4-methoxybutanoic acid

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

Procedure: Piperidine (1.0 mL, 10 mmol) was added to a solution of (S)-2-(9H-fluoren-9-yl)methoxy)carbonylamino)-4-methoxybutanoic acid (0.355 g, 1 mmol) in DMF (3 mL), and the mixture was stirred at rt for 3 h. The volatiles were removed and the residue was partitioned between sat. NaHCO3 (aq.) (5 mL) and EtOAc (5 mL). The aqueous layer was further washed with EtOAc and Et2O. To the aqueous solution was added Na2CO3 (212 mg, 2.0 mmol) followed by methyl chloroformate (0.16 mL, 2.0 mmol) and the reaction mixture was stirred at rt for 16 h. The reaction mixture was acidified with 1 N HCl (aq.) until pH <7 and then extracted with EtOAc (2×10 mL). The combined organic layers were dried (Na2SO4), filtered and concentrated. The residue was purified by flash silica chromatography (EtOAc/hexanes, gradient from 20% to 70%) to yield (S)-4-methoxy-2-(methoxycarbonylamino)butanoic acid (Cap-194) (91.5 mg) as viscous colorless oil. LC-MS retention time=0.61 min; m/z 214 [M+Na]+. (Column: PHENOMENEX® Luna 3.0×50 mm S10. Solvent A=90% Water:10% Methanol: 0.1% TFA. Solvent B=10% Water:90% Methanol: 0.1% TFA. Flow Rate=4 mL/min. Start % B=0. Final % B=100. Gradient Time=3 min. Wavelength=220). 1H NMR (400 MHz, chloroform-d) δ ppm 7.41 (br. s., 1 H), 5.74-6.02 (m, 1 H), 4.32-4.56 (m, 1 H), 3.70 (s, 3 H), 3.54 (t, J=5.0 Hz, 2 H), 3.34 (s, 3 H), 1.99-2.23 (m, 2 H). The volatiles were removed the residue was partitioned between sat. NaHCO3 (aq.) (5 mL) and EtOAc (5 mL) The aqueous layer was further washed with EtOAc and Et2O the reaction mixture was stirred at rt for 16 h extracted with EtOAc (2×10 mL) The combined organic layers were dried (Na2SO4) filtered concentrated The residue was purified by flash silica chromatography (EtOAc/hexanes, gradient from 20% to 70%)

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

Procedure: Carbazic acid tert-butyl ester (9.21 g) was dissolved in pyridine (120 ml), followed by addition of 4-methoxybutyric acid (9.06 g) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride salt (20.0 g), and stirred at ambient temperature for 64 hours. After the reaction solution was concentrated under reduced pressure, ethyl acetate was added to the residue, which was then washed with aqueous 1 mol/liter hydrochloric acid solution, saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride, and dried over anhydrous sodium sulfate. After the solvent was evaporated under reduced pressure, N′-(4-methoxybutyryl)hydrazine carboxylic acid tert-butyl ester was obtained in yellow oil (9.30 g, 57%). The physico-chemical values are as follows. After the reaction solution was concentrated under reduced pressure, ethyl acetate was added to the residue, which was then washed with aqueous 1 mol/liter hydrochloric acid solution, saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride dried over anhydrous sodium sulfate After the solvent was evaporated under reduced pressure

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

Procedure: Carbazic acid tert-butyl ester (9.21 g) was dissolved in pyridine (120 ml), followed by addition of 4-methoxybutyric acid (9.06 g) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride salt (20.0 g), and stirred at ambient temperature for 64 hours. After the reaction solution was concentrated under reduced pressure, ethyl acetate was added to the residue, which was then washed with aqueous 1 mol/liter hydrochloric acid solution, saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride, and dried over anhydrous sodium sulfate. After the solvent was evaporated under reduced pressure, N′-(4-methoxybutyryl)hydrazine carboxylic acid tert-butyl ester was obtained in yellow oil (9.30 g, 57%). The physico-chemical values are as follows. After the reaction solution was concentrated under reduced pressure, ethyl acetate was added to the residue, which was then washed with aqueous 1 mol/liter hydrochloric acid solution, saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride dried over anhydrous sodium sulfate After the solvent was evaporated under reduced pressure

