2-methylcyclopropane-1-carboxylic acid

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

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

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

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

Procedure: Triethylamine (0.030 mL, 0.22 mmol), the title compound of Example 7 (15 mg, 0.054 mmol) and 2-methyl-cyclopropanecarboxylic acid (6 mg, 0.062 mmol) were stirred in N,N-dimethylformamide (1.0 mL). O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (25 mg, 0.065 mmol) was added and the reaction was stirred overnight at which point the volatile components were removed under vacuum. The resulting mixture was purified on silica gel, eluting with 3:2 hexane:ethyl acetate. The purest fractions were combined and after solvent removal, the resulting solids were triturated with diethyl ether to give the title compound (7 mg, 0.020 mmol) as yellow powder in 36% yield. were removed under vacuum The resulting mixture was purified on silica gel eluting with 3:2 hexane after solvent removal the resulting solids were triturated with diethyl ether

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

Procedure: Triethylamine (0.030 mL, 0.22 mmol), the title compound of Example 7 (15mg, 0.054 mmol) and 2-methyl-cyclopropanecarboxylic acid (6 mg, 0.062 mmol) were stirred in N,N-dimethylformamide (1.0 mL). O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (25 mg, 0.065 mmol) was added and the reaction was stirred overnight at which point the volatile components were removed under vacuum. The resulting mixture was purified on silica gel, eluting with 3:2 hexane:ethyl acetate. The purest fractions were combined and after solvent removal, the resulting solids were triturated with diethyl ether to give the title compound (7 mg, 0.020 mmol) as yellow powder in 36% yield. were removed under vacuum The resulting mixture was purified on silica gel eluting with 3:2 hexane after solvent removal the resulting solids were triturated with diethyl ether

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

Procedure: 2-Methylcyclopropanecarboxylic acid (0.86 g, 8.6 mmol) was dissolved in DCM (10 mL) and cooled to 0° C. The solution was treated with oxalyl chloride (1.2 mL, 13.8 mmol) and DMF (0.07 mL, 0.87 mmol), allowed to warm to RT, and stirred for 2 h for complete conversion to 2-methylcyclopropanecarboxylic acid chloride. The solution was cooled to 0° C. and added via syringe to a stirred solution of semicarbazide hydrochloride (1.4 g, 12.9 mmol) and NaOH (1.4 g, 34.4 mmol) in a mixture of dioxane (10 mL) and water (2.0 mL) at 0° C. The reaction mixture was allowed to warm to RT and stirred for 12 h. The organic solvent was evaporated in vacuo, and the resultant slurry was diluted with 2 M NaOH (aq) (50 mL, 100 mmol). The suspension was stirred at 100° C. for 24 h. The aqueous solution was saturated with solid NH4Cl and extracted with EtOAc (5×50 mL). The combined organics were dried (Na2SO4) and concentrated in vacuo to afford 3-(1-methylcyclopropyl)-1H-1,2,4-triazol-5(4H)-one (0.65 g, 54.3%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 11.02 (m, 2H), 1.26 (s, 3H), 0.90-0.89 (m, 2H), 0.66-0.65 (m, 2H); MS (ESI) m/z: 140.1 (M+H+). to warm to RT The solution was cooled to 0° C. to warm to RT The organic solvent was evaporated in vacuo The suspension was stirred at 100° C. for 24 h extracted with EtOAc (5×50 mL) The combined organics were dried (Na2SO4) concentrated in vacuo

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

Procedure: 2-Methylcyclopropanecarboxylic acid (0.86 g, 8.6 mmol) was dissolved in DCM (10 mL) and cooled to 0° C. The solution was treated with oxalyl chloride (1.2 mL, 13.8 mmol) and DMF (0.07 mL, 0.87 mmol), allowed to warm to RT, and stirred for 2 h for complete conversion to 2-methylcyclopropanecarboxylic acid chloride. The solution was cooled to 0° C. and added via syringe to a stirred solution of semicarbazide hydrochloride (1.4 g, 12.9 mmol) and NaOH (1.4 g, 34.4 mmol) in a mixture of dioxane (10 mL) and water (2.0 mL) at 0° C. The reaction mixture was allowed to warm to RT and stirred for 12 h. The organic solvent was evaporated in vacuo, and the resultant slurry was diluted with 2 M NaOH (aq) (50 mL, 100 mmol). The suspension was stirred at 100° C. for 24 h. The aqueous solution was saturated with solid NH4Cl and extracted with EtOAc (5×50 mL). The combined organics were dried (Na2SO4) and concentrated in vacuo to afford 3-(1-methylcyclopropyl)-1H-1,2,4-triazol-5(4H)-one (0.65 g, 54.3%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 11.02 (m, 2H), 1.26 (s, 3H), 0.90-0.89 (m, 2H), 0.66-0.65 (m, 2H); MS (ESI) m/z: 140.1 (M+H+). to warm to RT The solution was cooled to 0° C. to warm to RT The organic solvent was evaporated in vacuo The suspension was stirred at 100° C. for 24 h extracted with EtOAc (5×50 mL) The combined organics were dried (Na2SO4) concentrated in vacuo

