Carbamic acid, [1-(2-hydroxyethyl)cyclopropyl]-, 1,1-dimethylethyl ester (9CI)

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a cooled solution of tert-butyl [1-(2-hydroxyethyl)cyclopropyl]carbamate (8.0 g, 0.04 mol) and triethylamine (12.14 g) in anhydrous tetrahydrofuran (120 mL) at −20° C. was added a solution of mesyl chloride (17.8 g) in anhydrous tetrahydrofuran (30 mL). The resulting mixture was allowed to warm to room temperature and stirred at this temperature for 2 hours. The resulting mixture was poured into ice-water (50 mL) and the separated organic layer was washed with brine (100 mL), dried over sodium sulfate and concentrated in vacuo. The residue was triturated with petroleum ether and filtered to give 9.5 g of the pure product as an orange solid (yield was 95%). the separated organic layer was washed with brine (100 mL) dried over sodium sulfate concentrated in vacuo The residue was triturated with petroleum ether filtered

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a cooled solution of tert-butyl [1-(2-hydroxyethyl)cyclopropyl]carbamate (8.0 g, 0.04 mol) and triethylamine (12.14 g) in anhydrous tetrahydrofuran (120 mL) at −20° C. was added a solution of mesyl chloride (17.8 g) in anhydrous tetrahydrofuran (30 mL). The resulting mixture was allowed to warm to room temperature and stirred at this temperature for 2 hours. The resulting mixture was poured into ice-water (50 mL) and the separated organic layer was washed with brine (100 mL), dried over sodium sulfate and concentrated in vacuo. The residue was triturated with petroleum ether and filtered to give 9.5 g of the pure product as an orange solid (yield was 95%). the separated organic layer was washed with brine (100 mL) dried over sodium sulfate concentrated in vacuo The residue was triturated with petroleum ether filtered

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: RuCl3.H2O (124 mg, 0.6 mmol) was added to a solution of tert-butyl 1-(2-hydroxyethyl)cyclopropylcarbamate (6.1 g, 30 mmol), and NaIO4 (19.0 g, 90 mmol) in DCM/H2O/CH3CN (20 mL/40 mL/20 mL). The mixture was stirred at rt for 3 hrs. The mixture was then diluted with H2O (100 mL), and extracted with DCM (3×). The combined organic layer was dried over Na2SO4 and concentrated. The residue was purified by silica gel column chromatography (0-30% gradient elution EtOAc/petroleum ether) to afford 2-(1-(tert-butoxycarbonylamino)cyclopropyl)acetic acid (6.0 g, 90%) as a white solid. ESI-MS (EI+, m/z): 238 [M+Na]+. extracted with DCM (3×) The combined organic layer was dried over Na2SO4 concentrated The residue was purified by silica gel column chromatography (0-30% gradient elution EtOAc/petroleum ether)

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A solution of tert-butyl 1-(2-(tert-butyldimethylsilyloxy)ethyl)cyclopropylcarbamate (11.9 g, 37.8 mmol) and 3HF.TEA (22.0 g) in DCM (50 mL) was stirred at rt for 17 hrs. The mixture was concentrated and the residue was purified by silica gel column chromatography (0-20% gradient elution EtOAc/petroleum ether) to afford tert-butyl 1-(2-hydroxyethyl)cyclopropylcarbamate (4.6 g, 60%) as a white solid. The mixture was concentrated the residue was purified by silica gel column chromatography (0-20% gradient elution EtOAc/petroleum ether)

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: RuCl3.H2O (124 mg, 0.6 mmol) was added to a solution of tert-butyl 1-(2-hydroxyethyl)cyclopropylcarbamate (6.1 g, 30 mmol), and NaIO4 (19.0 g, 90 mmol) in DCM/H2O/CH3CN (20 mL/40 mL/20 mL). The mixture was stirred at rt for 3 hrs. The mixture was then diluted with H2O (100 mL), and extracted with DCM (3×). The combined organic layer was dried over Na2SO4 and concentrated. The residue was purified by silica gel column chromatography (0˜30% gradient elution EtOAc/petroleum ether) to afford 2-(1-(tert-butoxycarbonylamino)cyclopropyl)acetic acid (6.0 g, 90%) as a white solid. ESI-MS (EI+, m/z): 238 [M+Na]+. extracted with DCM (3×) The combined organic layer was dried over Na2SO4 concentrated The residue was purified by silica gel column chromatography (0˜30% gradient elution EtOAc/petroleum ether)

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A solution of tert-butyl 1-(2-(tert-butyldimethylsilyloxy)ethyl)cyclopropylcarbamate (11.9 g, 37.8 mmol) and 3HF.TEA (22.0 g) in DCM (50 mL) was stirred at rt for 17 hrs. The mixture was concentrated and the residue was purified by silica gel column chromatography (0˜20% gradient elution EtOAc/petroleum ether) to afford tert-butyl 1-(2-hydroxyethyl)cyclopropylcarbamate (4.6 g, 60%) as a white solid. The mixture was concentrated the residue was purified by silica gel column chromatography (0˜20% gradient elution EtOAc/petroleum ether)

反応条件: temp:-20.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of 6.472 g (32.16 mmol) of tert-butyl 1-(2-hydroxyethyl)cyclopropylcarbamate in 61 ml of anhydrous dichloromethane was added 12.79 ml (91 mmol) of anhydrous triethylamine. The resulting mixture is cooled at −20° C. Then 3.54 ml (45.66 mmol) of mesyl chloride in 11 ml of anhydrous dichloromethane was added. The resulting mixture was stirred at room temperature for 2 h. The mixture was poured into ice-water and the organic layer was washed with saturated aqueous sodium chloride, dried over sodium sulfate and evaporated. The crude product was triturated with petroleum ether and filtered to give 7.82 g of pure product as an orange solid. Mp: 88-89° C. the organic layer was washed with saturated aqueous sodium chloride dried over sodium sulfate evaporated The crude product was triturated with petroleum ether filtered

