3-fluorobenzohydrazide

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

実験手順: To a solution of 3-fluorobenzhydrazide (5.0 g, 0.033 mol) in tetrahydrofuran (100 mL) was added ethyl isocyanate (2.6 g, 0.036 mol) at room temperature. After stirring for 24 hr, the resultant precipitate was collected by suction-filtration to give 1-(3-fluorobenzoyl)-4-ethyl semicarbazide in quantitative yield. the resultant precipitate was collected by suction-filtration

反応条件: temp:-15.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: (2R,3S)-2-(3-chloro-4-cyano-2-methylphenylamino)-3-hydroxybutanoic acid (intermediate 1a) (2 g, 7.44 mmol) and 3-Fluorobenzohydrazide (1.26 g, 8.19 mmol) were mixed together in THF (100 ml) and cooled to −15° C. under N2 atmosphere. To the pre-cooled reaction mixture were added hydroxybenzotriazole (HOBT) (1.0 g, 7.44 mmol), TEA (1.56 mL, 11.16 mmol) followed by N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDCI) (2.14 g, 11.16 mmol). The reaction mixture was allowed to stir at −20° C. for 20 min and then at room temperature overnight. After the reaction was complete based on TLC, the urea was filtered off and the solution was washed with 5% citric acid (2×80 mL), 5% NaHCO3 (2×80 mL) followed by water (80 mL) and then dried (Na2SO4) to provide the crude product as a yellow solid (2.75 g, 91%): 1H NMR (400 MHz, d6-acetone, δ in ppm) 9.84 (br s, 2H), 7.79-7.76 (m, 1H), 7.67-7.63 (m, 1H), 7.58-7.51 (m, 2H), 7.41-7.35 (m, 1H), 6.68 (d, J=9 Hz, 1H), 5.55 (d, J=9 Hz, 1H), 4.79 (br s, 1H), 4.42-4.36 (m, 1H), 4.14-4.10 (m, 1H), 2.36 (s, 3H) and 1.36 (d, J=6.5 Hz). To the pre-cooled reaction mixture at room temperature overnight the urea was filtered off the solution was washed with 5% citric acid (2×80 mL), 5% NaHCO3 (2×80 mL) dried (Na2SO4)

反応条件: temp:-15.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: (2R,3S)-2-(3-chloro-4-cyano-2-methylphenylamino)-3-hydroxybutanoic acid (intermediate 1a) (2 g, 7.44 mmol) and 3-Fluorobenzohydrazide (1.26 g, 8.19 mmol) were mixed together in THF (100 ml) and cooled to −15° C. under N2 atmosphere. To the pre-cooled reaction mixture were added hydroxybenzotriazole (HOBT) (1.0 g, 7.44 mmol), TEA (1.56 mL, 11.16 mmol) followed by N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDCI) (2.14 g, 11.16 mmol). The reaction mixture was allowed to stir at −20° C. for 20 min and then at room temperature overnight. After the reaction was complete based on TLC, the urea was filtered off and the solution was washed with 5% citric acid (2×80 mL), 5% NaHCO3 (2×80 mL) followed by water (80 mL) and then dried (Na2SO4) to provide the crude product as a yellow solid (2.75 g, 91%): 1H NMR (400 MHz, d6-acetone, δ in ppm) 9.84 (br s, 2H), 7.79-7.76 (m, 1H), 7.67-7.63 (m, 1H), 7.58-7.51 (m, 2H), 7.41-7.35 (m, 1H), 6.68 (d, J=9 Hz, 1H), 5.55 (d, J=9 Hz, 1H), 4.79 (br s, 1H), 4.42-4.36 (m, 1H), 4.14-4.10 (m, 1H), 2.36 (s, 3H) and 1.36 (d, J=6.5 Hz). To the pre-cooled reaction mixture at room temperature overnight the urea was filtered off the solution was washed with 5% citric acid (2×80 mL), 5% NaHCO3 (2×80 mL) dried (Na2SO4)

反応条件: temp:-15.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: (2R,3S)-2-(3-chloro-4-cyano-2-methylphenylamino)-3-hydroxybutanoic acid (intermediate 1a) (2 g, 7.44 mmol) and 3-Fluorobenzohydrazide (1.26 g, 8.19 mmol) were mixed together in THF (100 ml) and cooled to −15° C. under N2 atmosphere. To the pre-cooled reaction mixture were added hydroxybenzotriazole (HOST) (1.0 g, 7.44 mmol), TEA (1.56 mL, 11.16 mmol) followed by N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDCl) (2.14 g, 11.16 mmol). The reaction mixture was allowed to stir at −20° C. for 20 min and then at room temperature overnight. After the reaction was complete based on TLC, the urea was filtered off and the solution was washed with 5% citric acid (2×80 mL), 5% NaHCO3 (2×80 mL) followed by water (80 mL) and then dried (Na2SO4) to provide the crude product as a yellow solid (2.75 g, 91%); 1H NMR (400 MHz, d6-acetone, δ in ppm) 9.84 (br s, 2H), 7.79-7.76 (m, 1H), 7.67-7.63 (m, 1H), 7.58-7.51 (m, 2H), 7.41-7.35 (m, 1H), 6.68 (d, J=9 Hz, 1H), 5.55 (d, J=9 Hz, 1H), 4.79 (br s, 1H), 4.42-4.36 (1H), 4.14-4.10 (m, 1H), 2.36 (s, 3H) and 1.36 (d, J=6.5 Hz). To the pre-cooled reaction mixture at room temperature overnight the urea was filtered off the solution was washed with 5% citric acid (2×80 mL), 5% NaHCO3 (2×80 mL) dried (Na2SO4)

