2,2-dimethylpropanehydrazide

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:

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

実験手順: To the solution of acid (63) (330 mg, 0.74 mmol) in CH2Cl2 (10 mL) was added oxalyl chloride (77 μL, 0.88 mmol) and the catalytic amount of DMF. The reaction mixture was stirred for 1 hr and concentrated in vacuo. The residue (crude acyl chloride) was diluted with CH2Cl2 (10 mL) and pivalohydrazide (128 mg, 1.10 mmol) and triethylamine (0.31 mL, 2.21 mmol) was added. The reaction mixture was stirred for 2 hrs at room temperature. The reaction mixture was concentrated in vacuo and diluted with EtOAc (50 mL). The organic layer was washed with aq. 1N HCl and aq. sat'd NaHCO3 solution, dried over anhydrous MgSO4, filtered, and concentrated in vacuo. Purification by Prep-LC (Gilson) provided 244 mg (61%) of desired diamide as solid. concentrated in vacuo was added The reaction mixture was stirred for 2 hrs at room temperature The reaction mixture was concentrated in vacuo diluted with EtOAc (50 mL) The organic layer was washed with aq. 1N HCl and aq. sat'd NaHCO3 solution dried over anhydrous MgSO4 filtered concentrated in vacuo Purification by Prep-LC (Gilson)

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

実験手順: To the solution of acid (63) (330 mg, 0.74 mmol) in CH2Cl2 (10 mL) was added oxalyl chloride (77 μL, 0.88 mmol) and the catalytic amount of DMF. The reaction mixture was stirred for 1 hr and concentrated in vacuo. The residue (crude acyl chloride) was diluted with CH2Cl2 (10 mL) and pivalohydrazide (128 mg, 1.10 mmol) and triethylamine (0.31 mL, 2.21 mmol) was added. The reaction mixture was stirred for 2 hrs at room temperature. The reaction mixture was concentrated in vacuo and diluted with EtOAc (50 mL). The organic layer was washed with aq. 1N HCl and aq. sat'd NaHCO3 solution, dried over anhydrous MgSO4, filtered, and concentrated in vacuo. Purification by Prep-LC (Gilson) provided 244 mg (61%) of desired diamide as solid. concentrated in vacuo was added The reaction mixture was stirred for 2 hrs at room temperature The reaction mixture was concentrated in vacuo diluted with EtOAc (50 mL) The organic layer was washed with aq. 1N HCl and aq. sat'd NaHCO3 solution dried over anhydrous MgSO4 filtered concentrated in vacuo Purification by Prep-LC (Gilson)

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

実験手順: To a mixture of (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylic acid 1 (0.250 g, 0.905 mmol) in DCM (15.0 mL) were added 2,2-dimethylpropanehydrazide 253 (0.137 g, 1.358 mmol), 1-hydroxybenzotriazole (0.186 g, 1.358 mmol) and 1-ethyl-(3-dimethylamino propyl) carbodiimide hydrochloride (0.260 g, 1.358 mmol) sequentially at room temperature. The mixture was stirred at room temperature overnight, diluted with DCM and concentrated to provide a residue which was subjected to chromatography to give 254 (0.32 g, 94%) as a white foam. concentrated to provide a residue which

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

実験手順: 5.8 g (49.929 mmol) of 2,2-dimethylpropanehydrazide were dissolved in 600 ml of dry ethyl acetate and heated to reflux. 6.767 g (59.915 mmol) of chloroacetyl chloride, dissolved in 45 ml of dry ethyl acetate, were added dropwise to the solution. The mixture was stirred under reflux for 30 min. After cooling, the reaction mixture was concentrated on a rotary evaporator and the residue was dried under high vacuum. This gave 10.14 g of the title compound. The crude product was reacted further without further purification. heated to reflux were added dropwise to the solution under reflux for 30 min After cooling the reaction mixture was concentrated on a rotary evaporator the residue was dried under high vacuum The crude product was reacted further without further purification

反応条件: temp:-60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: In a 50 mL, 3-neck round-bottom flask, (Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acrylic acid (0.2 g, 1.0 eq.) was dissolved in EtOAc (20 mL) and cooled to −60° C. where pivalohydrazide (0.08 g, 1.2 eq.) was introduced dropwise. T3P (50% in EtOAc) (0.4 mL, 4 eq.) was added dropwise followed by DIPEA (0.4 mL, 4 eq.) and the reaction mixture was stirred for 1 h at −60° C. The reaction mixture was concentrated under reduced pressure (25° C., 20 mm Hg) to afford the crude product that was purified by column chromatography (60/120 silica gel) using methanol/dichloromethane gradient (the column was packed in dichloromethane and the desired compound started eluting from 3% methanol/dichloromethane). Fractions containing the desired compounds were combined to afford (Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)-N′-pivaloylacrylohydrazide (0.11 g, yield: 43%); was introduced dropwise The reaction mixture was concentrated under reduced pressure (25° C., 20 mm Hg) to afford the crude product that was purified by column chromatography (60/120 silica gel) the desired compound started eluting from 3% methanol/dichloromethane) Fractions containing the desired compounds

