4-Bromoanisole → (1-(1-(Benzylamino)-2,2,2-trifluoro-1-(4-(4,4,4-trifluorobutoxy)phenyl)ethyl)-cyclopropyl)-(4-methoxyphenyl)methanone

HRID 1629782Notes

Reaction equation

HRID 1629782 reaction equation
[Mg].Br[C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][CH:4]=1.[CH2:11]([N:18]1[C:23]([C:28]2[CH:33]=CC(OCCCC(F)(F)F)=[CH:30][CH:29]=2)([C:24]([F:27])([F:26])[F:25])[C:20]2([CH2:22][CH2:21]2)[C:19]1=[O:42])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.CO.O.[C:46](O)([C:48]([F:51])([F:50])[F:49])=O.C([O-])(O)=O.[Na+].[CH2:58]1[CH2:62][O:61][CH2:60][CH2:59]1>BrCCBr>[CH2:11]([NH:18][C:23]([C:20]1([C:19]([C:3]2[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][CH:4]=2)=[O:42])[CH2:22][CH2:21]1)([C:28]1[CH:33]=[CH:58][C:62]([O:61][CH2:60][CH2:59][CH2:46][C:48]([F:51])([F:50])[F:49])=[CH:30][CH:29]=1)[C:24]([F:25])([F:26])[F:27])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1

Participants

8

Reactant 6

HCID 77304-BromoanisoleHCID 8028Tetrahydrofuran2×HCID 516892Sodium BicarbonateHCID 5462224Magnesium2×HCID 21999908MeOH water TFAHCID 866858725-Benzyl-6-(4-(4,4,4-trifluorobutoxy)phenyl)-6-(trifluoromethyl)-5-azaspiro[2.3]-hexan-4-one

Product 1

HCID 86685873(1-(1-(Benzylamino)-2,2,2-trifluoro-1-(4-(4,4,4-trifluorobutoxy)phenyl)ethyl)-cyclopropyl)-(4-methoxyphenyl)methanoneYield 2.5%

Reagents, catalysts & solvents 1

HCID 78391,2-DibromoethaneCatalyst

Conditions

Temperature
50 °C

Procedure

Magnesium turnings (130 mg, 5.4 mmol) were suspended in anhydrous THF (13 mL). 4-Bromoanisole (1 g, 670 μL, 5.4 mmol) was added followed by a few drops of 1,2-dibromoethane. The reaction mixture was stirred at rt for 1.5 h after which most of the magnesium had dissolved. The reaction was warmed to 50° C. for 30 min, then cooled to rt. Final concentration of the Grignard reagent was 0.4 M assuming complete conversion. To a cold solution (−40° C.) of Intermediate 14F (200 mg, 0.44 mmol) in THF (4.4 mL) was added the freshly prepared Grignard reagent. The reaction was warmed from −40° C. to rt, then heated to reflux overnight. The reaction was cooled to room temperature and quenched with sat'd aq NH4Cl. The layers were separated and the aqueous layer was extracted with EtOAc. The combined organic extracts were washed with sat'd aq NaCl, dried over MgSO4, filtered and concentrated. The product was isolated using preparative HPLC (MeOH/H2O/TFA). Fractions containing the product were combined and reduced in volume in vacuo. The resulting aqueous solution was made basic with sat'd aq NaHCO3 and extracted with EtOAc. The combined organic extracts were washed with sat'd aq NaCl, dried over Na2SO4, filtered and concentrated to provide Intermediate 14G (6.1 mg, 2.5%). LCMS Anal. Calc'd for C30H29F6NO3 565.55, found [M+H] 566.3.

Workup

  1. dissolutionhad dissolved
  2. temperaturecooled to rt
  3. temperatureThe reaction was warmed from −40° C. to rt
  4. temperatureheated
  5. temperatureto reflux overnight
  6. temperatureThe reaction was cooled to room temperature
  7. customquenched with sat'd aq NH4Cl
  8. customThe layers were separated
  9. extractionthe aqueous layer was extracted with EtOAc
  10. washThe combined organic extracts were washed with sat'd aq NaCl
  11. dry with materialdried over MgSO4
  12. filtrationfiltered
  13. concentrationconcentrated
  14. customThe product was isolated
  15. additionFractions containing the product
  16. extractionextracted with EtOAc
  17. washThe combined organic extracts were washed with sat'd aq NaCl
  18. dry with materialdried over Na2SO4
  19. filtrationfiltered
  20. concentrationconcentrated

Sources & evidence

ORD record
ord-95b93367d9614fc3a9748e4aaab38043
Source dataset
uspto-grants-2014_07
Patent number
US08791091B2

Reaction notes

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