tert-butyl 4-fluoro-5-oxoazepane-1-carboxylate

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:-5.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a tert-butyl 4-fluoro-5-oxoazepane-1-carboxylate (20.0 g, 86.5 mmol) was dissolved in THF (430 mL) solution and the solution was cooled to −5° C. L-Selectride (112 mL, 112 mmol, 1.0 M in THF) was added via syringe. The mixture was gradually warmed to ambient temperature over 3 hours and stirred for an additional 20 hours. The resulting cloudy mixture was diluted with 110 mL of MeOH, followed by addition of NaOH (355 mL, 355 mmol, 1.0M aqueous). The mixture was cooled in a water bath and H2O2 (80.4 mL, 709 mmol, 30% aqueous) was added carefully via addition funnel over 30 minutes. The mixture was stirred vigorously for 1 hour. The mixture was diluted with water and extracted with EtOAc (3×200 mL). The combined organic layers were washed with water and 1N KHSO4 (2×150 mL), and the combined aqueous phases were back extracted with EtOAc (200 mL). The combined organic layers were washed with saturated aqueous NaHCO3, dried over Na2SO4, filtered and concentrated. The crude product was purified via column chromatography (15% to 60% EtOAc/hexanes) to provide the product as a thick colorless oil which slowly became a white solid (13.9 g, 69%; diastereomeric ratio (dr): ˜7:1 trans:cis). The mixture was gradually warmed to ambient temperature over 3 hours The mixture was cooled in a water bath The mixture was stirred vigorously for 1 hour extracted with EtOAc (3×200 mL) The combined organic layers were washed with water and 1N KHSO4 (2×150 mL) the combined aqueous phases were back extracted with EtOAc (200 mL) The combined organic layers were washed with saturated aqueous NaHCO3 dried over Na2SO4 filtered concentrated The crude product was purified via column chromatography (15% to 60% EtOAc/hexanes)

反応条件: temp:-5.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a tert-butyl 4-fluoro-5-oxoazepane-1-carboxylate (20.0 g, 86.5 mmol) was dissolved in THF (430 mL) solution and the solution was cooled to −5° C. L-Selectride (112 mL, 112 mmol, 1.0 M in THF) was added via syringe. The mixture was gradually warmed to ambient temperature over 3 hours and stirred for an additional 20 hours. The resulting cloudy mixture was diluted with 110 mL of MeOH, followed by addition of NaOH (355 mL, 355 mmol, 1.0M aqueous). The mixture was cooled in a water bath and H2O2 (80.4 mL, 709 mmol, 30% aqueous) was added carefully via addition funnel over 30 minutes. The mixture was stirred vigorously for 1 hour. The mixture was diluted with water and extracted with EtOAc (3×200 mL). The combined organic layers were washed with water and 1N KHSO4 (2×150 mL), and the combined aqueous phases were back extracted with EtOAc (200 mL). The combined organic layers were washed with saturated aqueous NaHCO3, dried over Na2SO4, filtered and concentrated. The crude product was purified via column chromatography (15% to 60% EtOAc/hexanes) to provide the product as a thick colorless oil which slowly became a white solid (13.9 g, 69%; diastereomeric ratio (dr): ˜7:1 trans:cis). The mixture was gradually warmed to ambient temperature over 3 hours The mixture was cooled in a water bath The mixture was stirred vigorously for 1 hour extracted with EtOAc (3×200 mL) The combined organic layers were washed with water and 1N KHSO4 (2×150 mL) the combined aqueous phases were back extracted with EtOAc (200 mL) The combined organic layers were washed with saturated aqueous NaHCO3 dried over Na2SO4 filtered concentrated The crude product was purified via column chromatography (15% to 60% EtOAc/hexanes)

反応条件: temp:-5.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a tert-butyl 4-fluoro-5-oxoazepane-1-carboxylate (20.0 g, 86.5 mmol) was dissolved in THF (430 mL) solution and the solution was cooled to −5° C. L-selectride (112 mL, 112 mmol, 1.0 M in THF) was added via syringe. The mixture was gradually warmed to ambient temperature over 3 hours and stirred for an additional 20 hours. The resulting cloudy mixture was diluted with 110 mL of MeOH which was followed by the addition of NaOH (355 mL, 355 mmol, 1.0M aqueous). The mixture was cooled in a water bath, and H2O2 (80.4 mL, 709 mmol, 30% aqueous) was added carefully via addition funnel over 30 minutes. The mixture was stirred vigorously for 1 hour, then diluted with water and extracted with EtOAc (3×200 mL). The combined organic layers were washed with water and 1N KHSO4 (2×150 mL), and the combined aqueous phases were back-extracted with EtOAc (200 mL). The combined organic layers were washed with saturated aqueous NaHCO3, then dried over Na2SO4, filtered and concentrated. The crude product was purified via column chromatography (15% to 60% EtOAc/hexanes) to provide the product as a thick colorless oil which slowly became a white solid (13.9 g, 69%; diastereomeric ratio (dr): ˜7:1 trans:cis). The mixture was gradually warmed to ambient temperature over 3 hours The mixture was cooled in a water bath The mixture was stirred vigorously for 1 hour extracted with EtOAc (3×200 mL) The combined organic layers were washed with water and 1N KHSO4 (2×150 mL) the combined aqueous phases were back-extracted with EtOAc (200 mL) The combined organic layers were washed with saturated aqueous NaHCO3 dried over Na2SO4 filtered concentrated The crude product was purified via column chromatography (15% to 60% EtOAc/hexanes)

