2,5-二氟-N'-羟基苯甲酰亚胺

反应条件: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: The title compound was prepared following procedure described for Example 1, but starting from 1-(2-bromophenyl)-5-methyl-1H-1,2,3-triazole-4-carboxylic acid, prepared according to Zhang, Z.-Y. et al. Magn. Reson. Chem. 1998, 36, 159-460 (56.42 mg; 0.20 mmol) and 2,5-difluoro-N′-hydroxybenzenecarboximid amide (JRD-Fluoro, 37.87 mg; 0.22 mmol). The reaction mixture was filtered through an NH2 SPE column (1 g) and evaporated. The residue was taken up into pyridine and heated at 100° C. for 7 h, in order to complete oxadiazole formation. Pyridine was evaporated and the crude product was purified by flash chromatography (SiO2: 10 g; cyclohexane/EtOAc gradient from 90/10 till 50/50) and dried to afford Example 3 as a yellow solid. 1H NMR: (DMSO-d6, 300 MHz) δ 8.06 (dd, J=1.70 Hz, J=7.73 Hz, 1H), 8.02-7.97 (m, 1H), 7.86 (dd, J=1.89 Hz, J=7.53 Hz, 1H), 7.80-7.69 (m, 2H), 7.63 (dt, J=1.91 Hz, J=6.58 Hz, 2H), 2.61 (s, 3H). LC/MS: 419.93 (M+H)+. HPLC (Method A) Rt 4.92 min (Purity: 96%). prepared The reaction mixture was filtered through an NH2 SPE column (1 g) evaporated Pyridine was evaporated the crude product was purified by flash chromatography (SiO2: 10 g; cyclohexane/EtOAc gradient from 90/10 till 50/50) dried

反应条件: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: The title compound was prepared following procedure described for Example 1, but starting from 1-(2-bromophenyl)-5-methyl-1H-1,2,3-triazole-4-carboxylic acid, prepared according to Zhang, Z.-Y. et al. Magn. Reson. Chem. 1998, 36, 159-460 (56.42 mg; 0.20 mmol) and 2,5-difluoro-N′-hydroxybenzenecarboximid amide (JRD-Fluoro, 37.87 mg; 0.22 mmol). The reaction mixture was filtered through an NH2 SPE column (1 g) and evaporated. The residue was taken up into pyridine and heated at 100° C. for 7 h, in order to complete oxadiazole formation. Pyridine was evaporated and the crude product was purified by flash chromatography (SiO2: 10 g; cyclohexane/EtOAc gradient from 90/10 till 50/50) and dried to afford Example 3 as a yellow solid. 1H NMR: (DMSO-d6, 300 MHz) δ 8.06 (dd, J=1.70 Hz, J=7.73 Hz, 1H), 8.02-7.97 (m, 1H), 7.86 (dd, J=1.89 Hz, J=7.53 Hz, 1H), 7.80-7.69 (m, 2H), 7.63 (dt, J=1.91 Hz, J=6.58 Hz, 2H), 2.61 (s, 3H). LC/MS: 419.93 (M+H)+. HPLC (Method A) Rt 4.92 min (Purity: 96%). prepared The reaction mixture was filtered through an NH2 SPE column (1 g) evaporated Pyridine was evaporated the crude product was purified by flash chromatography (SiO2: 10 g; cyclohexane/EtOAc gradient from 90/10 till 50/50) dried

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

实验步骤: Ethyl 3-chloro-3-oxopropanoate (1.7 mL; 13.2 mmol) was added to 2,5-difluoro-N′-hydroxybenzenecarboximidamide (JRD-Fluorochemical, 1.13 g; 0.6 mmol) in pyridine (30 mL). The mixture was heated to reflux for 4 hours and the solvent removed in vacuo. The residue was taken up into DCM (20 mL) and washed with water (10 mL). The organic phase was passed through a hydrophobic frit and the solvent removed in vacuo. The residue was purified on a Biotage 25+M column, eluting with petrol containing increasing amounts of EtOAc to give ethyl 2-(3-(2,5-difluorophenyl)-1,2,4-oxadiazol-5-yl)acetate (1.24 g, 70%). The mixture was heated to reflux for 4 hours the solvent removed in vacuo washed with water (10 mL) the solvent removed in vacuo The residue was purified on a Biotage 25+M column eluting with petrol containing increasing amounts of EtOAc

