tert-butyl 2-methylpiperidine-1-carboxylate

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

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

Procedure: N-(3-Dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (0.46 g, 2.42 mmol) and 1-hydroxy-benzotriazole monohydrate(0.37 g, 2.41 mmol) were added to a solution of 2-methylpiperidine-1,4-dicarboxylic acid-1-tert-butylester (0.59 g, 2.42 mmol) in N,N-dimethylformamide (8 mL). After 30 min at 20° C. a solution of (2R)-2-amino-N-methyl-N-[(1R)-1-(3-methyl-1,2,4-oxadiazol-5-yl)-2-(2-naphthyl)ethyl]-3-(2-naphthyl)propionamide (as a trifluoroacetate) (1.0 g, 1.73 mmol) and diisopropylethylamine (0.22 g, 1.73 mmol) in N,N-dimethylformamide (4 mL) was added. After 18 h at 20° C. the reaction mixture was poured on water (100 mL) and extracted several times with ethyl acetate (total 60 mL). The collected organic phases were washed with aqueous citric acid (10%, 20 mL), a saturated solution of sodium hydrogen carbonate (20 mL) and water (3×20 mL). After drying (magnesium sulfate) the solution was concentrated in vacuo to give 1.25 g of crude 4-(1-{methyl-[1-(3-methyl-1,2,4-oxadiazol-5-yl)-2-(2-naphthyl)ethyl]carbamoyl}-2-(2-naphthyl)ethyl)-carbamoyl)-2-methylpiperidine-1-carboxylic acid tert-butyl ester that was used for the next step without further purification. After 18 h at 20° C. the reaction mixture was poured on water (100 mL) extracted several times with ethyl acetate (total 60 mL) The collected organic phases were washed with aqueous citric acid (10%, 20 mL) After drying (magnesium sulfate) the solution was concentrated in vacuo

Conditions: temp:-20.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of N-Boc-2-Methyl-Piperidine (9.4 g, 46.9 mmol) in 94 mL of ether was cooled to −60° C. and treated with TMEDA (7.1 mL, 46.9 mmol) followed by sec-BuLi (49.2 mL, 51.66 mmol) dropwise. The mixture was slowly warmed to −20° C. and stirred for 30 min and then cooled to −78° C. The mixture was treated with a solution of DMF (5.5 mL, 70.44 mmol) in 16 mL of ether via syringe, stirred for 10 min, and then quenched with 75 mL saturated ammonium chloride solution. The mixture was warmed to room temperature, and the organic layer was separated. The aqueous layer was extracted with ether, and the combined extracts were dried over K2CO3. The organic layer was concentrated to give a crude product as an oil which was chromatographed on silica with hexanes:EtOAc (4:1) to afford 6.5 g (66%) of the trans isomer and 2.1 g (21%) of the cis isomer. Both products were homogeneous by TLC analysis, with the cis isomer positiioned just above the trans isomer. 1H NMR (250 MHz) δ9.28-9.26 (d, 1 H), 4.25 (br. d, 1 H), 3.64-3.57 (m, 1H), 1.74-1.46 (m, 15 H), 1.09-1.04 (d, 3 H); 13C NMR (62.7 MHz) 196.3 (s), 155.1 (s), 77.4 (s), 59.2 (s), 47.3 (s), 29.3 (s), 28.2 (s), 25.4 (s), 16.3 (s) ppm. cooled to −78° C stirred for 10 min quenched with 75 mL saturated ammonium chloride solution The mixture was warmed to room temperature the organic layer was separated The aqueous layer was extracted with ether the combined extracts were dried over K2CO3 The organic layer was concentrated

Conditions: temp:-20.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of N-Boc-2-Methyl-Piperidine (9.4 g, 46.9 mmol) in 94 mL of ether was cooled to −60° C. and treated with TMEDA (7.1 mL, 46.9 mmol) followed by sec-BuLi (49.2 mL, 51.66 mmol) dropwise. The mixture was slowly warmed to −20° C. and stirred for 30 min and then cooled to −78° C. The mixture was treated with a solution of DMF (5.5 mL, 70.44 mmol) in 16 mL of ether via syringe, stirred for 10 min, and then quenched with 75 mL saturated ammonium chloride solution. The mixture was warmed to room temperature, and the organic layer was separated. The aqueous layer was extracted with ether, and the combined extracts were dried over K2CO3. The organic layer was concentrated to give a crude product as an oil which was chromatographed on silica with hexanes:EtOAc (4:1) to afford 6.5 g (66%) of the trans isomer and 2.1 g (21%) of the cis isomer. Both products were homogeneous by TLC analysis, with the cis isomer positiioned just above the trans isomer. 1H NMR (250 MHz) δ9.28-9.26 (d, 1 H), 4.25 (br. d, 1 H), 3.64-3.57 (m, 1H), 1.74-1.46 (m, 15 H), 1.09-1.04 (d, 3 H); 13C NMR (62.7 MHz) 196.3 (s), 155.1 (s), 77.4 (s), 59.2 (s), 47.3 (s), 29.3 (s), 28.2 (s), 25.4 (s), 16.3 (s) ppm. cooled to −78° C stirred for 10 min quenched with 75 mL saturated ammonium chloride solution The mixture was warmed to room temperature the organic layer was separated The aqueous layer was extracted with ether the combined extracts were dried over K2CO3 The organic layer was concentrated

