N-cyclopropylcyclopropanecarboxamide

Conditions: temp:130.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of N-cyclopropylcyclopropanecarboxamide (2-A) (26 mg, 0.210 mmol) in 0.50 ml toluene was added methyl triflate (1.45 mg, 1 eq) and the reaction was heated at 100° C. for 5-7 min until all of the amide went into solution. To this crude solution was added 0.740 mL of a 0.3 M solution of 4-pentylbicyclo[2.2.2]octane-1-carbohydrazide in DMF (1.1 eq, crude, prepared as described in Step A of Example 1) followed by triethylamine (0.059 mL, 2 eq) and the mixture was heated at 130° C. for 4 h. After this time the solvent was removed under reduced pressure, and the residue was chromatographed on C-18 reverse phase (gradient 90% water to 100% acetonitrile, 0.1% TPA). The fractions containing the compound were determined by LCMS, added to 200 mL of methylene chloride, and extracted with saturated aqueous sodium bicarbonate. The organic layer was dried over magnesium sulfate and evaporated under diminished. The residue was lyophilized from benzene to afford 3,4-dicyclopropyl-5-(4-pentylbicyclo[2.2.2]oct-1-yl)-4H-1,2,4-triazole (2-B); MS (ESI+)=328.3 (M+1). After this time the solvent was removed under reduced pressure the residue was chromatographed on C-18 reverse phase (gradient 90% water to 100% acetonitrile, 0.1% TPA) The fractions containing the compound added to 200 mL of methylene chloride extracted with saturated aqueous sodium bicarbonate The organic layer was dried over magnesium sulfate evaporated

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

Procedure: To a magnetically stirred solution of cyclopropanecarboxylic acid (1.00 g, 11.6 mmol) and cyclopropylamine (0.995 g, 1.5 eq) in 8 mL of methylene chloride was added DMAP (4-dimethylaminopyridine, 2.13 g, 1.5 eq) followed by EDC (1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 3.34 g, 1.5 eq). The reaction was stirred at room temperature for 2 h after which time it was diluted with 50 mL of methylene chloride and washed twice with 0.5 N aqueous HCl followed by water, saturated aqueous sodium bicarbonate, then brine. The solvent was removed under reduced pressure and the residue was purified by silica chromatography eluting with 1:1 hexane/ethyl acetate to afford N-cyclopropylcyclopropanecarboxamide (2-A). washed twice with 0.5 N aqueous HCl The solvent was removed under reduced pressure the residue was purified by silica chromatography eluting with 1:1 hexane/ethyl acetate

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

Procedure: To a magnetically stirred solution of cyclopropanecarboxylic acid (1.00 g, 11.6 mmol) and cyclopropylamine (0.995 g, 1.5 eq) in 8 mL of methylene chloride was added DMAP (4-dimethylaminopyridine, 2.13 g, 1.5 eq) followed by EDC (1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 3.34 g, 1.5 eq). The reaction was stirred at room temperature for 2 h after which time it was diluted with 50 mL of methylene chloride and washed twice with 0.5 N aqueous HCl followed by water, saturated aqueous sodium bicarbonate, then brine. The solvent was removed under reduced pressure and the residue was purified by silica chromatography eluting with 1:1 hexane/ethyl acetate to afford N-cyclopropylcyclopropanecarboxamide (2-A). washed twice with 0.5 N aqueous HCl The solvent was removed under reduced pressure the residue was purified by silica chromatography eluting with 1:1 hexane/ethyl acetate

Conditions: temp:130.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of N-cyclopropylcyclopropanecarboxamide (2-A) (26 mg, 0.210 mmol) in 0.50 ml toluene was added methyl triflate (1.45 mg, 1 eq) and the reaction was heated at 100° C. for 5-7 min until all of the amide went into solution. To this crude solution was added 0.740 mL of a 0.3 M solution of 4-pentylbicyclo[2.2.2]octane-1-carbohydrazide in DMF (1.1 eq, crude, prepared as described in Step A of Example 1) followed by triethylamine (0.059 mL, 2 eq) and the mixture was heated at 130° C. for 4 h. After this time the solvent was removed under reduced pressure, and the residue was chromatographed on C-18 reverse phase (gradient 90% water to 100% acetonitrile, 0.1% TPA). The fractions containing the compound were determined by LCMS, added to 200 mL of methylene chloride, and extracted with saturated aqueous sodium bicarbonate. The organic layer was dried over magnesium sulfate and evaporated under diminished. The residue was lyophilized from benzene to afford 3,4-dicyclopropyl-5-(4-pentylbicyclo[2.2.2]oct-1-yl)-4H-1,2,4-triazole (2-B); MS (ESI+)=328.3 (M+1). After this time the solvent was removed under reduced pressure the residue was chromatographed on C-18 reverse phase (gradient 90% water to 100% acetonitrile, 0.1% TPA) The fractions containing the compound added to 200 mL of methylene chloride extracted with saturated aqueous sodium bicarbonate The organic layer was dried over magnesium sulfate evaporated

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

Procedure: To a magnetically stirred solution of cyclopropanecarboxylic acid (1.00 g, 11.6 mmol) and cyclopropylamine (0.995 g, 1.5 eq) in 8 mL of methylene chloride was added DMAP (4-dimethylaminopyridine, 2.13 g, 1.5 eq) followed by EDC (1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 3.34 g, 1.5 eq). The reaction was stirred at room temperature for 2 h after which time it was diluted with 50 mL of methylene chloride and washed twice with 0.5 N aqueous HCl followed by water, saturated aqueous sodium bicarbonate, then brine. The solvent was removed under reduced pressure and the residue was purified by silica chromatography eluting with 1:1 hexane/ethyl acetate to afford N-cyclopropylcyclopropanecarboxamide (2-A). washed twice with 0.5 N aqueous HCl The solvent was removed under reduced pressure the residue was purified by silica chromatography eluting with 1:1 hexane/ethyl acetate