4,4-Difluoro-1-methylcyclohexan-1-ol → 1-Bromo-5-chloro-4-(((4,4-difluoro-1-methylcyclohexyl)-oxy)methyl)-2-fluorobenzene

HRID 1849602Notes

Reaction equation

HRID 1849602 reaction equation
ClC(Cl)(Cl)C(=N)O[CH2:5][C:6]1[CH:11]=[C:10]([F:12])[C:9]([Br:13])=[CH:8][C:7]=1[Cl:14].[F:18][C:19]1([F:27])[CH2:24][CH2:23][C:22]([CH3:26])([OH:25])[CH2:21][CH2:20]1>C(Cl)Cl.C1CCCCC1.FC(F)(F)S(O)(=O)=O>[Br:13][C:9]1[CH:8]=[C:7]([Cl:14])[C:6]([CH2:5][O:25][C:22]2([CH3:26])[CH2:23][CH2:24][C:19]([F:27])([F:18])[CH2:20][CH2:21]2)=[CH:11][C:10]=1[F:12]

Participants

6

Reactant 2

HCID 666026184,4-Difluoro-1-methylcyclohexan-1-olHCID 867028534-Bromo-2-chloro-5-fluorobenzyl 2,2,2-trichloroacetimidate

Product 1

HCID 867034571-Bromo-5-chloro-4-(((4,4-difluoro-1-methylcyclohexyl)-oxy)methyl)-2-fluorobenzeneYield 18.1%

Reagents, catalysts & solvents 3

HCID 62406Trifluoromethanesulfonic acidCatalystHCID 6344DichloromethaneSolventHCID 8078CyclohexaneSolvent

Procedure

To a solution of 4-bromo-2-chloro-5-fluorobenzyl 2,2,2-trichloroacetimidate (4.00 g, 10.40 mmol) and 4,4-difluoro-1-methylcyclohexanol (1.21 g, 8.05 mmol) in methylene chloride (50 mL) and cyclohexane (25 mL) was added trifluoromethanesulfonic acid (0.1 mL, 0.14 mmol) at 0 ?C. The reaction mixture was stirred for 56 hours at ambient temperature and quenched by addition of saturated sodium bicarbonate solution (10 mL), and then diluted with methylene chloride (100 mL). The organic layer was separated and washed with brine; dried over anhydrous sodium sulfate and concentrated in vacuo. Purification of the residue by column chromatography (5% ethyl acetate in hexanes) and recrystallization from methanol afforded the title compound (0.54 g, 17%) as a colorless solid: 1H NMR (300 MHz, CDCl3) δ 7.51 (d, J=6.0 Hz, 1H), 7.30 (d, J=9.3 Hz, 1H), 4.37 (s, 2H), 2.11-1.86 (m, 6H), 1.72-1.59 (m, 2H), 1.26 (s, 3H).

Workup

  1. customquenched by addition of saturated sodium bicarbonate solution (10 mL)
  2. additiondiluted with methylene chloride (100 mL)
  3. customThe organic layer was separated
  4. washwashed with brine
  5. dry with materialdried over anhydrous sodium sulfate
  6. concentrationconcentrated in vacuo
  7. customPurification of the residue
  8. customby column chromatography (5% ethyl acetate in hexanes) and recrystallization from methanol

Sources & evidence

ORD record
ord-746fd5b2a4b54983a61ed4921830cb89
Source dataset
uspto-grants-2015_02
Patent number
US08952169B2

Reaction notes

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