(Diethylamino)sulfur trifluoride → (3S,4S)-tert-butyl 3-fluoro-4-(3-fluoro-4-methoxyphenyl)piperidine-1-carboxylate

HRID 1507207Notes

Reaction equation

HRID 1507207 reaction equation
[F:1][C:2]1[CH:3]=[C:4]([C@@H:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][C@H:11]2O)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].CCN(S(F)(F)[F:30])CC>C(Cl)Cl>[F:30][C@H:11]1[C@H:10]([C:4]2[CH:5]=[CH:6][C:7]([O:8][CH3:9])=[C:2]([F:1])[CH:3]=2)[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12]1

Participants

4

Reactant 2

HCID 123472(Diethylamino)sulfur trifluorideHCID 95566615trans-Tert-butyl 4-(3-fluoro-4-methoxyphenyl)-3-hydroxypiperidine-1-carboxylate

Product 1

HCID 118207501(3S,4S)-tert-butyl 3-fluoro-4-(3-fluoro-4-methoxyphenyl)piperidine-1-carboxylateYield 69%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Conditions

Temperature
-78 °C

Procedure

A stirred solution of trans-tert-butyl 4-(3-fluoro-4-methoxyphenyl)-3-hydroxypiperidine-1-carboxylate (100 mg, 0.31 mmol) in DCM (15 mL) at −78° C. was treated dropwise with DAST (0.08 mL, 0.6 mmol). The resulting mixture was stirred at −78° C. for 90 min. It was then quenched with ice water, warmed to rt, and extracted with DCM (50 mL). The organic layer was separated, washed with brine, dried over anhydrous Na2SO4, filtered, and evaporated under reduced pressure to obtain 70 mg of (±)-rel-(3S,4S)-tert-butyl 3-fluoro-4-(3-fluoro-4-methoxyphenyl)piperidine-1-carboxylate. LCMS (Method P) RT 1.11, 1.13 min, m/z 313 (M+H++CH3CN−t-butyl). Three batches of product (˜210 mg total) were combined and subjected to HPLC purification (Method A) to give 140 mg (±)-rel-(3S,4S)-tert-butyl 3-fluoro-4-(3-fluoro-4-methoxyphenyl)piperidine-1-carboxylate; 1H NMR (400 MHz, DMSO-d6) δ ppm 1.43 (s, 9H) 1.55-1.67 (m, 1H) 1.74-1.82 (m, 1H) 2.72-2.90 (m, 3H) 3.82 (s, 3H) 3.89-4.03 (m, 1H) 4.24-4.34 (m, 1H) 4.50-4.71 (m, 1H) 7.09 (d, J=1.51 Hz, 2H) 7.18-7.28 (m, 1H).

Workup

  1. customIt was then quenched with ice water
  2. temperaturewarmed to rt
  3. extractionextracted with DCM (50 mL)
  4. customThe organic layer was separated
  5. washwashed with brine
  6. dry with materialdried over anhydrous Na2SO4
  7. filtrationfiltered
  8. customevaporated under reduced pressure

Sources & evidence

ORD record
ord-29cf8e47ce504d919d398e482e4922d7
Source dataset
uspto-grants-2015_12
Patent number
US09221796B2

Reaction notes

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