Ammonium Chloride → [4-(4-Hydroxy-tetrahydro-pyran-4-yl)-phenyl]carbamic acid tert-butyl ester

Temperature

-78 °C

THF (50 mL) in an oven-dried 500 mL single neck flask was cooled in −78° C. bath under N2. A solution of n-butyllithium in hexanes (15.4 mL, 2.5 M, 38.6 mmol) was added dropwise via syringe over 10 min. The clear solution was stirred at −78° C. for 30 min. N-Boc-4-bromoaniline (5.00 g, 18.4 mmol), dissolved in 10 mL THF, was added dropwise over 10 min with stirring then stirred a further 30 min at −78° C. Tetrahydro-4H-pyran-4-one (2.02 g, 20.2 mmol) in 5 mL THF added was dropwise over 10 min. After 150 min, the reaction mixture was allowed to warm to RT then added to 200 mL saturated NH4Cl and extracted with ether (3×100 mL). The combined organic layers were washed with water (50 mL) and brine (50 mL) and dried over MgSO4. Filtration and concentration provided the crude product that was recrystallized from 70 mL DCM to give the purified product as a white solid (2.29 g, 42%). MS (ESI): mass calcd. for C16H23NO4, 293.3; m/z found, 276.1 [M−H2O+H]+. 1H NMR (500 MHz, CDCl3): 7.46-7.38 (m, 2H), 7.36 (d, J=8.6 Hz, 2H), 6.48 (s, 1H), 3.90 (m, 4H), 2.30-1.98 (m, 2H), 1.68 (d, J=12.1 Hz, 2H), 1.52 (s, 9H).

1. additionwas added dropwise over 10 min
2. stirringwith stirring
3. stirringthen stirred a further 30 min at −78° C
4. waitwas dropwise over 10 min
5. waitAfter 150 min
6. temperatureto warm to RT
7. extractionextracted with ether (3×100 mL)
8. washThe combined organic layers were washed with water (50 mL) and brine (50 mL)
9. dry with materialdried over MgSO4
10. filtrationFiltration and concentration
11. customprovided the crude product that
12. customwas recrystallized from 70 mL DCM

ORD record

ord-1d8ed5be78e14ddc97d6434adce1adfb

Source dataset

uspto-grants-2015_01

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08937078B2