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

Procedure: Piperidine (1.0 mL, 10 mmol) was added to a solution of (S)-2-(9H-fluoren-9-yl)methoxy)carbonylamino)-4-methoxybutanoic acid (0.355 g, 1 mmol) in DMF (3 mL), and the mixture was stirred at rt for 3 h. The volatiles were removed and the residue was partitioned between sat. NaHCO3 (aq.) (5 mL) and EtOAc (5 mL). The aqueous layer was further washed with EtOAc and Et2O. To the aqueous solution was added Na2CO3 (212 mg, 2.0 mmol) followed by methyl chloroformate (0.16 mL, 2.0 mmol) and the reaction mixture was stirred at rt for 16 h. The reaction mixture was acidified with 1 N HCl (aq.) until pH<7 and then extracted with EtOAc (2×10 mL). The combined organic layers were dried (Na2SO4), filtered and concentrated. The residue was purified by flash silica chromatography (EtOAc/hexanes, gradient from 20% to 70%) to yield (S)-4-methoxy-2-(methoxycarbonylamino)butanoic acid (Cap-194) (91.5 mg) as viscous colorless oil. LC-MS retention time=0.61 min; m/z 214 [M+Na]+. (Column: PHENOMENEX® Luna 3.0×50 mm S10. Solvent A=90% Water: 10% Methanol: 0.1% TFA. Solvent B=10% Water: 90% Methanol: 0.1% TFA. Flow Rate=4 mL/min. Start % B=0. Final % B=100. Gradient Time=3 min. Wavelength=220). 1H NMR (400 MHz, chloroform-d) δ ppm 7.41 (br. s., 1H), 5.74-6.02 (m, 1H), 4.32-4.56 (m, 1H), 3.70 (s, 3H), 3.54 (t, J=5.0 Hz, 2H), 3.34 (s, 3H), 1.99-2.23 (m, 2H). The volatiles were removed the residue was partitioned between sat. NaHCO3 (aq.) (5 mL) and EtOAc (5 mL) The aqueous layer was further washed with EtOAc and Et2O the reaction mixture was stirred at rt for 16 h extracted with EtOAc (2×10 mL) The combined organic layers were dried (Na2SO4) filtered concentrated The residue was purified by flash silica chromatography (EtOAc/hexanes, gradient from 20% to 70%)

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

Procedure: A solution of 4 g of methyl 2,3-diaminobenzoate and 8.53 g of 4-methoxybutyric acid in 70 ml of 4N HCl is stirred at reflux over 21 hours. The reaction mixture is cooled to room temperature and partitioned between ethyl acetate and water. The aqueous phase is concentrated by evaporation—the residue is diluted with 100 ml of methanol and 2 ml of conc. H2SO4 and stirred at reflux over 45 hours. The reaction mixture is cooled to room temperature, neutralized with saturated aqueous sodium bicarbonate solution and concentrated by evaporation. The residue is diluted with water and extracted with ethyl acetate (2×)—the combined organic phases are dried over sodium sulphate and concentrated by evaporation. The title compound is obtained as a red solid from the residue by means of flash chromatography (SiO2 60F). Rf=0.31 (95:5 dichloromethane-methanol); Rt=2.53. at reflux over 21 hours partitioned between ethyl acetate and water The aqueous phase is concentrated by evaporation—the residue is diluted with 100 ml of methanol and 2 ml of conc. H2SO4 at reflux over 45 hours The reaction mixture is cooled to room temperature concentrated by evaporation The residue is diluted with water extracted with ethyl acetate (2×)—the combined organic phases are dried over sodium sulphate concentrated by evaporation

