2-(2-甲氧基苯基)乙酰胺

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: 2-Methoxyphenyl acetamide (13.0 g, 78.6 mmol) was dissolved in methylene chloride (10.0 mL). Subsequently, 1.0M boron tribromide in methylene chloride solution (157 mL, 157 mmol) was slowly added dropwise under ice-cooling, and the mixture was stirred for one hour at room temperature. Subsequently, water was slowly added thereto under ice-cooling, and the mixture was stirred for 30 minutes. The mixture was extracted with chloroform, followed by washing the organic layer with brine, drying over anhydrous sodium sulfate. The reaction mixture was subjected to concentration under reduced pressure and purification by column chromatography (n-hexane/ethyl acetate=20/1), whereby a white solid was obtained (1.8 g, 11.9 mmol, 15%). cooling under ice-cooling the mixture was stirred for 30 minutes The mixture was extracted with chloroform by washing the organic layer with brine drying over anhydrous sodium sulfate The reaction mixture was subjected to concentration under reduced pressure and purification by column chromatography (n-hexane/ethyl acetate=20/1), whereby a white solid was obtained (1.8 g, 11.9 mmol, 15%)

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: 2-Methoxyphenylacetic acid (10.0 g, 60.1 mmol) was dissolved in acetonitrile (15 mL). Subsequently, pyridine (2.84 g, 36.1 mmol) and di-tert-butyl dicarbonate [Boc2O (19.6 g, 90.2 mmol)] were added thereto. The mixture was stirred for 10 minutes at room temperature, and then ammonium hydrogencarbonate (7.1 g, 90.2 mmol) were added. After completion of reaction, the reaction mixture was concentrated under reduced pressure. Thereafter, the resultant concentrate was added to water, and the resultant mixture was extracted with chloroform, followed by washing sequentially with 1M hydrochloric acid and brine. The resultant mixture was subjected to drying over magnesium sulfate and concentration under reduced pressure. The resultant concentrate was used in Production Example 18 without purification. After completion of reaction the reaction mixture was concentrated under reduced pressure Thereafter, the resultant concentrate was added to water the resultant mixture was extracted with chloroform by washing sequentially with 1M hydrochloric acid and brine to drying over magnesium sulfate and concentration under reduced pressure The resultant concentrate was used in Production Example 18 without purification

反应条件: temp:25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A suspension of (2-methoxyphenyl)acetamide (0.9 g) in dry dichloromethane (3 cc) is treated with triethyloxonium tetrafluoborate (1.14 g) and the solution obtained is stirred for 20 hours at 25° C. After cooling to 0° C., a solution of 7,7-bis-(3-fluorophenyl)-4-perhydroisoindolone hydrochloride (1.5 g) and triethylamine (1.4 cc) in dichloromethane (9 cc) is added to the reaction mixture. The reaction mixture is stirred for 30 minutes at 25° C., then refluxed for 5 hours and finally stirred for a further 16 hours at 25° C. Saturated potassium carbonate solution (50 cc) is added, the mixture is stirred and filtered and the organic phase is washed with water (2×50 cc). After drying over magnesium sulphate and filtering and concentrating the filtrate to dryness under reduced pressure (2.7 kPa), the residue is chromatographed on an alumina column (diameter 2.6 cm, height 24 cm), eluting under a nitrogen pressure of 0.5 bar with a mixture of 1,2-dichloroethane and methanol (95/5 by volume) and collecting 15 cc fractions. Fractions 7 to 25 are combined and concentrated to dryness under reduced pressure (2.7 kPa) to give (3aRS,7aRS)-7,7-bis-(3-fluorophenyl)-2-[1-imino-2-(2-methoxyphenyl)ethyl]-4-perhydroisoindolone (0.54 g) in the form of a pale yellow meringue. the solution obtained After cooling to 0° C. The reaction mixture is stirred for 30 minutes at 25° C. refluxed for 5 hours finally stirred for a further 16 hours at 25° C the mixture is stirred filtered the organic phase is washed with water (2×50 cc) After drying over magnesium sulphate filtering concentrating the filtrate to dryness under reduced pressure (2.7 kPa) the residue is chromatographed on an alumina column (diameter 2.6 cm, height 24 cm) eluting under a nitrogen pressure of 0.5 bar with a mixture of 1,2-dichloroethane and methanol (95/5 by volume) collecting 15 cc fractions concentrated to dryness under reduced pressure (2.7 kPa)