反応条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a 50 mL flask containing the product from Step B (1.0 g, 4.32 mmol) was added MeOH (20 mL), and the resulting solution was cooled to 0° C. NaBH4 (0.409 g, 10.8 mmol) was carefully added and the mixture stirred at 0° C. for 3.0 hours. The mixture was concentrated to remove the solvent and the residue was taken up in EtOAc (50 mL) and a saturated aqueous NH4Cl solution (20 mL) was added followed by water (20 mL). The layers were mixed and separated and the aqueous phase extracted with EtOAc (2×20 mL). The combined organic extracts were washed with brine and dried over Na2SO4, then filtered and concentrated. The crude product was purified by column chromatography (10% to 60% EtOAc/hexanes gradient) to provide 0.980 g (97%) of the product as a thick colorless oil that solidified to a white solid while standing overnight. The product contained of a mixture of cis and trans isomers. The mixture was concentrated to remove the solvent a saturated aqueous NH4Cl solution (20 mL) was added The layers were mixed separated the aqueous phase extracted with EtOAc (2×20 mL) The combined organic extracts were washed with brine dried over Na2SO4 filtered concentrated The crude product was purified by column chromatography (10% to 60% EtOAc/hexanes gradient)

反応条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a 50 mL flask containing the product from Step B (1.0 g, 4.32 mmol) was added MeOH (20 mL), and the resulting solution was cooled to 0° C. NaBH4 (0.409 g, 10.8 mmol) was carefully added and the mixture stirred at 0° C. for 3.0 hours. The mixture was concentrated to remove the solvent and the residue was taken up in EtOAc (50 mL) and a saturated aqueous NH4Cl solution (20 mL) was added followed by water (20 mL). The layers were mixed and separated and the aqueous phase extracted with EtOAc (2×20 mL). The combined organic extracts were washed with brine and dried over Na2SO4, then filtered and concentrated. The crude product was purified by column chromatography (10% to 60% EtOAc/hexanes gradient) to provide 0.980 g (97%) of the product as a thick colorless oil that solidified to a white solid while standing overnight. The product contained of a mixture of cis and trans isomers. The mixture was concentrated to remove the solvent a saturated aqueous NH4Cl solution (20 mL) was added The layers were mixed separated the aqueous phase extracted with EtOAc (2×20 mL) The combined organic extracts were washed with brine dried over Na2SO4 filtered concentrated The crude product was purified by column chromatography (10% to 60% EtOAc/hexanes gradient)

反応条件: temp:125.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a 500 mL flask containing the product from Step A (23.5 g, 77.5 mmol) was added DMSO (160 mL) followed by H2O (6.98 mL, 387 mmol) and then LiCl (16.4 g, 387 mmol). The mixture was warmed to 125° C. and stirred for 5 hours. The resulting dark mixture was then cooled to ambient temperature and diluted with EtOAc (500 mL) and washed with a saturated aqueous NaHCO3:water (1:1, 3×250 mL). The combined aqueous phase was washed with EtOAc (100 mL) and the combined organic phases were washed with brine and dried over Na2SO4, filtered and concentrated. The crude oil was purified by column chromatography (10 to 30% EtOAc/hexanes) to provide 10.0 g (56%) of the desired product as a light golden oil. The resulting dark mixture was then cooled to ambient temperature washed with a saturated aqueous NaHCO3:water (1:1, 3×250 mL) The combined aqueous phase was washed with EtOAc (100 mL) the combined organic phases were washed with brine dried over Na2SO4 filtered concentrated The crude oil was purified by column chromatography (10 to 30% EtOAc/hexanes)

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:-5.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a tert-butyl 4-fluoro-5-oxoazepane-1-carboxylate (20.0 g, 86.5 mmol) was dissolved in THF (430 mL) solution and the solution was cooled to −5° C. L-Selectride (112 mL, 112 mmol, 1.0 M in THF) was added via syringe. The mixture was gradually warmed to ambient temperature over 3 hours and stirred for an additional 20 hours. The resulting cloudy mixture was diluted with 110 mL of MeOH, followed by addition of NaOH (355 mL, 355 mmol, 1.0M aqueous). The mixture was cooled in a water bath and H2O2 (80.4 mL, 709 mmol, 30% aqueous) was added carefully via addition funnel over 30 minutes. The mixture was stirred vigorously for 1 hour. The mixture was diluted with water and extracted with EtOAc (3×200 mL). The combined organic layers were washed with water and 1N KHSO4 (2×150 mL), and the combined aqueous phases were back extracted with EtOAc (200 mL). The combined organic layers were washed with saturated aqueous NaHCO3, dried over Na2SO4, filtered and concentrated. The crude product was purified via column chromatography (15% to 60% EtOAc/hexanes) to provide the product as a thick colorless oil which slowly became a white solid (13.9 g, 69%; diastereomeric ratio (dr): ˜7:1 trans:cis). The mixture was gradually warmed to ambient temperature over 3 hours The mixture was cooled in a water bath The mixture was stirred vigorously for 1 hour extracted with EtOAc (3×200 mL) The combined organic layers were washed with water and 1N KHSO4 (2×150 mL) the combined aqueous phases were back extracted with EtOAc (200 mL) The combined organic layers were washed with saturated aqueous NaHCO3 dried over Na2SO4 filtered concentrated The crude product was purified via column chromatography (15% to 60% EtOAc/hexanes)

