Methyl iodide → 4-(4-Iodo-phenyl)-4-{[methyl-(2,2,2-trifluoro-acetyl)-amino]-methyl}-piperidine-1-carboxylic acid tert-butyl ester

HRID 2180186Notes

Reaction equation

HRID 2180186 reaction equation
[H-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][C:13]([C:24]2[CH:29]=[CH:28][C:27]([I:30])=[CH:26][CH:25]=2)([CH2:16][NH:17][C:18](=[O:23])[C:19]([F:22])([F:21])[F:20])[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].[CH3:31]I>CN(C=O)C.CCOC(C)=O>[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][C:13]([C:24]2[CH:29]=[CH:28][C:27]([I:30])=[CH:26][CH:25]=2)([CH2:16][N:17]([CH3:31])[C:18](=[O:23])[C:19]([F:22])([F:21])[F:20])[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:4])[CH3:5]

Participants

6

Reactant 3

HCID 6328Methyl iodideHCID 24758Sodium hydrideHCID 207794704-(4-Iodo-phenyl)-4-[(2,2,2-trifluoro-acetylamino)-methyl]-piperidine-1-carboxylic acid tert-butyl ester

Product 1

HCID 207794714-(4-Iodo-phenyl)-4-{[methyl-(2,2,2-trifluoro-acetyl)-amino]-methyl}-piperidine-1-carboxylic acid tert-butyl esterYield 72.4%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 8857Ethyl AcetateSolvent

Procedure

To a flask containing sodium hydride (0.07 g, 2.9 mmol, 5 eq.) under Ar at 0° C. was added a solution of 4-(4-iodo-phenyl)-4-[(2,2,2-trifluoro-acetylamino)-methyl]-piperidine-1-carboxylic acid tert-butyl ester (0.298 g, 0.58 mmol) in DMF (5 mL). The resulting mixture was warmed to room temperature and stirred for 2 h, heated to 35° C. for 0.5 h and CH3I (0.36 mL, 5.8 mmol, 10 eq.) was added. The mixture heated at 35° C. for a further 2 h. The reaction was diluted with EtOAc (25 mL) and washed with saturated NaHCO3 (25 mL) and saturated brine (25 mL). The combined organic extracts were dried over anhydrous Na2SO4, filtered and concentrated by rotary evaporation. The crude product was purified by flash column chromatography by eluting with 30% EtOAc/hexanes to give 4-(4-iodo-phenyl)-4-{[methyl-(2,2,2-trifluoro-acetyl)-amino]-methyl}-piperidine-1-carboxylic acid tert-butyl ester (0.022 g, 0.42 mmol, 72%). 1H NMR (CDCl3): δ 7.83 (d, 2H), 7.20 (d, 2H), 3.93 (m, 2H), 3.78 (m, 1H), 3.53 (m, 1H), 3.07 (m, 2H), 2.60 (m, 3H), 2.24 (m, 2H), 1.93 (m, 2H), 1.54 (s, 9H).

Workup

  1. temperatureheated to 35° C. for 0.5 h
  2. temperatureThe mixture heated at 35° C. for a further 2 h
  3. washwashed with saturated NaHCO3 (25 mL) and saturated brine (25 mL)
  4. dry with materialThe combined organic extracts were dried over anhydrous Na2SO4
  5. filtrationfiltered
  6. concentrationconcentrated by rotary evaporation
  7. customThe crude product was purified by flash column chromatography
  8. washby eluting with 30% EtOAc/hexanes

Sources & evidence

ORD record
ord-f4cc5a05470e417595397abca097c698
Source dataset
uspto-grants-2005_05
Patent number
US06887889B2

Reaction notes

Loading…