反应条件: temp:25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A suspension of (2-methoxyphenyl)acetamide (0.9 g) in dry dichloromethane (3 cc) is treated with triethyloxonium tetrafluoborate (1.14 g) and the solution obtained is stirred for 20 hours at 25° C. After cooling to 0° C., a solution of 7,7-bis-(3-fluorophenyl)-4-perhydroisoindolone hydrochloride (1.5 g) and triethylamine (1.4 cc) in dichloromethane (9 cc) is added to the reaction mixture. The reaction mixture is stirred for 30 minutes at 25° C., then refluxed for 5 hours and finally stirred for a further 16 hours at 25° C. Saturated potassium carbonate solution (50 cc) is added, the mixture is stirred and filtered and the organic phase is washed with water (2×50 cc). After drying over magnesium sulphate and filtering and concentrating the filtrate to dryness under reduced pressure (2.7 kPa), the residue is chromatographed on an alumina column (diameter 2.6 cm, height 24 cm), eluting under a nitrogen pressure of 0.5 bar with a mixture of 1,2-dichloroethane and methanol (95/5 by volume) and collecting 15 cc fractions. Fractions 7 to 25 are combined and concentrated to dryness under reduced pressure (2.7 kPa) to give (3aRS,7aRS)-7,7-bis-(3-fluorophenyl)-2-[1-imino-2-(2-methoxyphenyl)ethyl]-4-perhydroisoindolone (0.54 g) in the form of a pale yellow meringue. the solution obtained After cooling to 0° C. The reaction mixture is stirred for 30 minutes at 25° C. refluxed for 5 hours finally stirred for a further 16 hours at 25° C the mixture is stirred filtered the organic phase is washed with water (2×50 cc) After drying over magnesium sulphate filtering concentrating the filtrate to dryness under reduced pressure (2.7 kPa) the residue is chromatographed on an alumina column (diameter 2.6 cm, height 24 cm) eluting under a nitrogen pressure of 0.5 bar with a mixture of 1,2-dichloroethane and methanol (95/5 by volume) collecting 15 cc fractions concentrated to dryness under reduced pressure (2.7 kPa)

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: Triethyloxonium tetrafluoborate (8.4 g) is added to a stirred suspension of 2-(2-methoxyphenyl)acetamide (6.6 g) in anhydrous dichloromethane (20 cc). Stirring of the reaction mixture is continued for 20 hours at ambient temperature. The mixture is cooled to +5° C. and a solution of (3aR,7aR)-7,7-diphenyl-4-perhydroisoindolone hydrochloride (9.8 g) and triethylamine (10.4 cc) in dichloromethane (60 cc) is then added. After the temperature has returned to ambient temperature, the reaction mixture is refluxed for 4 hours. It is then treated, after the temperature has returned to ambient temperature, with a 10% aqueous potassium carbonate solution (40 cc); the organic phase is washed with distilled water (20 cc), dried over magnesium sulphate and concentrated to dryness under reduced pressure (2.7 kPa). The residue is crystallized from acetonitrile (20 cc); the crystals obtained are drained, washed with acetonitrile (5 cc) and with isopropyl ether (10 cc) and dried. The crystals are recrystallized from acetonitrile (45 cc); the crystals obtained are drained and dried. (3aR,7aR)-2-[1-imino-2-(2-methoxyphenyl)ethyl]-7,7-diphenyl-4-perhydroisoindolone (3.8 g) melting at 191° C. is obtained. [α]D20 =-255° (c=1, methanol). The mixture is cooled to +5° C. has returned to ambient temperature the reaction mixture is refluxed for 4 hours It is then treated the organic phase is washed with distilled water (20 cc) dried over magnesium sulphate concentrated to dryness under reduced pressure (2.7 kPa) The residue is crystallized from acetonitrile (20 cc) the crystals obtained washed with acetonitrile (5 cc) and with isopropyl ether (10 cc) dried The crystals are recrystallized from acetonitrile (45 cc) the crystals obtained dried

