1-(2,6-Difluorophenyl)ethan-1-amine

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

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

Procedure: IPEA (1 mL.), EDC (257 mg) and HOBT (181 mg) were added to a solution of 5-chloro-2-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene)valeric acid trifluoroacetate (200 mg) and 1-(2,6-difluorophenyl)ethylamine (purity: 50 wt %, 210 mg) in DMF (5 mL), and the reaction solution was stirred at room temperature for 1 hour. Water and ethyl acetate were added to the reaction solution and the organic layer was partitioned. The resulting organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (Carrier: Chromatorex™ NH, elution solvent: heptane-ethyl acetate system->ethyl acetate-methanol system) to obtain 5-chloro-2-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene)valeric acid (1-(2,6-difluorophenyl)ethyl)amide. Sodium hydride (containing mineral oil at 40%, 30 mg) was added to a solution of the resulting 5-chloro-2-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene)valeric acid (1-(2,6-difluorophenyl)ethyl)amide in DMF (5 mL), and the reaction solution was stirred at room temperature for 5 minutes. Water and ethyl acetate were added to the reaction solution and the organic layer was partitioned. The resulting organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (Carrier: Chromatorex™ NH, elution solvent: heptane-ethyl acetate system->ethyl acetate-methanol system) to obtain 105 mg of the title compound as a racemate. The compound (15 mg) was fractionated using CHIRALPAK™ AD-H manufactured by Daicel Chemical Industries, Ltd. (2 cm×25 cm: mobile phase: hexane:ethanol=1:1) to obtain the title optically active substance with a retention time of 29 minutes (6.9 mg; >99% ee) and the title optically active substance with a retention time of 34 minutes (6.2 mg; >93% ee). The physical properties of the compounds are as follows. the organic layer was partitioned The resulting organic layer was dried over anhydrous magnesium sulfate the solvent was evaporated under reduced pressure The residue was purified by silica gel column chromatography (Carrier: Chromatorex™ NH, elution solvent: heptane-ethyl acetate system->ethyl acetate-methanol system)

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

Procedure: Triethylamine (2.37 mL) and hydroxylamine hydrochloride (634 mg) were added to a solution of 2,6-difluoroacetophenone (890 mg) in ethanol (30 mL), and the reaction solution was heated to reflux for 4 hours. The reaction solution was returned to room temperature, and the solvent was evaporated under reduced pressure. Zinc (1.86 g) was added to a solution of the resulting residue in trifluoroacetic acid (10 mL), and the reaction solution was stirred at room temperature overnight. The reaction solution was filtered on a celite, made basic with a 5 N aqueous solution of sodium hydroxide, and then extracted with chloroform. The resulting organic layer was dried over magnesium sulfate, and the solvent was evaporated under reduced pressure to obtain 210 mg of a crude purified product containing the title compound (purity: 50 wt %). The physical properties of the compound are as follows. the reaction solution was heated to reflux for 4 hours was returned to room temperature the solvent was evaporated under reduced pressure Zinc (1.86 g) was added to a solution of the resulting residue in trifluoroacetic acid (10 mL) The reaction solution was filtered on a celite extracted with chloroform The resulting organic layer was dried over magnesium sulfate the solvent was evaporated under reduced pressure to obtain 210 mg of a crude purified product containing the title compound (purity: 50 wt %)

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

Procedure: IPEA (1 mL), EDC (257 mg) and HOBT (181 mg) were added to a solution of 5-chloro-2-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene)valeric acid trifluoroacetate (200 mg) and 1-(2,6-difluorophenyl)ethylamine (purity: 50 wt %, 210 mg) in DMF (5 mL), and the reaction solution was stirred at room temperature for 1 hour. Water and ethyl acetate were added to the reaction solution and the organic layer was partitioned. The resulting organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (Carrier: Chromatorex™ NH, elution solvent:heptane-ethyl acetate system→ethyl acetate-methanol system) to obtain 5-chloro-2-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene)valeric acid (1-(2,6-difluorophenyl)ethyl)amide. Sodium hydride (containing mineral oil at 40%, 30 mg) was added to a solution of the resulting 5-chloro-2-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene)valeric acid (1-(2,6-difluorophenyl)ethyl)amide in DMF (5 mL), and the reaction solution was stirred at room temperature for 5 minutes. Water and ethyl acetate were added to the reaction solution and the organic layer was partitioned. The resulting organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (Carrier: Chromatorex™ NH, elution solvent:heptane-ethyl acetate system→ethyl acetate-methanol system) to obtain 105 mg of the title-compound as a racemate. The compound (15 mg) was fractionated using CHIRALPAK™ AD-H manufactured by Daicel Chemical Industries, Ltd. (2 cm×25 cm: mobile phase: hexane:ethanol=1:1) to obtain the title optically active substance with a retention time of 29 minutes (6.9 mg; >99% ee) and the title optically active substance with a retention time of 34 minutes (6.2 mg; >93% ee). The physical properties of the compounds are as follows. the organic layer was partitioned The resulting organic layer was dried over anhydrous magnesium sulfate the solvent was evaporated under reduced pressure The residue was purified by silica gel column chromatography (Carrier: Chromatorex™ NH, elution solvent:heptane-ethyl acetate system→ethyl acetate-methanol system)

