tert-butyl N-(4-hydroxybutyl)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:

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

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

Conditions: temp:-40.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: In a 25 ml flask 4-(t-butoxycarbonylamino)butanol was dissolved in tetrahydrofuran (15 ml) under a nitrogen atmosphere. The solution was cooled to −40° C. and potassium tert-butoxide (1M in tetrahydrofuran, 2.14 ml, 2.14 mmol) was added slowly. The resulting mixture was stirred at −40° C. for thirty minutes. To this reaction mixture was added 2-fluoro-5-bromobenzyl bromide (521 mg, 1.94 mmol), added dropwise as a solution in tetrahydrofuran (3.5 ml). The resulting mixture was slowly warmed to 0° C. and stirred at this temperature for two hours. The progress of the reaction was monitored by thin layer chromatography. The reaction mixture was partitioned between 1 M potassium carbonate and methylene chloride. The aqueous fraction was back-extracted with methylene chloride. The organic fractions were combined and dried over sodium sulfate. The solvents were removed in vacuo. The desired intermediate was further purified by liquid chromatography. The resulting mixture was slowly warmed to 0° C. stirred at this temperature for two hours The reaction mixture was partitioned between 1 M potassium carbonate and methylene chloride The aqueous fraction was back-extracted with methylene chloride dried over sodium sulfate The solvents were removed in vacuo The desired intermediate was further purified by liquid chromatography

Conditions: temp:-40.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: In a 25 ml flask 4-(t-butoxycarbonylamino)butanol was dissolved in tetrahydrofuran (15 ml) under a nitrogen atmosphere. The solution was cooled to −40° C. and potassium tert-butoxide (1M in tetrahydrofuran, 2.14 ml, 2.14 mmol) was added slowly. The resulting mixture was stirred at −40° C. for thirty minutes. To this reaction mixture was added 2-fluoro-5-bromobenzyl bromide (521 mg, 1.94 mmol), added dropwise as a solution in tetrahydrofuran (3.5 ml). The resulting mixture was slowly warmed to 0° C. and stirred at this temperature for two hours. The progress of the reaction was monitored by thin layer chromatography. The reaction mixture was partitioned between 1 M potassium carbonate and methylene chloride. The aqueous fraction was back-extracted with methylene chloride. The organic fractions were combined and dried over sodium sulfate. The solvents were removed in vacuo. The desired intermediate was further purified by liquid chromatography. The resulting mixture was slowly warmed to 0° C. stirred at this temperature for two hours The reaction mixture was partitioned between 1 M potassium carbonate and methylene chloride The aqueous fraction was back-extracted with methylene chloride dried over sodium sulfate The solvents were removed in vacuo The desired intermediate was further purified by liquid chromatography

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

Procedure: To a mixture of tert-butyl 4-hydroxybutylcarbamate (3.71 g) obtained in Reference Example 35 and ethyl acetate (20 mL) were added pyridine (1.71 mL) and ethyl chlorocarbonate (2.55 g) under ice-cooling, and the mixture was stirred at room temperature for 24 hrs. Ethyl acetate (100 mL) was added to the reaction mixture, and the mixture was washed with water (50 mL), an aqueous copper sulfate solution (30 ml), water (30 mL) and saturated brine (30 mL) and dried over anhydrous magnesium sulfate. Concentration under reduced pressure gave the title compound (4.92 g) as a colorless oil. cooling the mixture was washed with water (50 mL) an aqueous copper sulfate solution (30 ml), water (30 mL) and saturated brine (30 mL) and dried over anhydrous magnesium sulfate Concentration under reduced pressure

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

Procedure: To a mixture of tert-butyl 4-hydroxybutylcarbamate (3.71 g) obtained in Reference Example 35 and ethyl acetate (20 mL) were added pyridine (1.71 mL) and ethyl chlorocarbonate (2.55 g) under ice-cooling, and the mixture was stirred at room temperature for 24 hrs. Ethyl acetate (100 mL) was added to the reaction mixture, and the mixture was washed with water (50 mL), an aqueous copper sulfate solution (30 ml), water (30 mL) and saturated brine (30 mL) and dried over anhydrous magnesium sulfate. Concentration under reduced pressure gave the title compound (4.92 g) as a colorless oil. cooling the mixture was washed with water (50 mL) an aqueous copper sulfate solution (30 ml), water (30 mL) and saturated brine (30 mL) and dried over anhydrous magnesium sulfate Concentration under reduced pressure

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

Procedure: To a mixture of tert-butyl 4-hydroxybutylcarbamate (3.83 g) obtained in Reference Example 35 and ethyl acetate (20 mL) were added pyridine (1.80 mL) and acetic anhydride (2.27 g), and the mixture was stirred at room temperature for 19 hrs. Ethyl acetate (100 mL) was added to the reaction mixture, and the mixture was washed with water (50 mL), an aqueous copper sulfate solution (30 mL), water (30 mL) and saturated brine (30 mL) and dried over anhydrous magnesium sulfate. Concentration under reduced pressure gave the title compound (4.55 g) as a colorless oil. the mixture was washed with water (50 mL) an aqueous copper sulfate solution (30 mL), water (30 mL) and saturated brine (30 mL) and dried over anhydrous magnesium sulfate Concentration under reduced pressure

Conditions: temp:-10.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Methyl 4-fluoro-2-hydroxybenzoate (21 mmol), tert-butyl 4-hydroxybutylcarbamate (21 mmol) and triphenyl phosphine (24 mmol) in THF (70 ml) was cooled to −10° C. Then, DIAD (43 mmol) was added. The mixture was stirred for 30 min at −10° C. under N2. The ice-bath was removed and the mixture was stirred overnight at 20° C. The solvent was removed under vacuum. The residue was washed with petroleum and diethyl ether. The white solid was filtered and it was confirmed to be triphenylphosphine oxide (PPh3═O). The filtrate was evaporated to dryness. The residue was purified with flash column (petroleum/ethyl acetate 100:0 to 5:1). Yield: 8.18 g (purity 90%, yield 98%). The ice-bath was removed the mixture was stirred overnight at 20° C The solvent was removed under vacuum The residue was washed with petroleum and diethyl ether The white solid was filtered The filtrate was evaporated to dryness The residue was purified with flash column (petroleum/ethyl acetate 100:0 to 5:1)

Conditions: temp:-10.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Methyl 4-fluoro-2-hydroxybenzoate (21 mmol), tert-butyl 4-hydroxybutylcarbamate (21 mmol) and triphenyl phosphine (24 mmol) in THF (70 ml) was cooled to −10° C. Then, DIAD (43 mmol) was added. The mixture was stirred for 30 min at −10° C. under N2. The ice-bath was removed and the mixture was stirred overnight at 20° C. The solvent was removed under vacuum. The residue was washed with petroleum and diethyl ether. The white solid was filtered and it was confirmed to be triphenylphosphine oxide (PPh3═O). The filtrate was evaporated to dryness. The residue was purified with flash column (petroleum/ethyl acetate 100:0 to 5:1). Yield: 8.18 g (purity 90%, yield 98%). The ice-bath was removed the mixture was stirred overnight at 20° C The solvent was removed under vacuum The residue was washed with petroleum and diethyl ether The white solid was filtered The filtrate was evaporated to dryness The residue was purified with flash column (petroleum/ethyl acetate 100:0 to 5:1)