Triethylamine → 1,1-Dimethylethyl 3-fluoro-4-[(methylsulfonyl)oxy]-1-piperidinecarboxylate

HRID 588478Notes

Reaction equation

HRID 588478 reaction equation
[F:1][CH:2]1[CH:7]([OH:8])[CH2:6][CH2:5][N:4]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:3]1.C(N(CC)CC)C.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>C(Cl)Cl>[F:1][CH:2]1[CH:7]([O:8][S:24]([CH3:23])(=[O:26])=[O:25])[CH2:6][CH2:5][N:4]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:3]1

Participants

5

Reactant 3

HCID 8471TriethylamineHCID 31297Methanesulfonyl chlorideHCID 42609254Tert-butyl 3-fluoro-4-hydroxypiperidine-1-carboxylate

Product 1

HCID 454898981,1-Dimethylethyl 3-fluoro-4-[(methylsulfonyl)oxy]-1-piperidinecarboxylate

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

A solution of tert-butyl 3-fluoro-4-hydroxypiperidine-1-carboxylate, 2.4 (63 g, 0.287 mol) in anhydrous methylene chloride (630 mL) was treated with triethylamine (60 mL, 0.43 μmol) followed by methane sulfonyl chloride (26.7 mL, 0.345 mol) at 0° C. under N2 atmosphere. The solution was allowed to warm slowly to ambient temperature and stirred for 14 hours. The mixture was partitioned between saturated NaHCO3 (400 mL) and methylene chloride (400 mL). The aqueous layer was extracted with methylene chloride (2×500 mL). The combined organic phases were washed with 1N HCl, brine, dried over Na2SO4, filtered and concentrated under vacuum. The residue was purified by silica gel chromatography, eluting with 20-30% EtOAc/Hexane to provide the tert-butyl 3-fluoro-4-((methylsulfonyl)oxy)piperidine-1-carboxylate, 2.5 (78 g, 91%). 1HNMR (CDCl3, 400 MHz): δ 4.98-4.86 (m, 1H), 4.80-4.74 (m, 0.5H), 4.67-4.63 (m, 0.5H), 3.92-3.45 (m, 3H), 3.44-3.25 (m, 1H), 3.08 (s, 3H), 2.20-2.07 (m, 1H), 1.93-1.80 (m, 1H), 1.45 (s, 9H).

Workup

  1. customThe mixture was partitioned between saturated NaHCO3 (400 mL) and methylene chloride (400 mL)
  2. extractionThe aqueous layer was extracted with methylene chloride (2×500 mL)
  3. washThe combined organic phases were washed with 1N HCl, brine
  4. dry with materialdried over Na2SO4
  5. filtrationfiltered
  6. concentrationconcentrated under vacuum
  7. customThe residue was purified by silica gel chromatography
  8. washeluting with 20-30% EtOAc/Hexane

Sources & evidence

ORD record
ord-ceb07f101f2c45dbae05d1a87e128ad1
Source dataset
uspto-grants-2016_01
Patent number
US09227969B2

Reaction notes

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