Trifluoroacetic acid → Tert-butyl 4-hydroxypiperidine-1-carboxylate

Trifluoroacetic acid (40 ML) was added to crude carbamate 10.5 (18.6 g; 59.7 mmol) cooled in an ice-water bath. After 1 min the reaction was stirred at rt for 15 min, then concentrated on a rotary evaporator. Ether (200 mL) was added and this washed with 3 M NaOH (3×50 mL) and water (50 mL). The product was extracted into 1 M HCl (3×50 mL) and the aq phase was basified with 3 M NaOH (60 mL). The free base was extracted into DCM (1×50 mL then 2×25 mL), dried (MgSO4), filtered and concentrated to an oil. The hydrochloride salt was precipitated from a methanolic (6 mL) solution of the free base by the dropwise addition of HCl in ether (200 mL of HCl-saturated ether plus 150 mL of ether). The salt was collected by filtration and washed with ether (100 mfL) giving an off-white solid (7.97 g; 68% from 4-hydroxypiperidine-1-carboxylic acid tert-butyl ester). LC (method B) tR=8.2 min; 1H NMR (200 MHz, DMSO-d6) δ 8.94 (brs, 2H), 7.33 (m, 1H), 7.12 (m, 1H), 7.00 (m, 2H), 4.70 (m, 1H), 3.20 (m, 2H), 3.08 (m, 2H), 2.08 (m, 2H), 1.85 (m, 2H); ESIMS (free base) 212.0/213.9 (100/35) [MH+].

1. temperaturecooled in an ice-water bath
2. concentrationconcentrated on a rotary evaporator
3. additionEther (200 mL) was added
4. washthis washed with 3 M NaOH (3×50 mL) and water (50 mL)
5. extractionThe product was extracted into 1 M HCl (3×50 mL)
6. extractionThe free base was extracted into DCM (1×50 mL
7. dry with material2×25 mL), dried (MgSO4)
8. filtrationfiltered
9. concentrationconcentrated to an oil
10. customThe hydrochloride salt was precipitated from a methanolic (6 mL) solution of the free base by the dropwise addition of HCl in ether (200 mL of HCl-saturated ether plus 150 mL of ether)
11. filtrationThe salt was collected by filtration
12. washwashed with ether (100 mfL)

ORD record

ord-6af5db9c41694345a7e5cee02fa99385

Source dataset

uspto-grants-2005_07

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US06916804B2