反応条件: temp:35.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution in acetonitrile (275 mL) of the compound (11.1 g) obtained in step (4) above and 2,2,6,6-tetramethylpiperidin-1-oxyl free radical (602 mg), a sodium phosphate buffer (0.67 mol/L, pH 6.7, 206 mL) was added. After heating to 35° C., an aqueous solution of sodium hypochlorite (0.265%, 32.6 mL) and an aqueous solution of sodium chlorite (14.7%, 110 mL) were added simultaneously over a period of 2 hours and the mixture was stirred at that temperature for 55 hours. The mixture was cooled to room temperature and after adding water (400 mL), it was rendered basic with a solution of 2 mol/L sodium hydroxide in water. The reaction mixture was poured into an aqueous solution of sodium thiosulfate (5.75%, 291 mL) at 0° C. After washing with diethyl ether (750 mL), the aqueous layer was added to 2 mol/L hydrochloric acid (140 mL) for pH adjustment to between 2 and 3. The mixture was extracted with diethyl ether and ethyl acetate and the combined organic layers were washed with saturated brine and dried over anhydrous magnesium sulfate. The desiccant was removed by filtration and the filtrate was concentrated under reduced pressure. The resulting residue was crystallized with a liquid mixture of n-hexane/ethyl acetate to give {1-[(tert-butoxycarbonyl)amino]cyclopropyl}acetic acid as a colorless solid (9.45 g). The mixture was cooled to room temperature After washing with diethyl ether (750 mL) the aqueous layer was added to 2 mol/L hydrochloric acid (140 mL) for pH adjustment to between 2 and 3 The mixture was extracted with diethyl ether and ethyl acetate the combined organic layers were washed with saturated brine dried over anhydrous magnesium sulfate The desiccant was removed by filtration the filtrate was concentrated under reduced pressure The resulting residue was crystallized with a liquid mixture of n-hexane/ethyl acetate

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution in ethanol (112 mL) of the compound (16.3 g) obtained in step (3) above, 20% palladium hydroxide/carbon (3.25 g) was added and the mixture was stirred at 60° C. for 23 hours in a hydrogen atmosphere. After being cooled to room temperature, the reaction mixture was filtered through Celite (registered trademark). The filtrate was concentrated under reduced pressure to give tert-butyl[1-(2-hydroxyethyl)cyclopropyl]carbamate as a colorless solid (11.1 g). the reaction mixture was filtered through Celite (registered trademark) The filtrate was concentrated under reduced pressure

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: RuCl3.H2O (124 mg, 0.6 mmol) was added to a solution of tert-butyl 1-(2-hydroxyethyl)cyclopropylcarbamate (6.1 g, 30 mmol), and NaIO4 (19.0 g, 90 mmol) in DCM/H2O/CH3CN (20 mL/40 mL/20 mL). The mixture was stirred at rt for 3 hrs. The mixture was then diluted with H2O (100 mL), and extracted with DCM (3×). The combined organic layer was dried over Na2SO4 and concentrated. The residue was purified by silica gel column chromatography (0˜30% gradient elution EtOAc/petroleum ether) to afford 2-(1-(tert-butoxycarbonylamino)cyclopropyl)acetic acid (6.0 g, 90%) as a white solid. ESI-MS (EI+, m/z): 238 [M+Na]+. extracted with DCM (3×) The combined organic layer was dried over Na2SO4 concentrated The residue was purified by silica gel column chromatography (0˜30% gradient elution EtOAc/petroleum ether)

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A solution of tert-butyl 1-(2-(tert-butyldimethylsilyloxy)ethyl)cyclopropylcarbamate (11.9 g, 37.8 mmol) and 3HF.TEA (22.0 g) in DCM (50 mL) was stirred at rt for 17 hrs. The mixture was concentrated and the residue was purified by silica gel column chromatography (0˜20% gradient elution EtOAc/petroleum ether) to afford tert-butyl 1-(2-hydroxyethyl)cyclopropylcarbamate (4.6 g, 60%) as a white solid. The mixture was concentrated the residue was purified by silica gel column chromatography (0˜20% gradient elution EtOAc/petroleum ether)

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: RuCl3.H2O (124 mg, 0.6 mmol) was added to a solution of tert-butyl 1-(2-hydroxyethyl)cyclopropylcarbamate (6.1 g, 30 mmol), and NaIO4 (19.0 g, 90 mmol) in DCM/H2O/CH3CN (20 mL/40 mL/20 mL). The mixture was stirred at rt for 3 hrs. The mixture was then diluted with H2O (100 mL), and extracted with DCM (3×). The combined organic layer was dried over Na2SO4 and concentrated. The residue was purified by silica gel column chromatography (0˜30% gradient elution EtOAc/petroleum ether) to afford 2-(1-(tert-butoxycarbonylamino)cyclopropyl)acetic acid (6.0 g, 90%) as a white solid. ESI-MS (EI+, m/z): 238 [M+Na]+. extracted with DCM (3×) The combined organic layer was dried over Na2SO4 concentrated The residue was purified by silica gel column chromatography (0˜30% gradient elution EtOAc/petroleum ether)