methyl 4-piperidin-2-ylbutanoate;hydrochloride

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of DMSO (21.24 ml, 299 mmol) in CH2Cl2 (600 ml) was dropwise added to a solution of oxalyl chloride (15.0 ml, 171 mmol) in CH2Cl2 (300 ml) in 30 min while maintaining the internal temperature below −65° C. A solution of 3 (46.7 g, 142 mmol) in CH2Cl2 (300 ml) was added dropwise in 15 min. while maintaining the temperature below −65° C. The reaction mixture was stirred an additional 45 minutes at −78° C., after which Et3N (99.0 ml, 712 mmol) was added. After the reaction mixture was stirred at −78° C. for 45 min, the reaction mixture was allowed to warm to room temperature and stirring was continued for an additional hour. The reaction mixture was washed with H2O and brine, dried (Na2SO4) and concentrated. The residue was dissolved in Et2O, filtered and the filtrate was concentrated and crystallized (Et2O/heptane) to result in 4 (30.9 g, 67%). The mother liquor was concentrated and crystallized (Et2O/heptane) and gave extra 4 (2.27 g, 5%). while maintaining the internal temperature below −65° C while maintaining the temperature below −65° C After the reaction mixture was stirred at −78° C. for 45 min to warm to room temperature stirring was continued for an additional hour The reaction mixture was washed with H2O and brine dried (Na2SO4) concentrated The residue was dissolved in Et2O filtered the filtrate was concentrated crystallized (Et2O/heptane)

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

Procedure: NaHCO3 (35.1 g, 418 mmol) was added to a suspension of 2-aminophenol (2, 30.4 g, 279 mmol) and ethyl 4-chloro-3-oxobutanoate (1, 45.9 g, 279 mmol) in MeOH (280 ml) and the reaction mixture was stirred at room temperature for 2 days. After the addition of H2O (280 ml), the reaction mixture was extracted with Et2O (2×), washed with brine, dried (Na2SO4) and concentrated. The residue was purified by column chromatography (silica, heptane/EtOAc, 6:1) to yield 3 (33.71 g, 55%). the reaction mixture was extracted with Et2O (2×) washed with brine dried (Na2SO4) concentrated The residue was purified by column chromatography (silica, heptane/EtOAc, 6:1)

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

Procedure: A solution of 4-(2-piperidinyl)butanoic acid hydrochloride (5.95 g, 34.8 mmol) in Methanol (104 ml) is cooled to 0° C. At this temperature thionylchloride (7.54 ml, 104.3 mmol) is added slowly. The reaction mixture is heated to reflux for 12 h. The solvent is evaporated in vacuum. The residue is suspended in ethylacetate and is heated to reflux. The suspension is filtered while it is still hot. In the filtrate a white solid dropped out, which was filtered out and dried in vacuum to give Methyl 4-(piperidin-2-yl)butanoate hydrochloride (2) (3.49 g, 45%) The reaction mixture is heated to reflux for 12 h The solvent is evaporated in vacuum is heated to reflux The suspension is filtered while it In the filtrate a white solid dropped out which was filtered out dried in vacuum

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

Procedure: To a solution of tert-Butyl-2-(4-methoxy-4-oxobutyl)piperidine-1-carboxylate (3) (25.67 g, 89.9 mmol) in Methanol was added dropwise acetyl chloride. The reaction mixture was stirred for 5 h at room temperature. The completion of the reaction was controlled via Thin-layer chromatography. After completion the reaction mixture was evaporated in vacuum to give Methyl 4-(piperidin-2-yl)butanoate hydrochloride (4) (20.14 g, 100%) After completion the reaction mixture was evaporated in vacuum

