Azobisisobutyronitrile → (3R,4R)-4-azido-1-((4-(methylthio)quinazolin-5-yl)methyl)piperidin-3-ol

Temperature

80 °C

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+.

1. customThe mixture was degassed under vacuum
2. custompurged with nitrogen (2×)
3. temperatureAfter cooling to room temperature
4. customthe solid was removed by filtration
5. concentrationthe filtrate was concentrated under reduced pressure
6. dissolutionThe residue was dissolved in dichloroethane (30 ml)
7. waitat 75° C. for 30 min
8. temperatureAfter cooling to room temperature
9. washthe reaction mixture was washed with saturated NaHCO3
10. extractionextracted with 2N HCl (40 ml)
11. customThe acidic aqueous layer was separated
12. filtrationSolid product was collected by filtration
13. washwashed with water
14. customdried under high vacuum

ORD record

ord-388b880f9abc4c9faf784f01fcc118ac

Source dataset

uspto-grants-2008_04

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07358256B2