反応条件: temp:-60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: In a 50 mL, 3-neck round-bottom flask, (Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acrylic acid (0.2 g, 1.0 eq.) was dissolved in EtOAc (20 mL) and cooled to −60° C. where pivalohydrazide (0.08 g, 1.2 eq.) was introduced dropwise. T3P (50% in EtOAc) (0.4 mL, 4 eq.) was added dropwise followed by DIPEA (0.4 mL, 4 eq.) and the reaction mixture was stirred for 1 h at −60° C. The reaction mixture was concentrated under reduced pressure (25° C., 20 mm Hg) to afford the crude product that was purified by column chromatography (60/120 silica gel) using methanol/dichloromethane gradient (the column was packed in dichloromethane and the desired compound started eluting from 3% methanol/dichloromethane). Fractions containing the desired compounds were combined to afford (Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)-N′-pivaloylacrylohydrazide (0.11 g, yield: 43%); was introduced dropwise The reaction mixture was concentrated under reduced pressure (25° C., 20 mm Hg) to afford the crude product that was purified by column chromatography (60/120 silica gel) the desired compound started eluting from 3% methanol/dichloromethane) Fractions containing the desired compounds

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

実験手順: Intermediate 60 (0.255 g, 0.84 mmol), EDC (0.225 g, 1.17 mmol) and HOBT (0.136 g, 1.0 mmol) in DMF (5 ml) was stirred at 20° C. for 75 minutes. Pivalic acid hydrazide (0.107 g, 0.92 mmol) was added and stirring continued for 18 hours. The reaction mixture was concentrated in vacuo and the residue partitioned between DCM and water. The organic phase was washed with aqueous sodium hydrogen carbonate then evaporated in vacuo to afford Intermediate 61 as a white solid (0.27 g).). LCMS showed MH+=403; TRET=2.13 min. The reaction mixture was concentrated in vacuo the residue partitioned between DCM and water The organic phase was washed with aqueous sodium hydrogen carbonate then evaporated in vacuo

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

実験手順: To a mixture of 2,2-dimethyl-propionic acid hydrazide (2.32 g, 20 mmol), sodium bicarbonate (1.68 g, 20 mmol) in tetrahydrofuran and water (1:1, 40 mL) was added acetyl chloride (1.56 g, 20 mmol) dropwise. The mixture was stirred overnight and concentrated in vacuo. The residue was extracted with dichloromethane and isopropyl alcohol (10:1) (3×10 mL). The organic extracts were combined, dried over MgSO4 and concentrated to give a white solid. The solid was recrystallized from tetrahydrofuran and hexane (1:8) to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.11-1.14 (m, 9 H) 1.83 (s, 3 H) 9.28 (br s, 1 H) 9.53 (br s, 1 H); MS (ESI) m/z 159 (M+H)+. concentrated in vacuo The residue was extracted with dichloromethane and isopropyl alcohol (10:1) (3×10 mL) dried over MgSO4 concentrated to give a white solid The solid was recrystallized from tetrahydrofuran and hexane (1:8)

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

実験手順: To a mixture of 2,2-dimethyl-propionic acid hydrazide (2.32 g, 20 mmol), sodium bicarbonate (1.68 g, 20 mmol) in tetrahydrofuran and water (1:1, 40 mL) was added acetyl chloride (1.56 g, 20 mmol) dropwise. The mixture was stirred overnight and concentrated in vacuo. The residue was extracted with dichloromethane and isopropyl alcohol (10:1) (3×10 mL). The organic extracts were combined, dried over MgSO4 and concentrated to give a white solid. The solid was recrystallized from tetrahydrofuran and hexane (1:8) to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.11-1.14 (m, 9 H) 1.83 (s, 3 H) 9.28 (br s, 1 H) 9.53 (br s, 1 H); MS (ESI) m/z 159 (M+H)+. concentrated in vacuo The residue was extracted with dichloromethane and isopropyl alcohol (10:1) (3×10 mL) dried over MgSO4 concentrated to give a white solid The solid was recrystallized from tetrahydrofuran and hexane (1:8)