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of DMSO (21.24 ml, 299 mmol) in CH2Cl2 (600 ml) was added dropwise to a solution of oxalyl chloride (15.0 ml, 171 mmol) in CH2Cl2 (300 ml) at an internal temperature below −65° C. in the course of 30 min. A solution of 3 (46.7 g, 142 mmol) in CH2Cl2 (300 ml) was added dropwise in the course of 15 min, the temperature remaining below −65° C. The reaction mixture was stirred at −78° C. for a further 45 min and Et3N (99.0 ml, 712 mmol) was then added. After the reaction mixture had been stirred at −78° C. for 45 min, the reaction mixture was warmed to room temperature, while stirring, and was then stirred for a further hour. The reaction mixture was washed with H2O and sat. NaCl solution, dried over Na2SO4 and concentrated. The residue was dissolved in ether, the solution was filtered, the filtrate was concentrated and the residue was recrystallized (Et2O/heptane) to obtain 4 (30.9 g, 67%). The mother liquor was concentrated and the residue was recrystallized (Et2O/heptane) and gave additional product 4 (2.27 g, 5%). remaining below −65° C After the reaction mixture had been stirred at −78° C. for 45 min the reaction mixture was warmed to room temperature while stirring was then stirred for a further hour The reaction mixture was washed with H2O and sat. NaCl solution dried over Na2SO4 concentrated The residue was dissolved in ether the solution was filtered the filtrate was concentrated the residue was recrystallized (Et2O/heptane)

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

Procedure: The sulfonyl chloride 1 (9.76 g, 85.2 mmol) and Et3N (11.8 ml, 85.2 mmol) were dissolved in CH2Cl2 (100 ml), and a solution of diphenylmethanamine (2, 15.61 g, 85.2 mmol) in CH2Cl2 (40 ml) was added dropwise in the course of 10 min. The reaction mixture was stirred at room temperature for 18 h. The reaction mixture was washed with aqueous 0.5 M KHSO4 (2×200 ml) and sat. NaCl solution (100 ml), dried over Na2SO4 and concentrated to dryness. Recrystallization from CH2Cl2 at 0-5° C. gave 17.63 g (79%) of the sulfonamide 3. The reaction mixture was washed with aqueous 0.5 M KHSO4 (2×200 ml) and sat. NaCl solution (100 ml) dried over Na2SO4 concentrated to dryness Recrystallization from CH2Cl2 at 0-5° C.

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

Procedure: Naphthalene-1-sulfonyl chloride (13.7 g, 60.55 mmol) was added to a solution of methyl 4-(piperidine-2-yl)butanoate hydrochloride (2) (3.74 g, 20.2 mmol) in methylene chloride (143 ml). N-Ethyl-diisopropylamine (10.2 ml, 60.55 mmol) was then added dropwise. The reaction mixture was stirred overnight at room temperature. The completeness of the reaction was checked by means of TLC. When the reaction was complete, the reaction mixture was acidified with 1 M HCl (aqueous) and the aqueous phase was saturated with NaCl solution and then extracted 4× with methylene chloride. The combined organic phases were dried over MgSO4, filtered and concentrated under reduced pressure. Purification via column chromatography (aluminium oxide; hexane/ethyl acetate 97.3→9:1) gave the desired product methyl 4-(1-(naphthalen-1-ylsulfonyl)piperidin-2-yl)butanoate 3 (4.95 g, 65%). extracted 4× with methylene chloride The combined organic phases were dried over MgSO4 filtered concentrated under reduced pressure Purification via column chromatography (aluminium oxide; hexane/ethyl acetate 97.3→9:1)

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

Procedure: A solution of 4-(2-piperidinyl)butanoic acid hydrochloride (5.95 g, 34.8 mmol) in methanol (104 ml) was cooled to 0° C. Thionyl chloride (7.54 ml, 104.3 mmol) was slowly added at this temperature. The reaction mixture was heated under reflux for 12 h. The solvent was evaporated off under reduced pressure. The residue was suspended in ethyl acetate and the suspension was heated under reflux. The suspension was filtered hot. A white precipitate precipitates out in the filtrate, and was filtered out and dried under reduced pressure to give the product methyl 4-(piperidine-2-yl)butanoate hydrochloride (2) (3.49 g, 45%). The reaction mixture was heated under reflux for 12 h The solvent was evaporated off under reduced pressure the suspension was heated under reflux The suspension was filtered hot A white precipitate precipitates out in the filtrate was filtered out dried under reduced pressure

