cyclopropanecarbohydrazide

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

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

Procedure: (6-Bromopyridin-2-yl)acetic acid (Example 235, Step 2) (41% wt, 1.50 g, 2.85 mmol), EDC (1.64 g, 8.54 mmol), HOBT (872 mg, 5.69 mmol), and cyclopropanecarboxylic acid hydrazide (570 mg, 5.69 mmol) were combined in DMF (15 mL), and DIEA (994 μL, 5.69 mmol) was added. The reaction was stirred overnight at room temperature. After evaporation of the DMF, the residue was diluted with water and extracted with 5:1 CH2Cl2:MeOH (3×). The combined organic layers were dried (MgSO4), filtered, and evaporated. The solid residue was triturated with CH2Cl2 and filtered to isolate the title compound as a colorless solid. After evaporation of the DMF the residue was diluted with water extracted with 5:1 CH2Cl2 The combined organic layers were dried (MgSO4) filtered evaporated The solid residue was triturated with CH2Cl2 filtered

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

Procedure: A mixture of cyclopropanecarboxylic acid hydrazide (1.6 g, 16 mmol) in 5% aqueous sodium hydroxide (50 mL) was cooled to 0° C. with stirring and a solution of 5,6-dichloronicotinoyl chloride (3.1 g, 14.8 mmol) in dimethoxyethane (10 mL) added over 20 minutes. This was stirred at room temperature overnight, acidified to pH 3-4 with 1N hydrochloric acid and filtered. The resulting tan solid was dried to give the desired product (1.4 g, 35%). This was stirred at room temperature overnight filtered The resulting tan solid was dried

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

Procedure: Following the general method of procedure 53 and making non-critical variations, except the product was purified by recrystallization from absolute ethanol rather than by chromatography, 5.25 gm (0.0337 mole) of 3-acetyl-6-chloropyridine and 3.40 gm (0.034 mole) of cyclopropanecarboxylic acid hydrazide yield 6.52 gm (81%) of the title compound having a melting point of 218.1° C.

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

Procedure: To a solution of (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylic acid 1 (0.25 g, 0.90 mmol) in dry DCM (30 mL) were added cyclopropanecarbohydrazide 196 (0.135 g, 1.35 mmol), 1-hydroxybenzotriazole (0.19 g, 1.35 mmol), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.26 g, 1.35 mmol) and 4-(dimethylamino)pyridine (0.16 g, 1.35 mmol) at room temperature. The reaction mixture was stirred at room temperature overnight, and concentrated under vacuum. The residue was purified by column chromatography to give (2R,5S)-6-(benzyloxy)-N′-(cyclopropylcarbonyl)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide 197 (0.27 g, 84%) as a white solid. concentrated under vacuum The residue was purified by column chromatography

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

Procedure: A solution of 2-amino-5-bromo-nicotinic acid (300 mg, 1.38 mmol) and cyclopropanecarboxylic acid hydrazide (300 mg, 3.0 mmol) in POCl3 (30.0 mL,) was stirred for 18 h at 65° C. The reaction mixture was distilled under reduced pressure to obtain a residue, which was cooled to 0° C. by adding iced water and neutralizing with saturated NaHCO3 solution (100 mL). The aqueous layer was extracted with ethyl acetate. The ethyl acetate layer was separated, dried over anhydrous Na2SO4 and evaporated to afford 370 mg of crude 5-bromo-3-(5-cyclopropyl-[1,3,4]oxadiazol-2-yl)-pyridin-2-ylamine. Crude compound was purified by column chromatography using silica gel (100-200 mesh). The column was eluted with 15% EtOAc in petroleum ether to afford the title compound as a pale yellow solid used without further purification. The reaction mixture was distilled under reduced pressure to obtain a residue, which The aqueous layer was extracted with ethyl acetate The ethyl acetate layer was separated dried over anhydrous Na2SO4 evaporated

Conditions: temp:40.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of tert-butyl 3-[(methylamino)carbonothioyl]-5-(5-methylpyridin-2-yl)benzoate (0.56 g, 1.64 mmol) in tetrahydrofuran (15 mL) were added cyclopropanecarbohydrazide (0.49 g, 4.92 mmol) and mercury(II) acetate (1.05 g, 3.28 mmol). The reaction mixture was heated to 40° C. After 18 h, the mixture was cooled to ambient temperature. The mixture was filtered and the filtrate was concentrated. Purification by silica gel chromatography (100% dichloromethane→95% dichloromethane/methanol) gave the title compound. MS 391.1 (M+1). the mixture was cooled to ambient temperature The mixture was filtered the filtrate was concentrated Purification by silica gel chromatography (100% dichloromethane→95% dichloromethane/methanol)

Conditions: temp:40.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of tert-butyl 3-[(methylamino)carbonothioyl]-5-(5-methylpyridin-2-yl)benzoate (0.56 g, 1.64 mmol) in tetrahydrofuran (15 mL) were added cyclopropanecarbohydrazide (0.49 g, 4.92 mmol) and mercury(II) acetate (1.05 g, 3.28 mmol). The reaction mixture was heated to 40° C. After 18 h, the mixture was cooled to ambient temperature. The mixture was filtered and the filtrate was concentrated. Purification by silica gel chromatography (100% dichloromethane→95% dichloromethane/methanol) gave the title compound. MS 391.1 (M+1). the mixture was cooled to ambient temperature The mixture was filtered the filtrate was concentrated Purification by silica gel chromatography (100% dichloromethane→95% dichloromethane/methanol)