反応条件: temp:-15.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: (2R,3S)-2-(3-chloro-4-cyano-2-methylphenylamino)-3-hydroxybutanoic acid (intermediate 1a) (2 g, 7.44 mmol) and 3-Fluorobenzohydrazide (1.26 g, 8.19 mmol) were mixed together in THF (100 ml) and cooled to −15° C. under N2 atmosphere. To the pre-cooled reaction mixture were added hydroxybenzotriazole (HOBT) (1.0 g, 7.44 mmol), TEA (1.56 mL, 11.16 mmol) followed by N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDCI) (2.14 g, 11.16 mmol). The reaction mixture was allowed to stir at −20° C. for 20 min and then at room temperature overnight. After the reaction was complete based on TLC, the urea was filtered off and the solution was washed with 5% citric acid (2×80 mL), 5% NaHCO3 (2×80 mL) followed by water (80 mL) and then dried (Na2SO4) to provide the crude product as a yellow solid (2.75 g, 91%): 1H NMR (400 MHz, d6-acetone, δ in ppm) 9.84 (br s, 2H), 7.79-7.76 (m, 1H), 7.67-7.63 (m, 1H), 7.58-7.51 (m, 2H), 7.41-7.35 (m, 1H), 6.68 (d, J=9 Hz, 1H), 5.55 (d, J=9 Hz, 1H), 4.79 (br s, 1H), 4.42-4.36 (m, 1H), 4.14-4.10 (m, 1H), 2.36 (s, 3H), and 1.36 (d, J=6.5 Hz). To the pre-cooled reaction mixture at room temperature overnight the urea was filtered off the solution was washed with 5% citric acid (2×80 mL), 5% NaHCO3 (2×80 mL) dried (Na2SO4)

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

実験手順: 3-fluorobenzohydrazide (80.77 mg, 0.5240 mmol) was added to a solution of 3-amino-6-[4-(dimethylcarbamoyl)phenyl]pyrazine-2-carboxylic acid (150 mg, 0.5240 mmol), triethylamine (53.02 mg, 73.03 μL, 0.5240 mmol) and TBTU (252.4 mg, 0.7860 mmol) in DMF (3.000 mL) and the resulting solution stirred at RT for 2 hours. The reaction was diluted with EtOAc and water and the layers separated. The aqueous layer was extracted further with EtOAc (2×) and the combined organics washed with water (3×), dried (MgSO4), filtered and concentrated to give the desired product as a yellow solid (172 mg, 78% Yield). MS (ES+) 423.13 the layers separated The aqueous layer was extracted further with EtOAc (2×) the combined organics washed with water (3×) dried (MgSO4) filtered concentrated

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

実験手順: 3-fluorobenzohydrazide (80.77 mg, 0.5240 mmol) was added to a solution of 3-amino-6-[4-(dimethylcarbamoyl)phenyl]pyrazine-2-carboxylic acid (150 mg, 0.5240 mmol), triethylamine (53.02 mg, 73.03 μL, 0.5240 mmol) and TBTU (252.4 mg, 0.7860 mmol) in DMF (3.000 mL) and the resulting solution stirred at RT for 2 hours. The reaction was diluted with EtOAc and water and the layers separated. The aqueous layer was extracted further with EtOAc (2×) and the combined organics washed with water (3×), dried (MgSO4), filtered and concentrated to give the desired product as a yellow solid (172 mg, 78% Yield). MS (ES+) 423.13 the layers separated The aqueous layer was extracted further with EtOAc (2×) the combined organics washed with water (3×) dried (MgSO4) filtered concentrated

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

実験手順: To a solution of 3-fluorobenzhydrazide (5.0 g, 0.033 mol) in tetrahydrofuran (100 mL) was added ethyl isocyanate (2.6 g, 0.036 mol) at room temperature. After stirring for 24 hr, the resultant precipitate was collected by suction-filtration to give 1-(3-fluorobenzoyl)-4-ethyl semicarbazide in quantitative yield. the resultant precipitate was collected by suction-filtration