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

实验步骤: A solution of ethyl 3-oxo-3-o-tolylpropanoate (0.44 mL; 2.5 mmol) and 2,5-difluoro-N′-hydroxybenzenecarboximidamide (JRD-Fluorochemical, 215 mg; 1.25 mmol) in toluene (1.5 mL) was heated to 120° C. 18 hours. The solvent was removed in vacuo and the residue purified by flash chromatography on a Biotage 25+M column, eluting with petrol containing increasing amounts of EtOAc. The residue was triturated with petrol to give the title compound as an off-white solid which was used directly without any further purification. 1H NMR (CDCl3, 400 MHz) δ 11.62‡ (1H, br s), 7.82-7.74 (1H, m), 7.55-7.12 (6H, m), 5.95‡ (1H, s), 4.68* (2H, s), [2.58, 2.55 and 2.47] (3H, s) (compound isolated as a mixture of keto and enol forms and as a mixture of rotamers, *=keto form, ‡=enol form). LC/MS: 315 (M+H)+. HPLC (Method D) Rt=4.28 min (Purity: 98.4%). 18 hours The solvent was removed in vacuo the residue purified by flash chromatography on a Biotage 25+M column eluting with petrol containing increasing amounts of EtOAc The residue was triturated with petrol

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

实验步骤: 90.0 mg (0.242 mmol) of 1-[(3-hydroxyazetidin-1-yl)carbonyl]-5-[4-(trifluoromethyl)phenyl]piperidine-3-carboxylic acid (Example 101A) and 45.7 (0.266 mmol) of 2,5-difluoro-N′-hydroxybenzenecarboximidamide (Example 74A) were reacted according to the General Method 1. Yield: 42.9 mg (34% of theory).

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

实验步骤: 100 mg (0.244 mmol) of 1-[(4-cyanopiperidin-1-yl)carbonyl]-5-[4-(trifluoromethyl)phenyl]piperidine-3-carboxylic acid (Example 100A) and 46.2 mg (0.269 mmol) of 2,5-difluoro-N′-hydroxybenzenecarboximidamide (Example 74A) were reacted according to the General Method 1. Yield: 72.5 mg (54% of theory).

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

实验步骤: 100 mg (0.250 mmol) of 1-[(4-hydroxypiperidin-1-yl)carbonyl]-5-[4-(trifluoromethyl)phenyl]piperidine-3-carboxylic acid (Example 99A) and 47.3 (0.275 mmol) of 2,5-difluoro-N′-hydroxybenzenecarboximidamide (Example 74A) were reacted according to the General Method 1. Yield: 68.1 mg (51% of theory).

反应条件: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: The title compound was prepared following procedure described for Example 1, but starting from 1-(2-bromophenyl)-5-methyl-1H-1,2,3-triazole-4-carboxylic acid, prepared according to Zhang, Z.-Y. et al. Magn. Reson. Chem. 1998, 36, 159-460 (56.42 mg; 0.20 mmol) and 2,5-difluoro-N′-hydroxybenzenecarboximid amide (JRD-Fluoro, 37.87 mg; 0.22 mmol). The reaction mixture was filtered through an NH2 SPE column (1 g) and evaporated. The residue was taken up into pyridine and heated at 100° C. for 7 h, in order to complete oxadiazole formation. Pyridine was evaporated and the crude product was purified by flash chromatography (SiO2: 10 g; cyclohexane/EtOAc gradient from 90/10 till 50/50) and dried to afford Example 3 as a yellow solid. 1H NMR: (DMSO-d6, 300 MHz) δ 8.06 (dd, J=1.70 Hz, J=7.73 Hz, 1H), 8.02-7.97 (m, 1H), 7.86 (dd, J=1.89 Hz, J=7.53 Hz, 1H), 7.80-7.69 (m, 2H), 7.63 (dt, J=1.91 Hz, J=6.58 Hz, 2H), 2.61 (s, 3H). LC/MS: 419.93 (M+H)+. HPLC (Method A) Rt 4.92 min (Purity: 96%). prepared The reaction mixture was filtered through an NH2 SPE column (1 g) evaporated Pyridine was evaporated the crude product was purified by flash chromatography (SiO2: 10 g; cyclohexane/EtOAc gradient from 90/10 till 50/50) dried