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

Procedure: A solution of N-Boc-Piperidine (15.0 g, 80.95 mmol) in ether (160 mL) was cooled to −78° C. and treated with TMEDA (15.9 mL, 105.2 mmol) followed by sec-BuLi (85 mL, 105.2 mmol) dropwise. The mixture was stirred for 3 h at −78° C. and then treated with a solution of dimethyl sulfate (15.3 mL, 161.9 mmol) in 65 mL of ether. The mixture was warmed to room temperature and then was diluted with water and extracted with ether. The combined extracts were dried over K2CO3 and then concentrated to give a crude product as a colorless oil. The product was purified by column chromatography on silca gel with 5% EtOAc/hexane to afford 16.0 g (81%) of product as a clear oil which was homogeneous by TLC analysis. 1H NMR (300 MHz) 67 4.33 (m, 1 H), 3.92-3.81 (pair of br. d, 1 H), 2.81-2.72 (dt, 1H), 1.60-1.36 (m, 15 H), 1.09-1.07 (d, 3 H); 13C NMR (75 MHz) 154.9 (s), 78.6 (s), 45.9 (s), 38.6 (s), 29.9 (s), 28.4 (s), 25.6 (s), 18.6 (s), 15.6 (s), ppm. The mixture was warmed to room temperature extracted with ether The combined extracts were dried over K2CO3 concentrated to give a crude product as a colorless oil The product was purified by column chromatography on silca gel with 5% EtOAc/hexane

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

Procedure: N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.46 g, 2.42 mmol) and 1-hydroxy-benzotriazole monohydrate(0.37 g, 2.41 mmol) were added to a solution of 2-methylpiperidine-1,4-dicarboxylic acid-1-tert-butylester (0.59 g, 2.42 mmol) in N,N-dimethylformamide (8 mL). After 30 min at 20° C. a solution of (2R)-2-amino-N-methyl-N-[(1R)-1-(3-methyl-1,2,4-oxadiazol-5-yl)-2-(2-naphthyl)ethyl]-3-(2-naphthyl)propionamide (as a trifluoroacetate) (1.0 g, 1.73 mmol) and diisopropylethylamine (0.22 g, 1.73 mmol) in N,N-dimethylformamide (4 mL) was added. After 18 h at 20° C. the reaction mixture was poured on water (100 mL) and extracted several times with ethyl acetate (total 60 mL). The collected organic phases were washed with aqueous citric acid (10%, 20 mL), a saturated solution of sodium hydrogen carbonate (20 mL) and water (3×20 mL). After drying (magnesium sulfate) the solution was concentrated in vacuo to give 1.25g of crude 4-(1-{methyl-[1-(3-methyl-1,2,4-oxadiazol-5-yl)-2-(2-naphthyl)ethyl]carbamoyl}2-(2-naphthyl)ethyl)-carbamoyl)-2-methylpiperidine-1-carboxylic acid tert-butyl ester that was used for the next step without further purification. After 18 h at 20° C. the reaction mixture was poured on water (100 mL) extracted several times with ethyl acetate (total 60 mL) The collected organic phases were washed with aqueous citric acid (10%, 20 mL) After drying (magnesium sulfate) the solution was concentrated in vacuo

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

Procedure: N-(3-Dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (0.46 g, 2.42 mmol) and 1-hydroxy-benzotriazole monohydrate(0.37 g, 2.41 mmol) were added to a solution of 2-methylpiperidine-1,4-dicarboxylic acid-1-tert-butylester (0.59 g, 2.42 mmol) in N,N-dimethylformamide (8 mL). After 30 min at 20° C. a solution of (2R)-2-amino-N-methyl-N-[(1R)-1-(3-methyl-1,2,4-oxadiazol-5-yl)-2-(2-naphthyl)ethyl]-3-(2-naphthyl)propionamide (as a trifluoroacetate) (1.0 g, 1.73 mmol) and diisopropylethylamine (0.22 g, 1.73 mmol) in N,N-dimethylformamide (4 mL) was added. After 18 h at 20° C. the reaction mixture was poured on water (100 mL) and extracted several times with ethyl acetate (total 60 mL). The collected organic phases were washed with aqueous citric acid (10%, 20 mL), a saturated solution of sodium hydrogen carbonate (20 mL) and water (3×20 mL). After drying (magnesium sulfate) the solution was concentrated in vacuo to give 1.25 g of crude 4-(1-{methyl-[1-(3-methyl-1,2,4-oxadiazol-5-yl)-2-(2-naphthyl)ethyl]carbamoyl}-2-(2-naphthyl)ethyl)-carbamoyl)-2-methylpiperidine-1-carboxylic acid tert-butyl ester that was used for the next step without further purification. After 18 h at 20° C. the reaction mixture was poured on water (100 mL) extracted several times with ethyl acetate (total 60 mL) The collected organic phases were washed with aqueous citric acid (10%, 20 mL) After drying (magnesium sulfate) the solution was concentrated in vacuo

