2,2-dimethylbutanoic 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:

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

Procedure: To a stirring solution of 23.5 g (0.2 mole) 2,2-dimethylbutanoic acid in 150 ml. acetone, there is added 30 ml. triethylamine. The temperature is lowered to 0°, and 21.1 ml. (0.22 mol) ethyl chloroformate are added over one-half hour, keeping the temperature at 0°. At the end of the addition, the mixture is stirred for 15 minutes, keeping the temperature at 0°. At the end of this period, a solution of 26.0 g. (0.4 mole) sodium azide in 75 ml. of water is added over one-half hour, keeping the temperature at 0°. The resulting mixture is stirred one hour at 0°. At the end of this period, the mixture is poured into 750 ml. of ice water. This mixture is extracted 4 times with 200 ml. toluene. The toluene portions are combined and dried. The toluene solution is added dropwise to 150 ml. of toluene refluxing in a nitrogen atmosphere. After the addition is complete, the solution is heated to reflux until the IR shows the disappearance of the azide peak (about two and one-half hours). The solution is then cooled and 14.0 g. (0.2 mole) 2-aminopropionitrile are added. The resulting mixture is refluxed for 5 hours. At the end of this period, the toluene is removed at reduced pressure. The residue is put through a column of Silica AR CC7 using toluene:ethyl acetate, 80:20 as the liquid phase. The desired portions are combined and the toluene and ethyl acetate are removed under reduced pressure. The residue is recrystallized from ethyl acetate/cyclohexane to give the product, N-(1-cyanoethyl)-N'-(1,1-dimethylpropyl)urea, m.p. 129°-30°. Anal. Calcd. for C8H17N3O: C: 58.99, H: 9.35, N: 22.93; Found: C: 58.82, H: 9.13, N: 22.92. is lowered to 0° at 0° At the end of the addition at 0° at 0° The resulting mixture is stirred one hour at 0° At the end of this period, the mixture is poured into 750 ml This mixture is extracted 4 times with 200 ml dried The toluene solution is added dropwise to 150 ml After the addition the solution is heated to reflux until the IR The solution is then cooled The resulting mixture is refluxed for 5 hours At the end of this period, the toluene is removed at reduced pressure the toluene and ethyl acetate are removed under reduced pressure The residue is recrystallized from ethyl acetate/cyclohexane

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

Procedure: To a stirring solution of 23.5 g (0.2 mole) 2,2-dimethylbutanoic acid in 150 ml. acetone, there is added 30 ml. triethylamine. The temperature is lowered to 0°, and 21.1 ml. (0.22 mol) ethyl chloroformate are added over one-half hour, keeping the temperature at 0°. At the end of the addition, the mixture is stirred for 15 minutes, keeping the temperature at 0°. At the end of this period, a solution of 26.0 g. (0.4 mole) sodium azide in 75 ml. of water is added over one-half hour, keeping the temperature at 0°. The resulting mixture is stirred one hour at 0°. At the end of this period, the mixture is poured into 750 ml. of ice water. This mixture is extracted 4 times with 200 ml. toluene. The toluene portions are combined and dried. The toluene solution is added dropwise to 150 ml. of toluene refluxing in a nitrogen atmosphere. After the addition is complete, the solution is heated to reflux until the IR shows the disappearance of the azide peak (about two and one-half hours). The solution is then cooled and 14.0 g. (0.2 mole) 2-aminopropionitrile are added. The resulting mixture is refluxed for 5 hours. At the end of this period, the toluene is removed at reduced pressure. The residue is put through a column of Silica AR CC7 using toluene:ethyl acetate, 80:20 as the liquid phase. The desired portions are combined and the toluene and ethyl acetate are removed under reduced pressure. The residue is recrystallized from ethyl acetate/cyclohexane to give the product, N-(1-cyanoethyl)-N'-(1,1-dimethylpropyl)urea, m.p. 129°-30°. Anal. Calcd. for C8H17N3O: C: 58.99, H: 9.35, N: 22.93; Found: C: 58.82, H: 9.13, N: 22.92. is lowered to 0° at 0° At the end of the addition at 0° at 0° The resulting mixture is stirred one hour at 0° At the end of this period, the mixture is poured into 750 ml This mixture is extracted 4 times with 200 ml dried The toluene solution is added dropwise to 150 ml After the addition the solution is heated to reflux until the IR The solution is then cooled The resulting mixture is refluxed for 5 hours At the end of this period, the toluene is removed at reduced pressure the toluene and ethyl acetate are removed under reduced pressure The residue is recrystallized from ethyl acetate/cyclohexane

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

Procedure: 5 mmol of 2,2-dimethylbutyric acid, 5 mmol of triethylamine and 5 mmol of diphenyl phosphorazidate in 30 ml of anhydrous acetonitrile are stirred at 20° C. for 45 minutes and are then brought to reflux for 30 minutes. 6 mmol of 3-(1H-imidazol-4-yl)propanol.HCl are added and are brought to reflux for 40 hours. The mixture is evaporated and the residue dissolved in diethyl ether. The solution is washed successively with 30 ml of 5% aqueous citric acid, 30 ml of H2O and 30 ml of saturated aqueous NaHCO3. The organic layer is evaporated and the residue is purified by rotatory chromatography (eluent: chloroform/methanol (99:1-90:10)). After removal of the solvent under reduced pressure, the residue is crystallized in the form of hydrogen oxalate in diethyl ether and ethanol. to reflux for 30 minutes to reflux for 40 hours The mixture is evaporated the residue dissolved in diethyl ether The solution is washed successively with 30 ml of 5% aqueous citric acid, 30 ml of H2O and 30 ml of saturated aqueous NaHCO3 The organic layer is evaporated the residue is purified by rotatory chromatography (eluent: chloroform/methanol (99:1-90:10)) After removal of the solvent under reduced pressure the residue is crystallized in the form of hydrogen oxalate in diethyl ether and ethanol

