Hydrochloric Acid → Tert-butyl 4,4-bis(hydroxymethyl)piperidine-1-carboxylate

Temperature

-78 °C

A solution of 1-(1,1-dimethylethyl) 4-ethyl 1,4-piperidinedicarboxylate (10 g, 39 mmol) in tetrahydrofuran (100 mL) was added to a stirred, cooled (−78° C.) solution of lithium diisopropylamide in tetrahydrofuran (0.82M, 140 mL) and the mixture was stirred at −78° C. for 2 h, then at −40° C. for 3 hours. The mixture was cooled to −78° C., ethyl chloroformate (13 mL, 136 mmol) in tetrahydrofuran (80 mL) was added and the mixture was allowed to warm to room temperature over 16 hours. Saturated aqueous ammonium chloride (50 mL), hydrochloric acid (1M, 2000 mL) and ethyl acetate (3000 mL) were added and the layers were separated. The aqueous layer was extracted with ethyl acetate (3×150 mL), the combined organic fractions were dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was dissolved in toluene/tetrahydrofuran (1:1, 400 mL) and lithium borohydride (4.5 g, 207 mmol) was added. The mixture was heated at 60° C. for 16 hours, cooled and saturated aqueous ammonium chloride was added slowly until the organic layer was a clear solution. The mixture was adjusted to pH 12 with saturated aqueous sodium carbonate and the layers were separated. The aqueous layer was extracted with ethyl acetate (2×150 mL), the combined organic fractions were dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with isohexane/EtOAc (50:50 increasing to 0:100), to give the title compound (6.1 g, 63%). m/z (ES+) 190 (M+1-C4H8).

1. waitat −40° C. for 3 hours
2. temperatureThe mixture was cooled to −78° C.
3. temperatureto warm to room temperature over 16 hours
4. customthe layers were separated
5. extractionThe aqueous layer was extracted with ethyl acetate (3×150 mL)
6. dry with materialthe combined organic fractions were dried (MgSO4)
7. customthe solvent was evaporated under reduced pressure
8. dissolutionThe residue was dissolved in toluene/tetrahydrofuran (1:1, 400 mL)
9. temperatureThe mixture was heated at 60° C. for 16 hours
10. temperaturecooled
11. customthe layers were separated
12. extractionThe aqueous layer was extracted with ethyl acetate (2×150 mL)
13. dry with materialthe combined organic fractions were dried (MgSO4)
14. customthe solvent was evaporated under reduced pressure
15. customThe residue was purified by flash column chromatography on silica gel
16. washeluting with isohexane/EtOAc (50:50 increasing to 0:100)

ORD record

ord-1fbf1022478c4268bf7ba2d335837b28

Source dataset

uspto-grants-2006_09

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07105507B2