(3R,4R)-4-azidopiperidin-3-ol

反応条件: temp:55.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mixture of 14A (120 mg, 0.34 mmol) and 1-(3-fluorobenzyl)-1H-indazole-5-amine (81.0 mg, 0.34 mmol; prepared as described in US 2003/0186983 A1) in CH3CN (1.2 ml) was heated at 55° C. for 45 min. After cooled to rt, (3R,4R)-4-azidopiperidin-3-ol (475 mg, 3.34 mmol; prepared as described in U.S. patent application Ser. No. 10146 PSP) was added and the mixture was heated at 60° C. for 16 h. This mixture was diluted with CH3CN (2.4 mL), and then heated at 70° C. for 4 h and at 80° C. for 4 d. The reaction mixture was concentrated in vacuo and the residue was purified by prep HPLC. to give 19A (78 mg, 45%). It has an analytical HPLC retention time=2.43 min (Chromolith SpeedROD column 4.6×50 mm, 10-90% aqueous methanol containing 0.2% H3PO4 over 4 minutes, 4 mL/min, monitoring at 220 nm) and a LC/MS M++H=524+. After cooled to rt prepared 10146 PSP) was added the mixture was heated at 60° C. for 16 h heated at 70° C. for 4 h and at 80° C. for 4 d The reaction mixture was concentrated in vacuo the residue was purified by prep HPLC

反応条件: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a mixture of 1C (1.19 g, 6.25 mmol), AIBN (111.2 mg, 0.625 mmol), and NBS (1.129 g, 6.875 mmol) under N2 was added CCl4 (30 ml). The mixture was degassed under vacuum, purged with nitrogen (2×) and heated to 80° C. for 40 min. After cooling to room temperature, the solid was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was dissolved in dichloroethane (30 ml). (3R,4R)-4-azidopiperidin-3-ol (976 mg, 6.875 mmol), (prepared as described in U.S. patent application Ser. No. 11/019,901) and TEA (1.04 ml, 7.5 mmol) were subsequently added. The mixture was stirred at room temperature for 1 h, then at 75° C. for 30 min. After cooling to room temperature, the reaction mixture was washed with saturated NaHCO3, then extracted with 2N HCl (40 ml). The acidic aqueous layer was separated and basified with 50% NaOH. Solid product was collected by filtration, washed with water and dried under high vacuum to give 1D (1.51 g, 73%) as a solid. The compound has an analytical HPLC retention time=1.106 min (Chromolith SpeedROD column 4.6×50 mm, 10-90% aqueous methanol containing 0.1% TFA over 4 minutes, 4 mL/min, monitoring at 254 nm) and a LC/MS M++H=331+. The mixture was degassed under vacuum purged with nitrogen (2×) After cooling to room temperature the solid was removed by filtration the filtrate was concentrated under reduced pressure The residue was dissolved in dichloroethane (30 ml) at 75° C. for 30 min After cooling to room temperature the reaction mixture was washed with saturated NaHCO3 extracted with 2N HCl (40 ml) The acidic aqueous layer was separated Solid product was collected by filtration washed with water dried under high vacuum

反応条件: temp:55.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mixture of 14A (120 mg, 0.34 mmol) and 1-(3-fluorobenzyl)-1H-indazole-5-amine (81.0 mg, 0.34 mmol; prepared as described in US 2003/0186983 A1) in CH3CN (1.2 ml) was heated at 55° C. for 45 min. After cooled to rt, (3R,4R)-4-azidopiperidin-3-ol (475 mg, 3.34 mmol; prepared as described in U.S. patent application Ser. No. 10146 PSP) was added and the mixture was heated at 60° C. for 16 h. This mixture was diluted with CH3CN (2.4 mL), and then heated at 70° C. for 4 h and at 80° C. for 4 d. The reaction mixture was concentrated in vacuo and the residue was purified by prep HPLC. to give 19A (78 mg, 45%). It has an analytical HPLC retention time=2.43 min (Chromolith SpeedROD column 4.6×50 mm, 10-90% aqueous methanol containing 0.2% H3PO4 over 4 minutes, 4 mL/min, monitoring at 220 nm) and a LC/MS M++H=524+. After cooled to rt prepared 10146 PSP) was added the mixture was heated at 60° C. for 16 h heated at 70° C. for 4 h and at 80° C. for 4 d The reaction mixture was concentrated in vacuo the residue was purified by prep HPLC

反応条件: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a mixture of 1C (1.19 g, 6.25 mmol), AIBN (111.2 mg, 0.625 mmol), and NBS (1.129 g, 6.875 mmol) under N2 was added CCl4 (30 ml). The mixture was degassed under vacuum, purged with nitrogen (2×) and heated to 80° C. for 40 min. After cooling to room temperature, the solid was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was dissolved in dichloroethane (30 ml). (3R,4R)-4-azidopiperidin-3-ol (976 mg, 6.875 mmol), (prepared as described in U.S. patent application Ser. No. 11/019,901) and TEA (1.04 ml, 7.5 mmol) were subsequently added. The mixture was stirred at room temperature for 1 h, then at 75° C. for 30 min. After cooling to room temperature, the reaction mixture was washed with saturated NaHCO3, then extracted with 2N HCl (40 ml). The acidic aqueous layer was separated and basified with 50% NaOH. Solid product was collected by filtration, washed with water and dried under high vacuum to give 1D (1.51 g, 73%) as a solid. The compound has an analytical HPLC retention time=1.106 min (Chromolith SpeedROD column 4.6×50 mm, 10-90% aqueous methanol containing 0.1% TFA over 4 minutes, 4 mL/min, monitoring at 254 nm) and a LC/MS M++H=331+. The mixture was degassed under vacuum purged with nitrogen (2×) After cooling to room temperature the solid was removed by filtration the filtrate was concentrated under reduced pressure The residue was dissolved in dichloroethane (30 ml) at 75° C. for 30 min After cooling to room temperature the reaction mixture was washed with saturated NaHCO3 extracted with 2N HCl (40 ml) The acidic aqueous layer was separated Solid product was collected by filtration washed with water dried under high vacuum