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

Procedure: Triethylamine (2.37 mL) and hydroxylamine hydrochloride (634 mg) were added to a solution of 2,6-difluoroacetophenone (890 mg) in ethanol (30 mL), and the reaction solution was heated to reflux for 4 hours. The reaction solution was returned to room temperature, and the solvent was evaporated under reduced pressure. Zinc (1.86 g) was added to a solution of the resulting residue in trifluoroacetic acid (10 mL), and the reaction solution was stirred at room temperature overnight. The reaction solution was filtered on a celite, made basic with a 5 N aqueous solution of sodium hydroxide, and then extracted with chloroform. The resulting organic layer was dried over magnesium sulfate, and the solvent was evaporated under reduced pressure to obtain 210 mg of a crude purified product containing the title compound (purity: 50 wt %). The physical properties of the compound are as follows. the reaction solution was heated to reflux for 4 hours was returned to room temperature the solvent was evaporated under reduced pressure Zinc (1.86 g) was added to a solution of the resulting residue in trifluoroacetic acid (10 mL) The reaction solution was filtered on a celite extracted with chloroform The resulting organic layer was dried over magnesium sulfate the solvent was evaporated under reduced pressure to obtain 210 mg of a crude purified product containing the title compound (purity: 50 wt %)

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

Procedure: IPEA (1 mL.), EDC (257 mg) and HOBT (181 mg) were added to a solution of 5-chloro-2-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene)valeric acid trifluoroacetate (200 mg) and 1-(2,6-difluorophenyl)ethylamine (purity: 50 wt %, 210 mg) in DMF (5 mL), and the reaction solution was stirred at room temperature for 1 hour. Water and ethyl acetate were added to the reaction solution and the organic layer was partitioned. The resulting organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (Carrier: Chromatorex™ NH, elution solvent: heptane-ethyl acetate system->ethyl acetate-methanol system) to obtain 5-chloro-2-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene)valeric acid (1-(2,6-difluorophenyl)ethyl)amide. Sodium hydride (containing mineral oil at 40%, 30 mg) was added to a solution of the resulting 5-chloro-2-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene)valeric acid (1-(2,6-difluorophenyl)ethyl)amide in DMF (5 mL), and the reaction solution was stirred at room temperature for 5 minutes. Water and ethyl acetate were added to the reaction solution and the organic layer was partitioned. The resulting organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (Carrier: Chromatorex™ NH, elution solvent: heptane-ethyl acetate system->ethyl acetate-methanol system) to obtain 105 mg of the title compound as a racemate. The compound (15 mg) was fractionated using CHIRALPAK™ AD-H manufactured by Daicel Chemical Industries, Ltd. (2 cm×25 cm: mobile phase: hexane:ethanol=1:1) to obtain the title optically active substance with a retention time of 29 minutes (6.9 mg; >99% ee) and the title optically active substance with a retention time of 34 minutes (6.2 mg; >93% ee). The physical properties of the compounds are as follows. the organic layer was partitioned The resulting organic layer was dried over anhydrous magnesium sulfate the solvent was evaporated under reduced pressure The residue was purified by silica gel column chromatography (Carrier: Chromatorex™ NH, elution solvent: heptane-ethyl acetate system->ethyl acetate-methanol system)

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

Procedure: Triethylamine (2.37 mL) and hydroxylamine hydrochloride (634 mg) were added to a solution of 2,6-difluoroacetophenone (890 mg) in ethanol (30 mL), and the reaction solution was heated to reflux for 4 hours. The reaction solution was returned to room temperature, and the solvent was evaporated under reduced pressure. Zinc (1.86 g) was added to a solution of the resulting residue in trifluoroacetic acid (10 mL), and the reaction solution was stirred at room temperature overnight. The reaction solution was filtered on a celite, made basic with a 5 N aqueous solution of sodium hydroxide, and then extracted with chloroform. The resulting organic layer was dried over magnesium sulfate, and the solvent was evaporated under reduced pressure to obtain 210 mg of a crude purified product containing the title compound (purity: 50 wt %). The physical properties of the compound are as follows. the reaction solution was heated to reflux for 4 hours was returned to room temperature the solvent was evaporated under reduced pressure Zinc (1.86 g) was added to a solution of the resulting residue in trifluoroacetic acid (10 mL) The reaction solution was filtered on a celite extracted with chloroform The resulting organic layer was dried over magnesium sulfate the solvent was evaporated under reduced pressure to obtain 210 mg of a crude purified product containing the title compound (purity: 50 wt %)