Chlorotrimethylsilane → Racemic (5-chloropyridin-2-yl)(cyclohexyl)(3-fluoro-5-(trifluoromethyl)phenyl)methanamine

HRID 1365524Notes

Reaction equation

HRID 1365524 reaction equation
Br[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([F:12])[CH:3]=1.[Li]CCCC.[Cl:18][C:19]1[CH:20]=[CH:21][C:22]([C:25]#[N:26])=[N:23][CH:24]=1.C[Si](Cl)(C)C.[CH:32]1([Mg]Cl)[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1>C1COCC1.CCOCC>[Cl:18][C:19]1[CH:20]=[CH:21][C:22]([C:25]([CH:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)([C:2]2[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([F:12])[CH:3]=2)[NH2:26])=[N:23][CH:24]=1

Participants

8

Reactant 5

HCID 6397ChlorotrimethylsilaneHCID 27363233-Bromo-5-fluorobenzotrifluorideHCID 38339425-Chloro-2-cyanopyridineHCID 178418339ButyllithiumHCID 178478990HCID 178478990, compound

Product 1

HCID 58921044Racemic (5-chloropyridin-2-yl)(cyclohexyl)(3-fluoro-5-(trifluoromethyl)phenyl)methanamineYield 75%

Reagents, catalysts & solvents 2

HCID 3283Diethyl EtherSolventHCID 8028TetrahydrofuranSolvent

Conditions

Temperature
-78 °C

Procedure

A dry 200 mL flask under nitrogen was charged with 1-bromo-3-fluoro-5-(trifluoromethyl)benzene (1.22 g, 0.005 mol). Dry ether (50mL) was added and the solution was cooled to −78° C. n-BuLi (3.0 mL, 1.6 M in hexanes, 0.0048 mol) was added dropwise and the resulting solution was stirred at −78° C. for 30 min. A solution of 5-chloropicolinonitrile (0.692 g, 0.005 mol) in anhydrous THF (7 mL) was then added. The resulting solution was stirred at −78° C. for 1 hr. Redistilled TMSCl (0.65 mL, 0.00515 mol) was added dropwise. The reaction mixture was allowed to reach 0° C. and then cooled to −78° C. Cyclohexylmagnesium chloride (2.75 mL, 2.0 M, 0.0055 mol) was added dropwise. The solution was allowed to reach room temperature. The reaction was quenched by addition of water followed by aqueous ammonium chloride. The aqueous layer was extracted with ether (2×50 mL). The combined organic portions were filtered through a pad of silica and the silica was washed with 4:1 Hexanes:EtOAc. The solvents were evaporated to get the racemic (5 -chloropyridin-2-yl)(cyclohexyl)(3-fluoro-5-(trifluoromethyl)phenyl)methanamine as an oil (1.39 g, 75% yield). LCMS RT=3.28 min, [M+H] 387.14, Purity 79% (LCMS Method 6).

Workup

  1. additionwas added dropwise
  2. stirringThe resulting solution was stirred at −78° C. for 1 hr
  3. customto reach 0° C.
  4. temperaturecooled to −78° C
  5. customto reach room temperature
  6. customThe reaction was quenched by addition of water
  7. extractionThe aqueous layer was extracted with ether (2×50 mL)
  8. filtrationThe combined organic portions were filtered through a pad of silica
  9. washthe silica was washed with 4:1 Hexanes
  10. customThe solvents were evaporated

Sources & evidence

ORD record
ord-36418023f5f24b54b843cd58a19baf6b
Source dataset
uspto-grants-2011_02
Patent number
US07888376B2

Reaction notes

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