反応条件: temp:-5.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a tert-butyl 4-fluoro-5-oxoazepane-1-carboxylate (20.0 g, 86.5 mmol) was dissolved in THF (430 mL) solution and the solution was cooled to −5° C. L-selectride (112 mL, 112 mmol, 1.0 M in THF) was added via syringe. The mixture was gradually warmed to ambient temperature over 3 hours and stirred for an additional 20 hours. The resulting cloudy mixture was diluted with 110 mL of MeOH which was followed by the addition of NaOH (355 mL, 355 mmol, 1.0M aqueous). The mixture was cooled in a water bath, and H2O2 (80.4 mL, 709 mmol, 30% aqueous) was added carefully via addition funnel over 30 minutes. The mixture was stirred vigorously for 1 hour, then diluted with water and extracted with EtOAc (3×200 mL). The combined organic layers were washed with water and 1N KHSO4 (2×150 mL), and the combined aqueous phases were back-extracted with EtOAc (200 mL). The combined organic layers were washed with saturated aqueous NaHCO3, then dried over Na2SO4, filtered and concentrated. The crude product was purified via column chromatography (15% to 60% EtOAc/hexanes) to provide the product as a thick colorless oil which slowly became a white solid (13.9 g, 69%; diastereomeric ratio (dr): ˜7:1 trans:cis). The mixture was gradually warmed to ambient temperature over 3 hours The mixture was cooled in a water bath The mixture was stirred vigorously for 1 hour extracted with EtOAc (3×200 mL) The combined organic layers were washed with water and 1N KHSO4 (2×150 mL) the combined aqueous phases were back-extracted with EtOAc (200 mL) The combined organic layers were washed with saturated aqueous NaHCO3 dried over Na2SO4 filtered concentrated The crude product was purified via column chromatography (15% to 60% EtOAc/hexanes)

反応条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a 50 mL flask containing the product from Step B (1.0 g, 4.32 mmol) was added MeOH (20 mL), and the resulting solution was cooled to 0° C. NaBH4 (0.409 g, 10.8 mmol) was carefully added and the mixture stirred at 0° C. for 3.0 hours. The mixture was concentrated to remove the solvent and the residue was taken up in EtOAc (50 mL) and a saturated aqueous NH4Cl solution (20 mL) was added followed by water (20 mL). The layers were mixed and separated and the aqueous phase extracted with EtOAc (2×20 mL). The combined organic extracts were washed with brine and dried over Na2SO4, then filtered and concentrated. The crude product was purified by column chromatography (10% to 60% EtOAc/hexanes gradient) to provide 0.980 g (97%) of the product as a thick colorless oil that solidified to a white solid while standing overnight. The product contained of a mixture of cis and trans isomers. The mixture was concentrated to remove the solvent a saturated aqueous NH4Cl solution (20 mL) was added The layers were mixed separated the aqueous phase extracted with EtOAc (2×20 mL) The combined organic extracts were washed with brine dried over Na2SO4 filtered concentrated The crude product was purified by column chromatography (10% to 60% EtOAc/hexanes gradient)

反応条件: temp:125.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a 500 mL flask containing the product from Step A (23.5 g, 77.5 mmol) was added DMSO (160 mL) followed by H2O (6.98 mL, 387 mmol) and then LiCl (16.4 g, 387 mmol). The mixture was warmed to 125° C. and stirred for 5 hours. The resulting dark mixture was then cooled to ambient temperature and diluted with EtOAc (500 mL) and washed with a saturated aqueous NaHCO3:water (1:1, 3×250 mL). The combined aqueous phase was washed with EtOAc (100 mL) and the combined organic phases were washed with brine and dried over Na2SO4, filtered and concentrated. The crude oil was purified by column chromatography (10 to 30% EtOAc/hexanes) to provide 10.0 g (56%) of the desired product as a light golden oil. The resulting dark mixture was then cooled to ambient temperature washed with a saturated aqueous NaHCO3:water (1:1, 3×250 mL) The combined aqueous phase was washed with EtOAc (100 mL) the combined organic phases were washed with brine dried over Na2SO4 filtered concentrated The crude oil was purified by column chromatography (10 to 30% EtOAc/hexanes)