Diisopropylethylamine → Tert-butyl 1-(3-bromo-5-fluoropyridin-4-yl)piperidine-4-carboxylate

HRID 524888Notes

Reaction equation

HRID 524888 reaction equation
[Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([F:9])[C:7]=1Cl.[F-].[K+].Cl.[NH:13]1[CH2:18][CH2:17][CH:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1.CCN(C(C)C)C(C)C>[N+](C)(C)(C)C.[Cl-].CS(C)=O>[Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([F:9])[C:7]=1[N:13]1[CH2:18][CH2:17][CH:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1

Participants

7

Reactant 4

HCID 81531DiisopropylethylamineHCID 522689Potassium FluorideHCID 42614227Piperidine-4-carboxylic acid tert-butyl ester hydrochlorideHCID 709772193-Bromo-4-chloro-5-fluoropyridine

Product 1

HCID 86720943Tert-butyl 1-(3-bromo-5-fluoropyridin-4-yl)piperidine-4-carboxylateYield 65.3%

Reagents, catalysts & solvents 2

HCID 6379Tetramethylammonium chlorideCatalystHCID 679Dimethyl SulfoxideSolvent

Conditions

Temperature
130 °C

Procedure

A thoroughly stirred mixture of 3-bromo-4-chloro-5-fluoropyridine free base (55 g, 0.26 mol), potassium fluoride (31 g, 0.53 mol) and Me4NCl (5.8 g, 53 mmol) in DMSO (400 mL) was heated to 130° C. for 2 hours. The reaction mixture was cooled to room temperature and tert-butyl piperidine-4-carboxylate hydrochloride 22 (66 g, 0.30 mol) and DIPEA (65 g, 0.50 mol) were added. The reaction mixture was stirred at room temperature overnight. The solvent was evaporated in vacuo. The residue was portioned between DCM/water. The organic layer was washed with water (3×), dried over Na2SO4, and filtered over silica gel using DCM as eluent. The filtrated was evaporated to give tert-butyl 1-(3-bromo-5-fluoropyridin-4-yl)piperidine-4-carboxylate 26 (61 g, 65%) as a light yellow solid; 1H NMR (500 MHz, DMSO-d6) δ 8.47 (s, 1H), 8.41 (d, 1H), 3.39-3.36 (m, 2H), 3.12 (tt, 2H), 2.49-2.43 (m, 1H), 1.91-1.87 (m, 2H), 1.71-1.64 (m, 2H) and 1.43 (s, 9H); 19F NMR (500 MHz, DMSO-d6) δ −135.2; MS (ES+) 361.0.

Workup

  1. temperatureThe reaction mixture was cooled to room temperature
  2. customThe solvent was evaporated in vacuo
  3. washThe organic layer was washed with water (3×)
  4. dry with materialdried over Na2SO4
  5. filtrationfiltered over silica gel
  6. customThe filtrated was evaporated

Sources & evidence

ORD record
ord-3cfe3048887a4e94a4bf1b2edf9d095b
Source dataset
uspto-grants-2016_05
Patent number
US09340546B2

Reaction notes

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