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

Procedure: A solution of 4 g of methyl 2,3-diaminobenzoate and 8.53 g of 4-methoxybutyric acid in 70 ml of 4N HCl is stirred at reflux over 21 hours. The reaction mixture is cooled to room temperature and partitioned between ethyl acetate and water. The aqueous phase is concentrated by evaporation—the residue is diluted with 100 ml of methanol and 2 ml of conc. H2SO4 and stirred at reflux over 45 hours. The reaction mixture is cooled to room temperature, neutralized with saturated aqueous sodium bicarbonate solution and concentrated by evaporation. The residue is diluted with water and extracted with ethyl acetate (2×)—the combined organic phases are dried over sodium sulphate and concentrated by evaporation. The title compound is obtained as a red solid from the residue by means of flash chromatography (SiO2 60F). Rf=0.31 (95:5 dichloromethane-methanol); Rt=2.53. at reflux over 21 hours partitioned between ethyl acetate and water The aqueous phase is concentrated by evaporation—the residue is diluted with 100 ml of methanol and 2 ml of conc. H2SO4 at reflux over 45 hours The reaction mixture is cooled to room temperature concentrated by evaporation The residue is diluted with water extracted with ethyl acetate (2×)—the combined organic phases are dried over sodium sulphate concentrated by evaporation

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

Procedure: Piperidine (1.0 mL, 10 mmol) was added to a solution of (S)-2-(9H-fluoren-9-yl)methoxy)carbonylamino)-4-methoxybutanoic acid (0.355 g, 1 mmol) in DMF (3 mL), and the mixture was stirred at rt for 3 h. The volatiles were removed and the residue was partitioned between sat. NaHCO3 (aq.) (5 mL) and EtOAc (5 mL). The aqueous layer was further washed with EtOAc and Et2O. To the aqueous solution was added Na2CO3 (212 mg, 2.0 mmol) followed by methyl chloroformate (0.16 mL, 2.0 mmol) and the reaction mixture was stirred at rt for 16 h. The reaction mixture was acidified with 1 N HCl (aq.) until pH <7 and then extracted with EtOAc (2×10 mL). The combined organic layers were dried (Na2SO4), filtered and concentrated. The residue was purified by flash silica chromatography (EtOAc/hexanes, gradient from 20% to 70%) to yield (S)-4-methoxy-2-(methoxycarbonylamino)butanoic acid (Cap-194) (91.5 mg) as viscous colorless oil. LC-MS retention time=0.61 min; m/z 214 [M+Na]+. (Column: PHENOMENEX® Luna 3.0×50 mm S10. Solvent A=90% Water:10% Methanol: 0.1% TFA. Solvent B=10% Water:90% Methanol: 0.1% TFA. Flow Rate=4 mL/min. Start % B=0. Final % B=100. Gradient Time=3 min. Wavelength=220). 1H NMR (400 MHz, chloroform-d) δ ppm 7.41 (br. s., 1 H), 5.74-6.02 (m, 1 H), 4.32-4.56 (m, 1 H), 3.70 (s, 3 H), 3.54 (t, J=5.0 Hz, 2 H), 3.34 (s, 3 H), 1.99-2.23 (m, 2 H). The volatiles were removed the residue was partitioned between sat. NaHCO3 (aq.) (5 mL) and EtOAc (5 mL) The aqueous layer was further washed with EtOAc and Et2O the reaction mixture was stirred at rt for 16 h extracted with EtOAc (2×10 mL) The combined organic layers were dried (Na2SO4) filtered concentrated The residue was purified by flash silica chromatography (EtOAc/hexanes, gradient from 20% to 70%)

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

Procedure: Carbazic acid tert-butyl ester (9.21 g) was dissolved in pyridine (120 ml), followed by addition of 4-methoxybutyric acid (9.06 g) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride salt (20.0 g), and stirred at ambient temperature for 64 hours. After the reaction solution was concentrated under reduced pressure, ethyl acetate was added to the residue, which was then washed with aqueous 1 mol/liter hydrochloric acid solution, saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride, and dried over anhydrous sodium sulfate. After the solvent was evaporated under reduced pressure, N′-(4-methoxybutyryl)hydrazine carboxylic acid tert-butyl ester was obtained in yellow oil (9.30 g, 57%). The physico-chemical values are as follows. After the reaction solution was concentrated under reduced pressure, ethyl acetate was added to the residue, which was then washed with aqueous 1 mol/liter hydrochloric acid solution, saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride dried over anhydrous sodium sulfate After the solvent was evaporated under reduced pressure