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

Procedure: 5 mmol of 2,2-dimethylbutyric acid, 5 mmol of triethylamine and 5 mmol of diphenyl phosphorazidate in 30 ml of anhydrous acetonitrile are stirred at 20° C. for 45 minutes and are then brought to reflux for 30 minutes. 6 mmol of 3-(1H-imidazol-4-yl)propanol.HCl are added and are brought to reflux for 40 hours. The mixture is evaporated and the residue dissolved in diethyl ether. The solution is washed successively with 30 ml of 5% aqueous citric acid, 30 ml of H2O and 30 ml of saturated aqueous NaHCO3. The organic layer is evaporated and the residue is purified by rotatory chromatography (eluent: chloroform/methanol (99:1-90:10)). After removal of the solvent under reduced pressure, the residue is crystallized in the form of hydrogen oxalate in diethyl ether and ethanol. to reflux for 30 minutes to reflux for 40 hours The mixture is evaporated the residue dissolved in diethyl ether The solution is washed successively with 30 ml of 5% aqueous citric acid, 30 ml of H2O and 30 ml of saturated aqueous NaHCO3 The organic layer is evaporated the residue is purified by rotatory chromatography (eluent: chloroform/methanol (99:1-90:10)) After removal of the solvent under reduced pressure the residue is crystallized in the form of hydrogen oxalate in diethyl ether and ethanol

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

Procedure: 2,2-Dimethylbutyric acid (1 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 2,2-dimethylbutyric acid chloride. The solution was cooled to 0° C. and added 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. 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-(tert-pentyl)-1H-1,2,4-triazol-5(4H)-one (0.71 g, 53.1%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 11.17 (s, 1H), 11.02 (s, 1H), 1.49 (q, J=7.5 Hz, 2H), 1.11 (s, 6H), 0.68 (t, J=7.4 Hz, 3H); MS (ESI) m/z: 156.1 (M+H+). to warm to RT The solution was cooled to 0° C. to warm to RT 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: 2,2-Dimethylbutyric acid (1 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 2,2-dimethylbutyric acid chloride. The solution was cooled to 0° C. and added 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. 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-(tert-pentyl)-1H-1,2,4-triazol-5(4H)-one (0.71 g, 53.1%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 11.17 (s, 1H), 11.02 (s, 1H), 1.49 (q, J=7.5 Hz, 2H), 1.11 (s, 6H), 0.68 (t, J=7.4 Hz, 3H); MS (ESI) m/z: 156.1 (M+H+). to warm to RT The solution was cooled to 0° C. to warm to RT 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:; See reaction.notes.procedure_details.

Procedure: To a stirring solution of 23.5 g (0.2 mole) 2,2-dimethylbutanoic acid in 150 ml. acetone, there is added 30 ml. triethylamine. The temperature is lowered to 0°, and 21.1 ml. (0.22 mol) ethyl chloroformate are added over one-half hour, keeping the temperature at 0°. At the end of the addition, the mixture is stirred for 15 minutes, keeping the temperature at 0°. At the end of this period, a solution of 26.0 g. (0.4 mole) sodium azide in 75 ml. of water is added over one-half hour, keeping the temperature at 0°. The resulting mixture is stirred one hour at 0°. At the end of this period, the mixture is poured into 750 ml. of ice water. This mixture is extracted 4 times with 200 ml. toluene. The toluene portions are combined and dried. The toluene solution is added dropwise to 150 ml. of toluene refluxing in a nitrogen atmosphere. After the addition is complete, the solution is heated to reflux until the IR shows the disappearance of the azide peak (about two and one-half hours). The solution is then cooled and 14.0 g. (0.2 mole) 2-aminopropionitrile are added. The resulting mixture is refluxed for 5 hours. At the end of this period, the toluene is removed at reduced pressure. The residue is put through a column of Silica AR CC7 using toluene:ethyl acetate, 80:20 as the liquid phase. The desired portions are combined and the toluene and ethyl acetate are removed under reduced pressure. The residue is recrystallized from ethyl acetate/cyclohexane to give the product, N-(1-cyanoethyl)-N'-(1,1-dimethylpropyl)urea, m.p. 129°-30°. Anal. Calcd. for C8H17N3O: C: 58.99, H: 9.35, N: 22.93; Found: C: 58.82, H: 9.13, N: 22.92. is lowered to 0° at 0° At the end of the addition at 0° at 0° The resulting mixture is stirred one hour at 0° At the end of this period, the mixture is poured into 750 ml This mixture is extracted 4 times with 200 ml dried The toluene solution is added dropwise to 150 ml After the addition the solution is heated to reflux until the IR The solution is then cooled The resulting mixture is refluxed for 5 hours At the end of this period, the toluene is removed at reduced pressure the toluene and ethyl acetate are removed under reduced pressure The residue is recrystallized from ethyl acetate/cyclohexane

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

Procedure: In analogy to the procedure for Example 58A, 150 mg (0.67 mmol) 6-(1-aminopropyl)-3-cyclopentyl-1,2,4-triazin-5(4H)-one, 78 mg (0.67 mmol) 2,2-dimethylbutanoic acid and proportionate amounts of the other reagents are used. The crude product is used in the next step without further purification. The crude product is used in the next step without further purification