2-Bromo-4-trifluoromethylaniline → HCID 66884132, compound

HRID 2042673Notes

Reaction equation

HRID 2042673 reaction equation
Br[C:2]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[CH:5][C:3]=1[NH2:4].[C:13]([O:17][C:18]([N:20]1[CH2:25][CH:24]=[C:23](B2OC(C)(C)C(C)(C)O2)[CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14]>O1CCOCC1>[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][CH:23]([C:2]2[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[CH:5][C:3]=2[NH2:4])[CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:14])[CH3:15]

Participants

4

Reactant 2

HCID 938992-Bromo-4-trifluoromethylanilineHCID 4642098Tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine-1-carboxylate

Product 1

HCID 66884132HCID 66884132, compoundYield 92.7%

Reagents, catalysts & solvents 1

HCID 312751,4-DioxaneSolvent

Procedure

A 4.5 L reactor was charged with 2-bromo-4-trifluoromethyl aniline (100 g), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (124 g, prepared as described in WO 2006/003494), 1,4-dioxane (2500 ml) and the solution was degassed for 30 minutes with argon. Dichloro-bis(triphenylphosphine)-palladium (5.6 g) was added and the resulting solution was stirred for 30 minutes at ambient temperature under an argon atmosphere. A degassed solution of sodium carbonate (127 g) in water (1200 ml) was added and the mixture was stirred at 60° C. for 3 hours. The mixture was cooled to ambient temperature and extracted with ethyl acetate (3×300 ml). The combined organic layers were washed with water (3×400 ml), brine then dried over sodium sulfate and concentrated in vacuo. The residue was dissolved in heptane (200 ml) and cooled to −70° C. and then allowed to warm to 0° C. The solid was collected by filtration and rinsed with cold heptane to afford 4-(2-amino-5-trifluoromethyl-phenyl)-piperidine-1-carboxylic acid tert-butyl ester (128 g) as a brown solid. MS (ES+) 214/215; 243/244 (MH+-BOC); 287/288; 343 (MH+); 1H NMR (400 MHz, CDCl3) 1.5 (s, 9H), 2.4 (m, 2H), 3.65 (t, 2H), 4.05 (m, 2H), 5.8 (m, 1H), 6.7 (d, 1H), 7.2 (d, 1H), 7.3 (dd, 1H).

Workup

  1. customthe solution was degassed for 30 minutes with argon
  2. additionDichloro-bis(triphenylphosphine)-palladium (5.6 g) was added
  3. additionA degassed solution of sodium carbonate (127 g) in water (1200 ml) was added
  4. stirringthe mixture was stirred at 60° C. for 3 hours
  5. temperatureThe mixture was cooled to ambient temperature
  6. extractionextracted with ethyl acetate (3×300 ml)
  7. washThe combined organic layers were washed with water (3×400 ml), brine
  8. dry with materialthen dried over sodium sulfate
  9. concentrationconcentrated in vacuo
  10. dissolutionThe residue was dissolved in heptane (200 ml)
  11. temperaturecooled to −70° C.
  12. temperatureto warm to 0° C
  13. filtrationThe solid was collected by filtration
  14. washrinsed with cold heptane

Sources & evidence

ORD record
ord-d1cf7c28990340f9ba78e49466cd5131
Source dataset
uspto-grants-2013_11
Patent number
US08586593B2

Reaction notes

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