N-methoxy-N-methylcyclopentanecarboxamide

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

実験手順: Oxalyl chloride (7.5 ml, 85 mmol) was added dropwise to a stirred solution of cyclopentanecarboxylic acid (4.56 g, 40 mmol) and dimethylformamide (2 drops) in dichloromethane (20 ml) under nitrogen at room temperature. After 2 hours, the reaction mixture was evaporated under reduced pressure and the residual oxalyl chloride removed azeotropically using dichloromethane. The resulting oil was dissolved in dichloromethane (50 ml) and N,O-dimethylhydroxylamine (4.3 g, 44 mmol) added portionwise to the stirred solution. The resulting mixture was cooled using an ice bath, pyridine (7.1 ml, 88 mmol) added, the cooling bath removed and stirring continued for 18 hours. The reaction mixture was then diluted with dichloromethane (50 ml), washed with 5% aqueous citric acid solution (×2) and saturated brine, dried (Na2SO4) and evaporated under reduced pressure. The residue was purified by chromatography on silica gel, eluting with a solvent gradient of methanol:dichloromethane (0:100 to 2:98), to furnish the required amide as an oil. Rf 0.50 (SS 18). Found: C,59.28; H,9.74; N,8.81. C8H15NO2 ; 0.25 H2O requires C,59.41; H,9.66; N,8.66%. the reaction mixture was evaporated under reduced pressure the residual oxalyl chloride removed azeotropically using dichloromethane The resulting oil was dissolved in dichloromethane (50 ml) The resulting mixture was cooled the cooling bath removed continued for 18 hours The reaction mixture was then diluted with dichloromethane (50 ml) washed with 5% aqueous citric acid solution (×2) and saturated brine dried (Na2SO4) evaporated under reduced pressure The residue was purified by chromatography on silica gel eluting with a solvent gradient of methanol:dichloromethane (0:100 to 2:98)

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

実験手順: Oxalyl chloride (7.5 ml, 85 mmol) was added dropwise to a stirred solution of cyclopentanecarboxylic acid (4.56 g, 40 mmol) and dimethylformamide (2 drops) in dichloromethane (20 ml) under nitrogen at room temperature. After 2 hours, the reaction mixture was evaporated under reduced pressure and the residual oxalyl chloride removed azeotropically using dichloromethane. The resulting oil was dissolved in dichloromethane (50 ml) and N,O-dimethylhydroxylamine (4.3 g, 44 mmol) added portionwise to the stirred solution. The resulting mixture was cooled using an ice bath, pyridine (7.1 ml, 88 mmol) added, the cooling bath removed and stirring continued for 18 hours. The reaction mixture was then diluted with dichloromethane (50 ml), washed with 5% aqueous citric acid solution (×2) and saturated brine, dried (Na2SO4) and evaporated under reduced pressure. The residue was purified by chromatography on silica gel, eluting with a solvent gradient of methanol:dichloromethane (0:100 to 2:98), to furnish the required amide as an oil. Rf 0.50 (SS 18). Found: C,59.28; H,9.74; N,8.81. C8H15NO2 ; 0.25 H2O requires C,59.41; H,9.66; N,8.66%. the reaction mixture was evaporated under reduced pressure the residual oxalyl chloride removed azeotropically using dichloromethane The resulting oil was dissolved in dichloromethane (50 ml) The resulting mixture was cooled the cooling bath removed continued for 18 hours The reaction mixture was then diluted with dichloromethane (50 ml) washed with 5% aqueous citric acid solution (×2) and saturated brine dried (Na2SO4) evaporated under reduced pressure The residue was purified by chromatography on silica gel eluting with a solvent gradient of methanol:dichloromethane (0:100 to 2:98)

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

実験手順: Cyclopentane carbonyl chloride (65 g, 0.49 mol) was added dropwise into a mixture of Et3N (180 mL, 1.3 mol) and N,O-dimethyl hydroxylamine hydrochloride (50 g, 0.52 mol) in anhydrous CH2Cl2 at 0° C. After the addition, the reaction mixture was allowed to stir at ambient temperature overnight. To the reaction mixture was added about 100 g of crushed ice followed 100 g of water. The mixture was separated, and the aqueous layer was extracted with CH2Cl2 (100 mL×2). The combined organic layers were washed with 1 N HCl, water, brine and dried over Na2SO4. The solvent was removed under reduced pressure to afford 61 g of desired product as oil in 78.8% of yield. After the addition The mixture was separated the aqueous layer was extracted with CH2Cl2 (100 mL×2) The combined organic layers were washed with 1 N HCl, water, brine dried over Na2SO4 The solvent was removed under reduced pressure

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

実験手順: Cyclopentane carbonyl chloride (65 g, 0.49 mol) was added dropwise into a mixture of Et3N (180 mL, 1.3 mol) and N,O-dimethyl hydroxylamine hydrochloride (50 g, 0.52 mol) in anhydrous CH2Cl2 at 0° C. After the addition, the reaction mixture was allowed to stir at ambient temperature overnight. To the reaction mixture was added about 100 g of crushed ice followed 100 g of water. The mixture was separated, and the aqueous layer was extracted with CH2Cl2 (100 mL×2). The combined organic layers were washed with 1 N HCl, water, brine and dried over Na2SO4. The solvent was removed under reduced pressure to afford 61 g of desired product as oil in 78.8% of yield. After the addition The mixture was separated the aqueous layer was extracted with CH2Cl2 (100 mL×2) The combined organic layers were washed with 1 N HCl, water, brine dried over Na2SO4 The solvent was removed under reduced pressure