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: 2-Methoxyphenyl acetamide (13.0 g, 78.6 mmol) was dissolved in methylene chloride (10.0 mL). Subsequently, 1.0M boron tribromide in methylene chloride solution (157 mL, 157 mmol) was slowly added dropwise under ice-cooling, and the mixture was stirred for one hour at room temperature. Subsequently, water was slowly added thereto under ice-cooling, and the mixture was stirred for 30 minutes. The mixture was extracted with chloroform, followed by washing the organic layer with brine, drying over anhydrous sodium sulfate. The reaction mixture was subjected to concentration under reduced pressure and purification by column chromatography (n-hexane/ethyl acetate=20/1), whereby a white solid was obtained (1.8 g, 11.9 mmol, 15%). cooling under ice-cooling the mixture was stirred for 30 minutes The mixture was extracted with chloroform by washing the organic layer with brine drying over anhydrous sodium sulfate The reaction mixture was subjected to concentration under reduced pressure and purification by column chromatography (n-hexane/ethyl acetate=20/1), whereby a white solid was obtained (1.8 g, 11.9 mmol, 15%)

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: 2-Methoxyphenylacetic acid (10.0 g, 60.1 mmol) was dissolved in acetonitrile (15 mL). Subsequently, pyridine (2.84 g, 36.1 mmol) and di-tert-butyl dicarbonate [Boc2O (19.6 g, 90.2 mmol)] were added thereto. The mixture was stirred for 10 minutes at room temperature, and then ammonium hydrogencarbonate (7.1 g, 90.2 mmol) were added. After completion of reaction, the reaction mixture was concentrated under reduced pressure. Thereafter, the resultant concentrate was added to water, and the resultant mixture was extracted with chloroform, followed by washing sequentially with 1M hydrochloric acid and brine. The resultant mixture was subjected to drying over magnesium sulfate and concentration under reduced pressure. The resultant concentrate was used in Production Example 18 without purification. After completion of reaction the reaction mixture was concentrated under reduced pressure Thereafter, the resultant concentrate was added to water the resultant mixture was extracted with chloroform by washing sequentially with 1M hydrochloric acid and brine to drying over magnesium sulfate and concentration under reduced pressure The resultant concentrate was used in Production Example 18 without purification

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: 2-Methoxyphenyl acetamide (13.0 g, 78.6 mmol) was dissolved in methylene chloride (10.0 mL). Subsequently, 1.0M boron tribromide in methylene chloride solution (157 mL, 157 mmol) was slowly added dropwise under ice-cooling, and the mixture was stirred for one hour at room temperature. Subsequently, water was slowly added thereto under ice-cooling, and the mixture was stirred for 30 minutes. The mixture was extracted with chloroform, followed by washing the organic layer with brine, drying over anhydrous sodium sulfate. The reaction mixture was subjected to concentration under reduced pressure and purification by column chromatography (n-hexane/ethyl acetate=20/1), whereby a white solid was obtained (1.8 g, 11.9 mmol, 15%). cooling under ice-cooling the mixture was stirred for 30 minutes The mixture was extracted with chloroform by washing the organic layer with brine drying over anhydrous sodium sulfate The reaction mixture was subjected to concentration under reduced pressure and purification by column chromatography (n-hexane/ethyl acetate=20/1), whereby a white solid was obtained (1.8 g, 11.9 mmol, 15%)

