N-propylacetamide

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

Procedure: Acrylic acid (20 g) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (30 g) were dissolved in water (300 mL). Then aminohydroxybutyric acid (2.0 g) was added to the obtained solution and reacted at room temperature for 10 hours. After the completion of the reaction, water was distilled off and the residue was sufficiently washed with hexane (200 mL) in 3 portions. Next, this residue was dissolved in dimethyl-formamide (350 mL), in which N-hydroxysuccinimide (3 g) and N,N′-dicyclohexylcarbodiimide (3 g) had been dissolved, and reacted overnight. After the completion of the reaction, the solvent was distilled off. Ethyl acetate was added to the residue thus obtained and the precipitate thus formed was filtered off. The filtrate was recovered and a fraction containing the target product was taken up by silica gel column chromatography with the use of ethyl acetate as a mobile phase and alumina column chromatography. Next, a half of the solvent was distilled off with an evaporator and recrystallization was carried out by adding a hexane solvent at −20° C. to thereby give the target monomers (N-propylacetamide, N-propyl acrylamide) (yield: 68%). reacted at room temperature for 10 hours was distilled off the residue was sufficiently washed with hexane (200 mL) in 3 portions Next, this residue was dissolved in dimethyl-formamide (350 mL), in which N-hydroxysuccinimide (3 g) and N,N′-dicyclohexylcarbodiimide (3 g) had been dissolved reacted overnight After the completion of the reaction the solvent was distilled off Ethyl acetate was added to the residue thus obtained the precipitate thus formed was filtered off The filtrate was recovered a fraction containing the target product Next, a half of the solvent was distilled off with an evaporator and recrystallization by adding a hexane solvent at −20° C.

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Oxalyl chloride (0.7 mL, 8 mmol) was added to N-propyl-acetamide (1.11 mL, 10 mmol) and 2,6-lutidine (1.39 mL, 12 mmol) in 50 mL 1,2-dichloroethane at 0° C. The reaction mixture was stirred at 0° C. for 30 minutes. 2-({[(S)-Cyclopropyl-(3-fluoro-phenyl)-methyl]-carbamoyl}-methyl)-6-fluoro-benzoic acid was added and the reaction mixture was refluxed for 20 hours. The reaction mixture was poured into 35 mL 1N HCl (aq.) and 50 mL brine. The mixture was extracted with ethyl acetate (250 mL). The organic phase was washed with brine, dried over MgSO4 and concentrated in vacuo. The crude product was flash chromatographed on silica gel (gradient heptane-ethyl acetate) to give 344 mg of the title compound, yield 42%. LC-MS (m/z) 411.3 (MH+); tR=1.34. the reaction mixture was refluxed for 20 hours The mixture was extracted with ethyl acetate (250 mL) The organic phase was washed with brine dried over MgSO4 concentrated in vacuo chromatographed on silica gel (gradient heptane-ethyl acetate)

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Oxalyl chloride (0.7 mL, 8 mmol) was added to N-propyl-acetamide (1.11 mL, 10 mmol) and 2,6-lutidine (1.39 mL, 12 mmol) in 50 mL 1,2-dichloroethane at 0° C. The reaction mixture was stirred at 0° C. for 30 minutes. 2-({[(S)-Cyclopropyl-(3-fluoro-phenyl)-methyl]-carbamoyl}-methyl)-6-fluoro-benzoic acid was added and the reaction mixture was refluxed for 20 hours. The reaction mixture was poured into 35 mL 1N HCl (aq.) and 50 mL brine. The mixture was extracted with ethyl acetate (250 mL). The organic phase was washed with brine, dried over MgSO4 and concentrated in vacuo. The crude product was flash chromatographed on silica gel (gradient heptane-ethyl acetate) to give 344 mg of the title compound, yield 42%. LC-MS (m/z) 411.3 (MH+); tR=1.34. the reaction mixture was refluxed for 20 hours The mixture was extracted with ethyl acetate (250 mL) The organic phase was washed with brine dried over MgSO4 concentrated in vacuo chromatographed on silica gel (gradient heptane-ethyl acetate)

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

Procedure: Acrylic acid (20 g) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (30 g) were dissolved in water (300 mL). Then aminohydroxybutyric acid (2.0 g) was added to the obtained solution and reacted at room temperature for 10 hours. After the completion of the reaction, water was distilled off and the residue was sufficiently washed with hexane (200 mL) in 3 portions. Next, this residue was dissolved in dimethyl-formamide (350 mL), in which N-hydroxysuccinimide (3 g) and N,N′-dicyclohexylcarbodiimide (3 g) had been dissolved, and reacted overnight. After the completion of the reaction, the solvent was distilled off. Ethyl acetate was added to the residue thus obtained and the precipitate thus formed was filtered off. The filtrate was recovered and a fraction containing the target product was taken up by silica gel column chromatography with the use of ethyl acetate as a mobile phase and alumina column chromatography. Next, a half of the solvent was distilled off with an evaporator and recrystallization was carried out by adding a hexane solvent at −20° C. to thereby give the target monomers (N-propylacetamide, N-propyl acrylamide) (yield: 68%). reacted at room temperature for 10 hours was distilled off the residue was sufficiently washed with hexane (200 mL) in 3 portions Next, this residue was dissolved in dimethyl-formamide (350 mL), in which N-hydroxysuccinimide (3 g) and N,N′-dicyclohexylcarbodiimide (3 g) had been dissolved reacted overnight After the completion of the reaction the solvent was distilled off Ethyl acetate was added to the residue thus obtained the precipitate thus formed was filtered off The filtrate was recovered a fraction containing the target product Next, a half of the solvent was distilled off with an evaporator and recrystallization by adding a hexane solvent at −20° C.

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Oxalyl chloride (0.7 mL, 8 mmol) was added to N-propyl-acetamide (1.11 mL, 10 mmol) and 2,6-lutidine (1.39 mL, 12 mmol) in 50 mL 1,2-dichloroethane at 0° C. The reaction mixture was stirred at 0° C. for 30 minutes. 2-({[(S)-Cyclopropyl-(3-fluoro-phenyl)-methyl]-carbamoyl}-methyl)-6-fluoro-benzoic acid was added and the reaction mixture was refluxed for 20 hours. The reaction mixture was poured into 35 mL 1N HCl (aq.) and 50 mL brine. The mixture was extracted with ethyl acetate (250 mL). The organic phase was washed with brine, dried over MgSO4 and concentrated in vacuo. The crude product was flash chromatographed on silica gel (gradient heptane-ethyl acetate) to give 344 mg of the title compound, yield 42%. LC-MS (m/z) 411.3 (MH+); tR=1.34. the reaction mixture was refluxed for 20 hours The mixture was extracted with ethyl acetate (250 mL) The organic phase was washed with brine dried over MgSO4 concentrated in vacuo chromatographed on silica gel (gradient heptane-ethyl acetate)