反応条件: temp:-10.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a stirred solution of phenyl-carbamic acid tert-butyl ester (1.2 g, 6.2 mmol) in Et2O (12 mL) under a nitrogen atmosphere was added dropwise a 1.7 M solution of t-BuLi in pentan (8.4 mL, 14.3 mmol) over a 10-min period at −20° C. The mixture was stirred at −10° C. for 2.5 h and then cyclopentanecarboxylic acid methoxy-methyl-amide (1.07 g, 6.8 mmol) was added over 5 min. The mixture was allowed to warm to room temperature and stirred for further 1 h before it was quenched with aqueous NH4Cl. The organic phase was isolated and the aqueous phase was extracted with CH2Cl2, and the combined organic phases were dried and concentrated in vacuo. The crude material was dissolved CH2Cl2 (18 mL) and TFA (6 mL) and stirred at room temperature for 2 h. The reaction mixture was evaporated in vacuo, and added aqueous NaHCO3 to pH 7 and extracted with CH2Cl2. The combined organic phases were dried and concentrated in vacuo to give 1.03 g (68%) of (2-amino-phenyl)-cyclopentyl-methanone as an oil. to warm to room temperature stirred for further 1 h before it was quenched with aqueous NH4Cl The organic phase was isolated the aqueous phase was extracted with CH2Cl2 the combined organic phases were dried concentrated in vacuo The crude material was dissolved CH2Cl2 (18 mL) and TFA (6 mL) stirred at room temperature for 2 h The reaction mixture was evaporated in vacuo added aqueous NaHCO3 to pH 7 extracted with CH2Cl2 The combined organic phases were dried concentrated in vacuo

反応条件: temp:-10.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a stirred solution of phenyl-carbamic acid tert-butyl ester (1.2 g, 6.2 mmol) in Et2O (12 mL) under a nitrogen atmosphere was added dropwise a 1.7 M solution of t-BuLi in pentan (8.4 mL, 14.3 mmol) over a 10-min period at −20° C. The mixture was stirred at −10° C. for 2.5 h and then cyclopentanecarboxylic acid methoxy-methyl-amide (1.07 g, 6.8 mmol) was added over 5 min. The mixture was allowed to warm to room temperature and stirred for further 1 h before it was quenched with aqueous NH4Cl. The organic phase was isolated and the aqueous phase was extracted with CH2Cl2, and the combined organic phases were dried and concentrated in vacuo. The crude material was dissolved CH2Cl2 (18 mL) and TFA (6 mL) and stirred at room temperature for 2 h. The reaction mixture was evaporated in vacuo, and added aqueous NaHCO3 to pH 7 and extracted with CH2Cl2. The combined organic phases were dried and concentrated in vacuo to give 1.03 g (68%) of (2-amino-phenyl)-cyclopentyl-methanone as an oil. to warm to room temperature stirred for further 1 h before it was quenched with aqueous NH4Cl The organic phase was isolated the aqueous phase was extracted with CH2Cl2 the combined organic phases were dried concentrated in vacuo The crude material was dissolved CH2Cl2 (18 mL) and TFA (6 mL) stirred at room temperature for 2 h The reaction mixture was evaporated in vacuo added aqueous NaHCO3 to pH 7 extracted with CH2Cl2 The combined organic phases were dried concentrated in vacuo

反応条件: temp:-10.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a stirred solution of phenyl-carbamic acid tert-butyl ester (1.2 g, 6.2 mmol) in Et2O (12 mL) under a nitrogen atmosphere was added dropwise a 1.7 M solution of t-BuLi in pentan (8.4 mL, 14.3 mmol) over a 10-min period at −20° C. The mixture was stirred at −10° C. for 2.5 h and then cyclopentanecarboxylic acid methoxy-methyl-amide (1.07 g, 6.8 mmol) was added over 5 min. The mixture was allowed to warm to room temperature and stirred for further 1 h before it was quenched with aqueous NH4Cl. The organic phase was isolated and the aqueous phase was extracted with CH2Cl2, and the combined organic phases were dried and concentrated in vacuo. The crude material was dissolved CH2Cl2 (18 mL) and TFA (6 mL) and stirred at room temperature for 2 h. The reaction mixture was evaporated in vacuo, and added aqueous NaHCO3 to pH 7 and extracted with CH2Cl2. The combined organic phases were dried and concentrated in vacuo to give 1.03 g (68%) of (2-amino-phenyl)-cyclopentyl-methanone as an oil. to warm to room temperature stirred for further 1 h before it was quenched with aqueous NH4Cl The organic phase was isolated the aqueous phase was extracted with CH2Cl2 the combined organic phases were dried concentrated in vacuo The crude material was dissolved CH2Cl2 (18 mL) and TFA (6 mL) stirred at room temperature for 2 h The reaction mixture was evaporated in vacuo added aqueous NaHCO3 to pH 7 extracted with CH2Cl2 The combined organic phases were dried concentrated in vacuo