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

Procedure: Acetyl chloride was slowly added dropwise to a solution of tert-butyl 2-(4-methoxy-4-oxobutyl)piperidine-1-carboxylate (3) (25.67 g, 89.9 mmol) in methanol. The reaction mixture was stirred at room temperature for 5 h. The complete reaction was checked by means of TLC. When the reaction was complete, the reaction mixture was concentrated under reduced pressure to obtain methyl 4-(piperidine-2-yl)butanoate hydrochloride (4) (20.14 g, 100%). The complete reaction the reaction mixture was concentrated under reduced pressure

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Perchloric acid (4.96 ml, 57.4 mmol) was added to a solution of 3 (56.02 g, 287 mmol) in dioxane (1124 ml) and H2O (856 ml) and the reaction mixture was stirred at 50° C. overnight. The reaction mixture was concentrated to half its volume and aqueous saturated NaHCO3 was added. The H2O layer was extracted with CH2Cl2 (2×) and the combined organic layer was washed with brine, dried (Na2SO4) and concentrated. Purification by column chromatography (silica, heptane/EtOAc, 2:3->1:2) yielded 4 (47.45 g, 78%). The reaction mixture was concentrated to half its volume and aqueous saturated NaHCO3 was added The H2O layer was extracted with CH2Cl2 (2×) the combined organic layer was washed with brine dried (Na2SO4) concentrated Purification by column chromatography (silica, heptane/EtOAc, 2:3->1:2)

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of DMSO (21.24 ml, 299 mmol) in CH2Cl2 (600 ml) was dropwise added to a solution of oxalyl chloride (15.0 ml, 171 mmol) in CH2Cl2 (300 ml) in 30 min while maintaining the internal temperature below −65° C. A solution of 3 (46.7 g, 142 mmol) in CH2Cl2 (300 ml) was added dropwise in 15 min. while maintaining the temperature below −65° C. The reaction mixture was stirred an additional 45 minutes at −78° C., after which Et3N (99.0 ml, 712 mmol) was added. After the reaction mixture was stirred at −78° C. for 45 min, the reaction mixture was allowed to warm to room temperature and stirring was continued for an additional hour. The reaction mixture was washed with H2O and brine, dried (Na2SO4) and concentrated. The residue was dissolved in Et2O, filtered and the filtrate was concentrated and crystallized (Et2O/heptane) to result in 4 (30.9 g, 67%). The mother liquor was concentrated and crystallized (Et2O/heptane) and gave extra 4 (2.27 g, 5%). while maintaining the internal temperature below −65° C while maintaining the temperature below −65° C After the reaction mixture was stirred at −78° C. for 45 min to warm to room temperature stirring was continued for an additional hour The reaction mixture was washed with H2O and brine dried (Na2SO4) concentrated The residue was dissolved in Et2O filtered the filtrate was concentrated crystallized (Et2O/heptane)

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

Procedure: A solution of 4-(2-piperidinyl)butanoic acid hydrochloride (5.95 g, 34.8 mmol) in Methanol (104 ml) is cooled to 0° C. At this temperature thionylchloride (7.54 ml, 104.3 mmol) is added slowly. The reaction mixture is heated to reflux for 12 h. The solvent is evaporated in vacuum. The residue is suspended in Ethylacetate and is heated to reflux. The suspension is filtered while it is still hot. In the filtrate a white solid dropped out, which was filtered out and dried in vacuum to give Methyl 4-(piperidin-2-yl)butanoate hydrochloride (2) (3.49 g, 45%) The reaction mixture is heated to reflux for 12 h The solvent is evaporated in vacuum is heated to reflux The suspension is filtered while it In the filtrate a white solid dropped out which was filtered out dried in vacuum