benzyl N-(4-aminobutyl)carbamate

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: The compound (413 mg) obtained in Example 2-2 and N-benzyloxycarbonyl-1,4-diaminobutane (247 mg) were dissolved in anhydrous DMF (8.0 ml) and added with WSCI hydrochloride (234 mg) and HOBt (165 mg), followed by stirring at room temperature for 14 hours. After completion of the reaction, the solvent was distilled off. The residue was dissolved in chloroform, washed with 1 mol/l hydrochloric acid, a 1 mol/l sodium hydroxide aqueous solution, and saturated saline solution, and dried with anhydrous magnesium sulfate, followed by distilling the solvent off. Subsequently, the residue was purified through silica gel column chromatography (chloroform/methanol/water) and treated with hydrochloric acid, thereby obtaining hydrochloride (23.0 mg) of the subject compound as a white solid. After completion of the reaction the solvent was distilled off The residue was dissolved in chloroform washed with 1 mol/l hydrochloric acid a 1 mol/l sodium hydroxide aqueous solution, and saturated saline solution, and dried with anhydrous magnesium sulfate by distilling the solvent off Subsequently, the residue was purified through silica gel column chromatography (chloroform/methanol/water) treated with hydrochloric acid

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

Procedure: To a solution of 1,4-diaminopentane (25 g, 155 mmol) in 100 mL DMF/H2O (1:1) was added 5N NaOH to adjust the pH to 9. CBZ-Cl (3.7 mL, 26 mmol) was added as one portion and stirred at room temperature for 16 hrs. The reaction was acidified to pH 1.25 and washed with diethyl ether. The pH of the reaction was then adjusted to 9.5 and the reaction extracted with EtOAc. The organic layer was washed with H2O, brine, dried over Na2SO4 and evaporated to give title compound (1.57 g, 30%). washed with diethyl ether the reaction extracted with EtOAc The organic layer was washed with H2O, brine dried over Na2SO4 evaporated

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

Procedure: To a solution of 1,4-diaminopentane (25 g, 155 mmol) in 100 mL DMF/H2O (1:1) was added 5N NaOH to adjust the pH to 9. CBZ-Cl (3.7 mL, 26 mmol) was added as one portion and stirred at room temperature for 16 hrs. The reaction was acidified to pH 1.25 and washed with diethyl ether. The pH of the reaction was then adjusted to 9.5 and the reaction extracted with EtOAc. The organic layer was washed with H2O, brine, dried over Na2SO4 and evaporated to give title compound (1.57 g, 30%). washed with diethyl ether the reaction extracted with EtOAc The organic layer was washed with H2O, brine dried over Na2SO4 evaporated

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

Procedure: 1,4-butanediamine dihydrochloride (5.96 g, 37 mmol) was dissolved in water (15 mL), and DMF (50 mL) was added. With rapid stirring, CBZ-Cl (1.0 mL, 7.0 mmol) was added dropwise over 2 minutes. The cloudy solution had pH~2.8. The pH was adjusted to 9.0 with 5N NaOH, (clear solution) and stirred for 2 hr. The reaction mixture was acidified to pH=1.25, extracted with ether (2×), made basic (pH>10) with 5N NaOH, and extracted with dichloromethane (2×). The dichloromethane fractions were combined and washed with water (2×), dried and evaporated in vacuo to provide the crude mono-CBZ amine (0.72 g, 3.24 mmol, 46%) which was used as is in the next step. extracted with ether (2×) extracted with dichloromethane (2×) washed with water (2×) dried evaporated in vacuo

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

Procedure: 1,4-butanediamine dihydrochloride (5.96 g, 37 mmol) was dissolved in water (15 mL), and DMF (50 mL) was added. With rapid stirring, CBZ-Cl (1.0 mL, 7.0 mmol) was added dropwise over 2 minutes. The cloudy solution had pH~2.8. The pH was adjusted to 9.0 with 5N NaOH, (clear solution) and stirred for 2 hr. The reaction mixture was acidified to pH=1.25, extracted with ether (2×), made basic (pH>10) with 5N NaOH, and extracted with dichloromethane (2×). The dichloromethane fractions were combined and washed with water (2×), dried and evaporated in vacuo to provide the crude mono-CBZ amine (0.72 g, 3.24 mmol, 46%) which was used as is in the next step. extracted with ether (2×) extracted with dichloromethane (2×) washed with water (2×) dried evaporated in vacuo