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:-20.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of N-Boc-2-Methyl-Piperidine (9.4 g, 46.9 mmol) in 94 mL of ether was cooled to −60° C. and treated with TMEDA (7.1 mL, 46.9 mmol) followed by sec-BuLi (49.2 mL, 51.66 mmol) dropwise. The mixture was slowly warmed to −20° C. and stirred for 30 min and then cooled to −78° C. The mixture was treated with a solution of DMF (5.5 mL, 70.44 mmol) in 16 mL of ether via syringe, stirred for 10 min, and then quenched with 75 mL saturated ammonium chloride solution. The mixture was warmed to room temperature, and the organic layer was separated. The aqueous layer was extracted with ether, and the combined extracts were dried over K2CO3. The organic layer was concentrated to give a crude product as an oil which was chromatographed on silica with hexanes:EtOAc (4:1) to afford 6.5 g (66%) of the trans isomer and 2.1 g (21%) of the cis isomer. Both products were homogeneous by TLC analysis, with the cis isomer positiioned just above the trans isomer. 1H NMR (250 MHz) δ 9.28-9.26 (d, 1H), 4.25 (br. d, 1H), 3.64-3.57 (m, 1H), 1.74-1.46 (m, 15H), 1.09-1.04 (d, 3H); 13C NMR (62.7 MHz) 196.3 (s), 155.1 (s), 77.4 (s), 59.2 (s), 47.3 (s), 29.3 (s), 28.2 (s), 25.4 (s), 16.3 (s) ppm. cooled to −78° C stirred for 10 min quenched with 75 mL saturated ammonium chloride solution The mixture was warmed to room temperature the organic layer was separated The aqueous layer was extracted with ether the combined extracts were dried over K2CO3 The organic layer was concentrated

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

Procedure: A solution of N-Boc-Piperidine (15.0 g, 80.95 mmol) in ether (160 mL) was cooled to −78° C. and treated with TMEDA (15.9 mL, 105.2 mmol) followed by sec-BuLi (85 mL, 105.2 mmol) dropwise. The mixture was stirred for 3 h at −78° C. and then treated with a solution of dimethyl sulfate (15.3 mL, 161.9 mmol) in 65 mL of ether. The mixture was warmed to room temperature and then was diluted with water and extracted with ether. The combined extracts were dried over K2CO3 and then concentrated to give a crude product as a colorless oil. The product was purified by column chromatography on silca gel with 5% EtOAc/hexane to afford 16.0 g (81%) of product as a clear oil which was homogeneous by TLC analysis. 1H NMR (300 MHz) δ 4.33 (m, 1H), 3.92-3.81 (pair of br. d, 1H), 2.81-2.72 (dt, 1H), 1.60-1.36 (m, 15H), 1.09-1.07 (d, 3H); 13C NMR (75 MHz) 154.9 (s), 78.6 (s), 45.9 (s), 38.6 (s), 29.9 (s), 28.4 (s), 25.6 (s), 18.6 (s), 15.6 (s) ppm. The mixture was warmed to room temperature extracted with ether The combined extracts were dried over K2CO3 concentrated to give a crude product as a colorless oil The product was purified by column chromatography on silca gel with 5% EtOAc/hexane

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

Procedure: N-(3-Dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (0.46 g, 2.42 mmol) and 1-hydroxy-benzotriazole monohydrate(0.37 g, 2.41 mmol) were added to a solution of 2-methylpiperidine-1,4-dicarboxylic acid-1-tert-butylester (0.59 g, 2.42 mmol) in N,N-dimethylformamide (8 mL). After 30 min at 20° C. a solution of (2R)-2-amino-N-methyl-N-[(1R)-1-(3-methyl-1,2,4-oxadiazol-5-yl)-2-(2-naphthyl)ethyl]-3-(2-naphthyl)propionamide (as a trifluoroacetate) (1.0 g, 1.73 mmol) and diisopropylethylamine (0.22 g, 1.73 mmol) in N,N-dimethylformamide (4 mL) was added. After 18h at 20° C. the reaction mixture was poured on water (100 mL) and extracted several times with ethyl acetate (total 60 mL). The collected organic phases were washed with aqueous citric acid (10%, 20 mL), a saturated solution of sodium hydrogen carbonate (20 mL) and water (3×20 mL). After drying (magnesium sulfate) the solution was concentrated in vacuo to give 1.25g of crude 4-(1-{methyl-[1-(3-methyl-1,2,4-oxadiazol-5-yl)-2-(2-naphthyl)ethyl]carbamoyl}-2-(2-naphthyl)ethyl)-carbamoyl)-2-methylpiperidine-1-carboxylic acid tert-butyl ester that was used for the next step without further purification. extracted several times with ethyl acetate (total 60 mL) The collected organic phases were washed with aqueous citric acid (10%, 20 mL) After drying (magnesium sulfate) the solution was concentrated in vacuo