Lithium Hexamethyldisilazide → 3-Bromo-N-[4-(2-chloro-phenyl)-pyridin-3-yl]-N-methyl-5-trifluoromethyl-benzamide

HRID 878059Notes

Reaction equation

HRID 878059 reaction equation
[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][C:9]=1[NH:14][CH3:15].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[Br:26][C:27]1[CH:28]=[C:29]([CH:33]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:35]=1)[C:30](Cl)=[O:31].BrC1C=C(C=C(C(F)(F)F)C=1)C(O)=O>C1COCC1.S(Cl)(Cl)=O>[Br:26][C:27]1[CH:28]=[C:29]([CH:33]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:35]=1)[C:30]([N:14]([C:9]1[CH:10]=[N:11][CH:12]=[CH:13][C:8]=1[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[Cl:1])[CH3:15])=[O:31]

Participants

7

Reactant 4

HCID 2733832Lithium HexamethyldisilazideHCID 110867883-Bromo-5-(trifluoromethyl)benzoic acidHCID 18403335[4-(2-Chloro-phenyl)-pyridin-3-yl]-methyl-amineHCID 534128943-Bromo-5-(trifluoromethyl)benzoyl chloride

Product 1

HCID 601975943-Bromo-N-[4-(2-chloro-phenyl)-pyridin-3-yl]-N-methyl-5-trifluoromethyl-benzamide

Reagents, catalysts & solvents 2

HCID 8028TetrahydrofuranSolventHCID 24386Thionyl ChlorideSolvent

Conditions

Temperature
-78 °C

Procedure

To a solution of [4-(2-chloro-phenyl)-pyridin-3-yl]-methyl-amine (300 mg, 1.37 mmol, prepared according to DE10008042) in THF (3 mL) was added dropwise lithium bis(trimethylsilyl)amide (1M solution in THF, 1.44 mL, 1.44 mmol) at −78° C. The reaction mixture was stirred for 10 minutes at −78° C. A solution of 3-bromo-5-trifluoromethyl-benzoyl chloride (prepared by stirring 3-bromo-5-(trifluoromethyl)benzoic acid (406 mg, 1.51 mmol, CAS RN 328-67-6) in thionylchloride (3 mL) at 100° C. for 1 hour. The reaction mixture was evaporated and the residue was dissolved in 5 mL toluene and concentrated under vacuum. This procedure was repeated three times to completely remove remainder of thionylchloride) in THF (3 mL) was added at −78° C. The reaction mixture was stirred for 1 hour at this temperature and then poured on 30 mL H2O and 30 mL EtOAc. The layers were separated and the aqueous layer extracted a second time with 30 mL EtOAc. The combined organic layers were washed with 30 mL brine, dried over MgSO4, filtered and concentrated under vacuum. The residue was purified by silica gel chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of n-heptane:EtOAc (100:0 to 0:100). Yellow solid (265 mg, 41%). MS (TurboSpray): m/z=470.991 [M+H]+.

Workup

  1. customThe reaction mixture was evaporated
  2. dissolutionthe residue was dissolved in 5 mL toluene
  3. concentrationconcentrated under vacuum
  4. additionwas added at −78° C
  5. stirringThe reaction mixture was stirred for 1 hour at this temperature
  6. additionpoured on 30 mL H2O and 30 mL EtOAc
  7. customThe layers were separated
  8. extractionthe aqueous layer extracted a second time with 30 mL EtOAc
  9. washThe combined organic layers were washed with 30 mL brine
  10. dry with materialdried over MgSO4
  11. filtrationfiltered
  12. concentrationconcentrated under vacuum
  13. customThe residue was purified by silica gel chromatography
  14. washeluting with a gradient of n-heptane:EtOAc (100:0 to 0:100)

Sources & evidence

ORD record
ord-589336d6d64b41c88a4ae32ebb109742
Source dataset
uspto-grants-2015_03
Patent number
US08987307B2

Reaction notes

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