反応条件: temp:-15.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: (2R,3S)-2-(3-chloro-4-cyano-2-methylphenylamino)-3-hydroxybutanoic acid (intermediate 1a) (2 g, 7.44 mmol) and 3-Fluorobenzohydrazide (1.26 g, 8.19 mmol) were mixed together in THF (100 ml) and cooled to −15° C. under N2 atmosphere. To the pre-cooled reaction mixture were added hydroxybenzotriazole (HOBT) (1.0 g, 7.44 mmol), TEA (1.56 mL, 11.16 mmol) followed by N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDCI) (2.14 g, 11.16 mmol). The reaction mixture was allowed to stir at −20° C. for 20 min and then at room temperature overnight. After the reaction was complete based on TLC, the urea was filtered off and the solution was washed with 5% citric acid (2×80 mL), 5% NaHCO3 (2×80 mL) followed by water (80 mL) and then dried (Na2SO4) to provide the crude product as a yellow solid (2.75 g, 91%): 1H NMR (400 MHz, d6-acetone, δ in ppm) 9.84 (br s, 2H), 7.79-7.76 (m, 1H), 7.67-7.63 (m, 1H), 7.58-7.51 (m, 2H), 7.41-7.35 (m, 1H), 6.68 (d, J=9 Hz, 1H), 5.55 (d, J=9 Hz, 1H), 4.79 (br s, 1H), 4.42-4.36 (m, 1H), 4.14-4.10 (m, 1H), 2.36 (s, 3H) and 1.36 (d, J=6.5 Hz). To the pre-cooled reaction mixture at room temperature overnight the urea was filtered off the solution was washed with 5% citric acid (2×80 mL), 5% NaHCO3 (2×80 mL) dried (Na2SO4)

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

実験手順: To a solution of 3-fluorobenzhydrazide (5.0 g, 0.033 mol) in tetrahydrofuran (100 mL) was added ethyl isocyanate (2.6 g, 0.036 mol) at room temperature. After stirring for 24 hr, the resultant precipitate was collected by suction-filtration to give 1-(3-fluorobenzoyl)-4-ethyl semicarbazide in quantitative yield. the resultant precipitate was collected by suction-filtration

反応条件: temp:-15.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: (2R,3S)-2-(3-chloro-4-cyano-2-methylphenylamino)-3-hydroxybutanoic acid (intermediate 1a) (2 g, 7.44 mmol) and 3-Fluorobenzohydrazide (1.26 g, 8.19 mmol) were mixed together in THF (100 ml) and cooled to −15° C. under N2 atmosphere. To the pre-cooled reaction mixture were added hydroxybenzotriazole (HOBT) (1.0 g, 7.44 mmol), TEA (1.56 mL, 11.16 mmol) followed by N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDCI) (2.14 g, 11.16 mmol). The reaction mixture was allowed to stir at −20° C. for 20 min and then at room temperature overnight. After the reaction was complete based on TLC, the urea was filtered off and the solution was washed with 5% citric acid (2×80 mL), 5% NaHCO3 (2×80 mL) followed by water (80 mL) and then dried (Na2SO4) to provide the crude product as a yellow solid (2.75 g, 91%): 1H NMR (400 MHz, d6-acetone, δ in ppm) 9.84 (br s, 2H), 7.79-7.76 (m, 1H), 7.67-7.63 (m, 1H), 7.58-7.51 (m, 2H), 7.41-7.35 (m, 1H), 6.68 (d, J=9 Hz, 1H), 5.55 (d, J=9 Hz, 1H), 4.79 (br s, 1H), 4.42-4.36 (m, 1H), 4.14-4.10 (m, 1H), 2.36 (s, 3H) and 1.36 (d, J=6.5 Hz). To the pre-cooled reaction mixture at room temperature overnight the urea was filtered off the solution was washed with 5% citric acid (2×80 mL), 5% NaHCO3 (2×80 mL) dried (Na2SO4)

反応条件: temp:-15.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: (2R,3S)-2-(3-chloro-4-cyano-2-methylphenylamino)-3-hydroxybutanoic acid (intermediate 1a) (2 g, 7.44 mmol) and 3-Fluorobenzohydrazide (1.26 g, 8.19 mmol) were mixed together in THF (100 ml) and cooled to −15° C. under N2 atmosphere. To the pre-cooled reaction mixture were added hydroxybenzotriazole (HOST) (1.0 g, 7.44 mmol), TEA (1.56 mL, 11.16 mmol) followed by N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDCl) (2.14 g, 11.16 mmol). The reaction mixture was allowed to stir at −20° C. for 20 min and then at room temperature overnight. After the reaction was complete based on TLC, the urea was filtered off and the solution was washed with 5% citric acid (2×80 mL), 5% NaHCO3 (2×80 mL) followed by water (80 mL) and then dried (Na2SO4) to provide the crude product as a yellow solid (2.75 g, 91%); 1H NMR (400 MHz, d6-acetone, δ in ppm) 9.84 (br s, 2H), 7.79-7.76 (m, 1H), 7.67-7.63 (m, 1H), 7.58-7.51 (m, 2H), 7.41-7.35 (m, 1H), 6.68 (d, J=9 Hz, 1H), 5.55 (d, J=9 Hz, 1H), 4.79 (br s, 1H), 4.42-4.36 (1H), 4.14-4.10 (m, 1H), 2.36 (s, 3H) and 1.36 (d, J=6.5 Hz). To the pre-cooled reaction mixture at room temperature overnight the urea was filtered off the solution was washed with 5% citric acid (2×80 mL), 5% NaHCO3 (2×80 mL) dried (Na2SO4)