removed in vacuo. The crude product was purified by column chromatography on silica gel (eluent, ethyl acetate:pentane=1:5) to give 4-hydroxy-5,6-dihydro-2H-pyridine-1,3-dicarboxylic acid 1-benzyl ester 3-ethyl ester as a colorless oil (7.26 g, 94%). MS (EI) 305 (M+). added The aqueous phase was extracted into ethyl acetate (2×100 mL) washed with brine (50 mL) dried (MgSO4) the solvent removed in vacuo The crude product was purified by column chromatography on silica gel (eluent, ethyl acetate:pentane=1:5)

Conditions: temp:140.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A suspension of 31.15 g (150 mmol) 3-Ethoxycarbonyl-4-piperidone hydrochloride was suspended in 400 ml hexamethyldisilazane and heated under reflux (140° C.) for 2.5 h. The solution was evaporated complete, the residue dissolved in 400 ml THF and treated with 34 g (150 mmol) of naphthalene-2-sulfonylchloride in 150 ml THF. The reaction was stirred 16 h at room temperature, evaporated, treated with 400 ml aqueous 10% NaCl, stirred for 10 min and extracted with EtOAc (3×400 ml). The organic phase was dried (Na2SO4) and evaporated and crystallized from Et2O at 5° C. to give 53.1 g (90%) of 4-hydroxy-1-(naphthalene-2-sulfonyl)-1,2,5,6-tetrahydro-pyridine-3-carboxylic acid ethyl ester, MS: 362 (MH+). heated The solution was evaporated complete the residue dissolved in 400 ml THF evaporated treated with 400 ml aqueous 10% NaCl stirred for 10 min extracted with EtOAc (3×400 ml) The organic phase was dried (Na2SO4) evaporated crystallized from Et2O at 5° C.

Conditions: temp:140.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A suspension of 31.15 g (150 mmol) 3-Ethoxycarbonyl-4-piperidone hydrochloride was suspended in 400 ml hexamethyldisilazane and heated under reflux (140° C.) for 2.5 h. The solution was evaporated complete, the residue dissolved in 400 ml THF and treated with 34 g (150 mmol) of naphthalene-2-sulfonylchloride in 150 ml THF. The reaction was stirred 16 h at room temperature, evaporated, treated with 400 ml aqueous 10% NaCl, stirred for 10 min and extracted with EtOAc (3×400 ml). The organic phase was dried (Na2SO4) and evaporated and crystallized from Et2O at 5° C. to give 53.1 g (90%) of 4-hydroxy-1-(naphthalene-2-sulfonyl)-1,2,5,6-tetrahydro-pyridine-3-carboxylic acid ethyl ester, MS: 362 (MH+). heated The solution was evaporated complete the residue dissolved in 400 ml THF evaporated treated with 400 ml aqueous 10% NaCl stirred for 10 min extracted with EtOAc (3×400 ml) The organic phase was dried (Na2SO4) evaporated crystallized from Et2O at 5° C.

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The reaction was run in the same manner as ethyl 1-benzoyl-3-piperidinecarboxylate, starting with ethyl 4-piperidone-3-carboxylate hydrochloride (200.4 mg; 0.97 mmol), diisopropylethylamine (360 μl; 2.08 mmol) and 4-fluorobenzoyl chloride (114 μl; 0.97 mmol), giving ethyl 1-(4-fluorobenzoyl)4-oxo-3-piperidinecarboxylate (240.2 mg) as a thick, light yellow oil without further purification. MS m/z (positive ion) 348 (25), 316 (M+Na+; 75), 294 (MH+; 100).

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Commercially available ethyl 4-piperidone-3-carboxylate hydrochloride (203.2 mg; 0.98 mmol) was suspended in dichloromethane (7 ml), diisopropylethylamine (180 μl; 0.99 mmol) was added, followed by commercially available methyl isocyanate and (57 μl; 0.98 mmol). This mixture was stirred at ambient temperature for approximately 3 hours, and then diluted with fresh dichloromethane and washed with water. The dichloromethane solution was dried with anhydrous potassium carbonate and evaporated at ambient temperature under reduced pressure, giving ethyl 1-(N-methylaminocarbonyl)-4-oxo-3-piperidinecarboxylate (74.4 mg) as a white solid. MS m/z (positive ion) 479 (dimer+Na+; 40), 457 (dimer+; 25), 251 (M+Na+; 100), 229 (MH+; 90), 205 (25), 130 (25). washed with water The dichloromethane solution was dried with anhydrous potassium carbonate evaporated at ambient temperature under reduced pressure