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

Procedure: To a stirring suspension of 3-iodo-1-tosyl-1H-indole-5-carboxylic acid (1.944 g, 4.41 mmol) and cyclopropanecarbohydrazide (0.441 g, 4.41 mmol) (Enamine) in THF (40 mL) was added N-ethyl-N-isopropylpropan-2-amine (1.919 mL, 11.01 mmol) (Sigma-Aldrich) followed by HATU (1.843 g, 4.85 mmol) (Oakwood Products) in one portion and the solution was stirred at RT for 45 min. Several ice chunks were added to the mixture followed by H2O (75 mL). The mixture was extracted with EtOAc (2×100 mL). The organic layer was washed with 50 mL of sat. NaHCO3, then brine, dried over MgSO4, filtered, and concentrated to a volume of about 50 mL of EtOAc. A precipitate formed and was isolated by filtration. The filter cake was washed with EtOAc (2×10 mL) to give N′-(cyclopropanecarbonyl)-3-iodo-1-tosyl-1H-indole-5-carbohydrazide (1.13 g, 2.159 mmol, 49.0%) as an off-white solid. MS (ESI, pos. ion) m/z: 523.8 (M+1). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.49 (s, 1H), 10.14 (s, 1H), 8.14-8.21 (m, 1H), 8.01-8.09 (m, 1H), 7.89-8.01 (m, 4H), 7.41 (d, J=8.2 Hz, 2H), 2.32 (s, 3H), 1.63-1.74 (m, 1H), 0.63-0.87 (m, 4H). Several ice chunks were added to the mixture The mixture was extracted with EtOAc (2×100 mL) The organic layer was washed with 50 mL of sat. NaHCO3 brine, dried over MgSO4 filtered concentrated to a volume of about 50 mL of EtOAc A precipitate formed was isolated by filtration The filter cake was washed with EtOAc (2×10 mL)

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

Procedure: A solution of 2-amino-5-bromo-nicotinic acid (300 mg, 1.38 mmol) and cyclopropanecarboxylic acid hydrazide (300 mg, 3.0 mmol) in POCl3 (30.0 mL) was stirred for 18 h at 65° C. The reaction mixture was distilled under reduced pressure to obtain a residue, which was cooled to 0° C. by adding iced water and neutralizing with saturated NaHCO3 solution (100 mL). The aqueous layer was extracted with ethyl acetate. The ethyl acetate layer was separated, dried over anhydrous Na2SO4 and evaporated to afford 370 mg of crude 5-bromo-3-(5-cyclopropyl-[1,3,4]oxadiazol-2-yl)-pyridin-2-ylamine. Crude compound was purified by column chromatography using silica gel (100-200 mesh). The column was eluted with 15% EtOAc in petroleum ether to afford the title compound as a pale yellow solid used without further purification. The reaction mixture was distilled under reduced pressure to obtain a residue, which The aqueous layer was extracted with ethyl acetate The ethyl acetate layer was separated dried over anhydrous Na2SO4 evaporated

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

Procedure: To a stirred mixture of 17.9 g (0.179 mole) cyclopropane carboxylic acid hydrazide (the product of Example 6) in about 75 ml dimethylformamide, 68.0 g (0.894 mole) carbon disulfide was added (and all solids dissolved). The solution turned orange and then green. The reaction mixture was stirred about 1 hour at room temperature, refluxed about 3 hours, and stirred overnight at room temperature. The mixture was added to an ice-water bath to give an oil. The mixture was extracted with methylene chloride. The methylene chloride fraction was dried over magnesium sulfate and stripped. Chromatography on silica gel, eluting with methylene chloride, gave the above-identified product as a solid, melting point 76°-78° C. dissolved) refluxed about 3 hours stirred overnight at room temperature The mixture was added to an ice-water bath to give an oil The mixture was extracted with methylene chloride The methylene chloride fraction was dried over magnesium sulfate Chromatography on silica gel, eluting with methylene chloride

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Methyl 10-bromo-3-iodo-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxylate (100 mg, 0.2178 mmol) and cyclopropanecarbohydrazide (1.5 equiv., 34.43 mg, 0.3267 mmol) were dissolved in dry N,N-dimethylformamide (0.87 mL) and triethylamine (0.13 mL). The solution was sparged with nitrogen. Palladium(II) acetate (0.05 equiv., 2.5 mg, 0.01089 mmol) and xantphos (0.05000, 6.430 mg, 0.01089 mmol) were added and the solution was purged and fixed with a CO balloon. The reaction was heated to 80° C. for 2 h. The reaction was monitored by LC/MS for consumption of starting material. The reaction was cooled to room temperature and diluted with methylene chloride. Saturated aqueous sodium bicarbonate was added and the mixture was extracted twice with methylene chloride. The organic layers were combined, dried with sodium sulfate and concentrated. Purified by flash chromatography (10-100% EtOAc in heptanes) to afford 26 mg (26% yield) of a white solid. The solution was sparged with nitrogen the solution was purged The reaction was monitored by LC/MS for consumption of starting material The reaction was cooled to room temperature diluted with methylene chloride Saturated aqueous sodium bicarbonate was added the mixture was extracted twice with methylene chloride dried with sodium sulfate concentrated Purified by flash chromatography (10-100% EtOAc in heptanes)