反応条件: temp:-10.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a stirred solution of phenyl-carbamic acid tert-butyl ester (1.2 g, 6.2 mmol) in Et2O (12 mL) under a nitrogen atmosphere was added dropwise a 1.7 M solution of t-BuLi in pentan (8.4 mL, 14.3 mmol) over a 10-min period at −20° C. The mixture was stirred at −10° C. for 2.5 h and then cyclopentanecarboxylic acid methoxy-methyl-amide (1.07 g, 6.8 mmol) was added over 5 min. The mixture was allowed to warm to room temperature and stirred for further 1 h before it was quenched with aqueous NH4Cl. The organic phase was isolated and the aqueous phase was extracted with CH2Cl2, and the combined organic phases were dried and concentrated in vacuo. The crude material was dissolved CH2Cl2 (18 mL) and TFA (6 mL) and stirred at room temperature for 2 h. The reaction mixture was evaporated in vacuo, and added aqueous NaHCO3 to pH 7 and extracted with CH2Cl2. The combined organic phases were dried and concentrated in vacuo to give 1.03 g (68%) of (2-amino-phenyl)-cyclopentyl-methanone as an oil. to warm to room temperature stirred for further 1 h before it was quenched with aqueous NH4Cl The organic phase was isolated the aqueous phase was extracted with CH2Cl2 the combined organic phases were dried concentrated in vacuo The crude material was dissolved CH2Cl2 (18 mL) and TFA (6 mL) stirred at room temperature for 2 h The reaction mixture was evaporated in vacuo added aqueous NaHCO3 to pH 7 extracted with CH2Cl2 The combined organic phases were dried concentrated in vacuo

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

実験手順: This compound is synthesized according to the method described in 3.2. by reacting 2-bromo-5-methoxybenzoic acid pretreated with n-butyllithium with cyclopentyl-N-methoxy-N-methylcarboxamide. It is used in crude form in the following reaction. This compound is synthesized in the following reaction

反応条件: temp:-10.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a stirred solution of phenyl-carbamic acid tert-butyl ester (1.2 g, 6.2 mmol) in Et2O (12 mL) under a nitrogen atmosphere was added dropwise a 1.7 M solution of t-BuLi in pentan (8.4 mL, 14.3 mmol) over a 10-min period at −20° C. The mixture was stirred at −10° C. for 2.5 h and then cyclopentanecarboxylic acid methoxy-methyl-amide (1.07 g, 6.8 mmol) was added over 5 min. The mixture was allowed to warm to room temperature and stirred for further 1 h before it was quenched with aqueous NH4Cl. The organic phase was isolated and the aqueous phase was extracted with CH2Cl2, and the combined organic phases were dried and concentrated in vacuo. The crude material was dissolved CH2Cl2 (18 mL) and TFA (6 mL) and stirred at room temperature for 2 h. The reaction mixture was evaporated in vacuo, and added aqueous NaHCO3 to pH 7 and extracted with CH2Cl2. The combined organic phases were dried and concentrated in vacuo to give 1.03 g (68%) of (2-amino-phenyl)-cyclopentyl-methanone as an oil. to warm to room temperature stirred for further 1 h before it was quenched with aqueous NH4Cl The organic phase was isolated the aqueous phase was extracted with CH2Cl2 the combined organic phases were dried concentrated in vacuo The crude material was dissolved CH2Cl2 (18 mL) and TFA (6 mL) stirred at room temperature for 2 h The reaction mixture was evaporated in vacuo added aqueous NaHCO3 to pH 7 extracted with CH2Cl2 The combined organic phases were dried concentrated in vacuo

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

実験手順: This compound is synthesized according to the method described in 3.2. by reacting 2-bromo-5-methoxybenzoic acid pretreated with n-butyllithium with cyclopentyl-N-methoxy-N-methylcarboxamide. It is used in crude form in the following reaction. This compound is synthesized in the following reaction

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

実験手順: Cyclopentane carbonyl chloride (65 g, 0.49 mol) was added dropwise into a mixture of Et3N (180 mL, 1.3 mol) and N,O-dimethyl hydroxylamine hydrochloride (50 g, 0.52 mol) in anhydrous CH2Cl2 at 0° C. After the addition, the reaction mixture was allowed to stir at ambient temperature overnight. To the reaction mixture was added about 100 g of crushed ice followed 100 g of water. The mixture was separated, and the aqueous layer was extracted with CH2Cl2 (100 mL×2). The combined organic layers were washed with 1N HCl, water, brine and dried over Na2SO4. The solvent was removed under reduced pressure to afford 61 g of desired product as oil in 78.8% of yield. After the addition The mixture was separated the aqueous layer was extracted with CH2Cl2 (100 mL×2) The combined organic layers were washed with 1N HCl, water, brine dried over Na2SO4 The solvent was removed under reduced pressure