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: 2-Methoxyphenyl acetamide (13.0 g, 78.6 mmol) was dissolved in methylene chloride (10.0 mL). Subsequently, 1.0M boron tribromide in methylene chloride solution (157 mL, 157 mmol) was slowly added dropwise under ice-cooling, and the mixture was stirred for one hour at room temperature. Subsequently, water was slowly added thereto under ice-cooling, and the mixture was stirred for 30 minutes. The mixture was extracted with chloroform, followed by washing the organic layer with brine, drying over anhydrous sodium sulfate. The reaction mixture was subjected to concentration under reduced pressure and purification by column chromatography (n-hexane/ethyl acetate=20/1), whereby a white solid was obtained (1.8 g, 11.9 mmol, 15%). cooling under ice-cooling the mixture was stirred for 30 minutes The mixture was extracted with chloroform by washing the organic layer with brine drying over anhydrous sodium sulfate The reaction mixture was subjected to concentration under reduced pressure and purification by column chromatography (n-hexane/ethyl acetate=20/1), whereby a white solid was obtained (1.8 g, 11.9 mmol, 15%)

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: 2-Methoxyphenylacetic acid (10.0 g, 60.1 mmol) was dissolved in acetonitrile (15 mL). Subsequently, pyridine (2.84 g, 36.1 mmol) and di-tert-butyl dicarbonate [Boc2O (19.6 g, 90.2 mmol)] were added thereto. The mixture was stirred for 10 minutes at room temperature, and then ammonium hydrogencarbonate (7.1 g, 90.2 mmol) were added. After completion of reaction, the reaction mixture was concentrated under reduced pressure. Thereafter, the resultant concentrate was added to water, and the resultant mixture was extracted with chloroform, followed by washing sequentially with 1M hydrochloric acid and brine. The resultant mixture was subjected to drying over magnesium sulfate and concentration under reduced pressure. The resultant concentrate was used in Production Example 18 without purification. After completion of reaction the reaction mixture was concentrated under reduced pressure Thereafter, the resultant concentrate was added to water the resultant mixture was extracted with chloroform by washing sequentially with 1M hydrochloric acid and brine to drying over magnesium sulfate and concentration under reduced pressure The resultant concentrate was used in Production Example 18 without purification

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: 2-Methoxyphenylacetic acid (10.0 g, 60.1 mmol) was dissolved in acetonitrile (15 mL). Subsequently, pyridine (2.84 g, 36.1 mmol) and di-tert-butyl dicarbonate [Boc2O (19.6 g, 90.2 mmol)] were added thereto. The mixture was stirred for 10 minutes at room temperature, and then ammonium hydrogencarbonate (7.1 g, 90.2 mmol) were added. After completion of reaction, the reaction mixture was concentrated under reduced pressure. Thereafter, the resultant concentrate was added to water, and the resultant mixture was extracted with chloroform, followed by washing sequentially with 1M hydrochloric acid and brine. The resultant mixture was subjected to drying over magnesium sulfate and concentration under reduced pressure. The resultant concentrate was used in Production Example 18 without purification. After completion of reaction the reaction mixture was concentrated under reduced pressure Thereafter, the resultant concentrate was added to water the resultant mixture was extracted with chloroform by washing sequentially with 1M hydrochloric acid and brine to drying over magnesium sulfate and concentration under reduced pressure The resultant concentrate was used in Production Example 18 without purification

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: 2-Methoxyphenylacetic acid (10.0 g, 60.1 mmol) was dissolved in acetonitrile (15 mL). Subsequently, pyridine (2.84 g, 36.1 mmol) and di-tert-butyl dicarbonate [Boc2O (19.6 g, 90.2 mmol)] were added thereto. The mixture was stirred for 10 minutes at room temperature, and then ammonium hydrogencarbonate (7.1 g, 90.2 mmol) were added. After completion of reaction, the reaction mixture was concentrated under reduced pressure. Thereafter, the resultant concentrate was added to water, and the resultant mixture was extracted with chloroform, followed by washing sequentially with 1M hydrochloric acid and brine. The resultant mixture was subjected to drying over magnesium sulfate and concentration under reduced pressure. The resultant concentrate was used in Production Example 18 without purification. After completion of reaction the reaction mixture was concentrated under reduced pressure Thereafter, the resultant concentrate was added to water the resultant mixture was extracted with chloroform by washing sequentially with 1M hydrochloric acid and brine to drying over magnesium sulfate and concentration under reduced pressure The resultant concentrate was used in Production Example 18 without purification