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

Procedure: A mixture of 20 g of 4-benzyloxycarbonylamino-1-butylamine, 21.04 g of ethyl α-(phenethyl)acrylate and 200 ml of ethanol was stirred at room temperature for 8 days and evaporated to dryness. The residue was dissolved in ethyl ether and the solution was extracted three times with 100 ml of 2N hydrochloric acid. The aqueous layer was basified with 2N sodium hydroxide and extracted three times with methylene chloride, dried over magnesium sulfate and evaporated to give the ethyl 2-(4-benzyloxycarbonylaminobutyl)aminomethyl-4-phenylbutyrate having signals in the NMR spectrum at δ=7.4, 7.25, and 5.1 ppm. evaporated to dryness The residue was dissolved in ethyl ether the solution was extracted three times with 100 ml of 2N hydrochloric acid extracted three times with methylene chloride dried over magnesium sulfate evaporated

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

Procedure: A mixture of 20 g of 4-benzyloxycarbonylamino-1-butylamine, 21.04 g of ethyl α-(phenethyl)acrylate and 200 ml of ethanol was stirred at room temperature for 8 days and evaporated to dryness. The residue was dissolved in ethyl ether and the solution was extracted three times with 100 ml of 2N hydrochloric acid. The aqueous layer was basified with 2N sodium hydroxide and extracted three times with methylene chloride, dried over magnesium sulfate and evaporated to give the ethyl 2-(4-benzyloxycarbonylaminobutyl)aminomethyl-4-phenylbutyrate having signals in the NMR spectrum at δ=7.4, 7.25, and 5.1 ppm. evaporated to dryness The residue was dissolved in ethyl ether the solution was extracted three times with 100 ml of 2N hydrochloric acid extracted three times with methylene chloride dried over magnesium sulfate evaporated

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

Procedure: To a solution of 147 g of 1,4-diaminobutane in 490 ml of methylene chloride, a solution of 41 ml of benzyl chloroformate in 84 ml of methylene chloride was added dropwise at 0° over a period of 1 hour. The mixture was stirred at 0° for 1 hour, then washed twice with water and extracted four times with 150 ml of 4N hydrochloric acid. The acidic extracts were washed with methylene chloride, basified with 450 ml of 22% of sodium hydroxide and extracted four times with methylene chloride. The organic extracts were dried over magnesium sulfate and evaporated to give 4-benzyloxycarbonylamino-1-butylamine, having NMR peaks at δ=7.3, 5.05 and 2.6 ppm. washed twice with water extracted four times with 150 ml of 4N hydrochloric acid The acidic extracts were washed with methylene chloride extracted four times with methylene chloride The organic extracts were dried over magnesium sulfate evaporated

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

Procedure: A solution of 46 g of methane sulfonic acid in 50 ml of water was added without exceeding 30° C. to a mixture of 23 g of 1,4-diamino butane and 50 ml of water and the reaction medium was diluted with 140 ml of ethanol. A solution of 39 g of benzyl chloroformate in 50 ml of 1,2-dimethoxy ethane and 100 ml of a 50% aqueous solution of potassium acetate were added alternately at pH 3.5 to 5.0. The additions were made alternately to maintain the pH value between 3.5 and 5.0. The mixture was stirred for 90 minutes at 20° to 25° C. and evaporated under reduced pressure. The residue was poured over 500 ml of water and the insoluble part was filtered off. The filtrate was washed 3 times with 150 ml of benzene, and then 100 ml of 30% sodium hydroxide saturated with sodium chloride were added. After extraction with benzene, the extracts were evaporated to dryness under reduced pressure to obtain 19.10 g of the expected product. to maintain the pH value between 3.5 and 5.0 evaporated under reduced pressure The residue was poured over 500 ml of water the insoluble part was filtered off The filtrate was washed 3 times with 150 ml of benzene 100 ml of 30% sodium hydroxide saturated with sodium chloride were added After extraction with benzene the extracts were evaporated to dryness under reduced pressure

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

Procedure: Into 30 mL of 50% aqueous methanol, was dissolved 1.76 g (20 mmoles) of 1,4-butanediamine followed by the addition of 5.48 g (20 mmoles) of S-benzyloxycarbonyl-4,6-dimethyl-2-mercaptopyrimidine (a product of Kokusan Kagaku Co.). The mixture was stirred for 3 hours. Thereafter, the reaction mixture was filtered to remove the precipitated di-N-benzyloxycarbonyl compound [2.09 g (29%) were recovered], and the filtrate was evaporated to dryness. The residue was dissolved in 250 mL of chloroform, washed 5 times with 100 mL of water. The chloroform layer was dried over anhydrous sodium sulfate, and evaporated to dryness to obtain 1.0 g (23% yield) of mono-N-benzyloxycarbonyl-1,4-butanediamine in colorless syrup form. Thereafter, the reaction mixture was filtered to remove the precipitated di-N-benzyloxycarbonyl compound [2.09 g (29%) were recovered] the filtrate was evaporated to dryness The residue was dissolved in 250 mL of chloroform washed 5 times with 100 mL of water The chloroform layer was dried over anhydrous sodium sulfate evaporated to dryness