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

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

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

Procedure: To an ice-cold solution of 2-methylcyclopropanecarboxylic acid (214 mg, 2.14 mmol) in dichloromethane (10 mL) was added oxalyl chloride (0.19 mL, 2.14 mmol) dropwise and a few drops of DMF. The ice bath was removed and stirring was continued for 1 h. 2-Amino-3-hydroxybenzoic acid hydrobromide (500 mg, 2.14 mmol) was added followed by triethylamine (0.90 mL, 6.42 mmol). The resulting reaction mixture was stirred at room temperature overnight. The reaction was quenched with aqueous 1 N HCl (25 mL) until the solution reached pH 1. The reaction mixture was extracted with dichloromethane. The combined organic layers were dried over Na2SO4, filtered and concentrated to a brown solid. The crude was dissolved in toluene (10 mL) and the solution was treated with p-toluenesulfonic acid monohydrate (574 mg, 3.0 mmol). The reaction mixture was then heated to reflux for 5 h. The reaction was cooled to room temperature, poured into water and extracted with ethyl acetate. The organic layer was separated then washed with water (5×150 mL), brine, dried (Na2SO4), filtered and concentrated to afford 2-(2-methylcyclopropyl)benzoxazole-4-carboxylic acid (409 mg, 88%) as a yellow solid: 1H NMR (500 MHz, DMSO-d6) δ 12.92 (br s, 1H), 7.84 (dd, J=8.1, 1.0 Hz, 1H), 7.81 (dd, J=7.8, 1.0 Hz, 1H), 7.38 (t, J=7.9 Hz, 1H), 2.10-2.05 (m, 1H), 1.62-1.57 (m, 1H), 1.41-1.34 (m, 1H), 1.28 (d, J=6.5 Hz, 3H), 1.08-1.02 (m, 1H); MS (ESI+) m/z 218 (M+H). The ice bath was removed The resulting reaction mixture was stirred at room temperature overnight The reaction was quenched with aqueous 1 N HCl (25 mL) until the solution The reaction mixture was extracted with dichloromethane The combined organic layers were dried over Na2SO4 filtered concentrated to a brown solid The crude was dissolved in toluene (10 mL) The reaction mixture was then heated to reflux for 5 h extracted with ethyl acetate The organic layer was separated then washed with water (5×150 mL), brine dried (Na2SO4) filtered concentrated

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

Conditions: temp:45.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 2-methylcyclopropanecarboxylic acid (commercial product which is a cis-trans mixture, 75.0 g, 0.75 mol) and 1 N NaOH (900 mL, 0.90 mol) is warmed and stirred at 45° C. To the stirring solution is added benzyl bromide (131.0 mL, 1.10 mol) and methyltrialkyl(C8-C10)ammonium chloride (Adogen™ 464, 37.5 g). The mixture is stirred at 40-45° C. for 4 h, cooled to room temperature, and extracted with ethyl ether (800 mL). The organic layer is dried (MgSO4) and evaporated to a liquid. Chromatography over silica gel, eluting with hexanes gradually increasing to 5% ethyl acetate in hexanes, provides the racemic benzyl trans-2-methylcyclopropanecarboxylate as a liquid (132.2 g, 93%); 1H NMR (DMSO-d6) δ 7.40 (m, 5H), 5.05 (s, 2H), 1.43 (m, 1H), 1.30 (m, 1H), 1.06 (d, J=6.0 Hz, 3H), 1.02 (m, 2H), 0.74 (m, 1H). [Note: If NMR reveals the presence of a minor amount of cis isomer, it is removable by the chiral HPLC separation which may be carried out as described above.] is warmed The mixture is stirred at 40-45° C. for 4 h cooled to room temperature extracted with ethyl ether (800 mL) The organic layer is dried (MgSO4) evaporated to a liquid Chromatography over silica gel, eluting with hexanes gradually increasing to 5% ethyl acetate in hexanes