p-Toluenesulfonic acid → 2-{[2'-(bromomethyl)-4-fluoro-5-isopropyl-2-methoxy-4'-(trifluoromethyl)biphenyl-3-yl]oxy}tetrahydro-2H-pyran

HRID 1994600Notes

Reaction equation

HRID 1994600 reaction equation
[O:1]1[CH:6]=[CH:5][CH2:4][CH2:3][CH2:2]1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[Br:18][CH2:19][C:20]1[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][C:21]=1[C:30]1[CH:35]=[C:34]([CH:36]([CH3:38])[CH3:37])[C:33]([F:39])=[C:32]([OH:40])[C:31]=1[O:41][CH3:42]>C(Cl)Cl>[Br:18][CH2:19][C:20]1[CH:25]=[C:24]([C:26]([F:27])([F:28])[F:29])[CH:23]=[CH:22][C:21]=1[C:30]1[CH:35]=[C:34]([CH:36]([CH3:38])[CH3:37])[C:33]([F:39])=[C:32]([O:40][CH:6]2[CH2:5][CH2:4][CH2:3][CH2:2][O:1]2)[C:31]=1[O:41][CH3:42]

Participants

5

Reactant 3

HCID 6101p-Toluenesulfonic acidHCID 80803,4-dihydro-2H-pyranHCID 866034362'-(Bromomethyl)-4-fluoro-5-isopropyl-2-methoxy-4'-(trifluoromethyl)biphenyl-3-ol

Product 1

HCID 866034372-{[2'-(bromomethyl)-4-fluoro-5-isopropyl-2-methoxy-4'-(trifluoromethyl)biphenyl-3-yl]oxy}tetrahydro-2H-pyran

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent2×

Procedure

3,4-Dihydro-2H-pyran (51.9 mg, 56 μL, 0.617 mmol) was added to a stirred solution of p-toluenesulfonic acid (2.3 mg, 0.0123 mmol) and 2′-(bromomethyl)-4-fluoro-5-isopropyl-2-methoxy-4′-(trifluoromethyl)biphenyl-3-ol (52.0 mg, 0.123 mmol) in dry CH2Cl2 (6.1 mL) at room temperature under N2 and the reaction was stirred overnight. The reaction mixture was diluted with CH2Cl2 (45 mL) and washed with saturated NaHCO3 (5 mL) and 30% saturated Na2SO3 (5 mL), dried (Na2SO4) and concentrated in vacuo to give the crude product. This was purified by flash chromatography (Si, 12×160 mm, 0-40% EtOAc in hexanes gradient) to afford 2-{[2′-(bromomethyl)-4-fluoro-5-isopropyl-2-methoxy-4′-(trifluoromethyl)biphenyl-3-yl]oxy}tetrahydro-2H-pyran. Rf=0.59 (20% EtOAc in hexanes). 1H NMR (600 MHz, CDCl3) δ 7.82 (s, 1H), 7.60 (d, J=7.0 Hz, 1H), 7.41 (d, J=8.0 Hz, 1H), 6.67 (d, J=7.8 Hz, 1H), 5.77 (s, 1H), 4.97 (dd, J=4.9, 2.9 Hz, 1H), 4.49 (d, J=9.8 Hz, 1H), 4.37 (d, J=9.8 Hz, 1H), 3.89-3.87 (m, 1H), 3.61-3.49 (m, 1H), 3.46 (s, 3H), 3.27-3.21 (m, 1H), 1.89-1.83 (m, 1H), 1.78-1.70 (m, 1H) 1.64-1.48 (m, 3H), 1.26 (d, J=6.8 Hz, 6H).

Workup

  1. washwashed with saturated NaHCO3 (5 mL) and 30% saturated Na2SO3 (5 mL)
  2. dry with materialdried (Na2SO4)
  3. concentrationconcentrated in vacuo
  4. customto give the crude product
  5. customThis was purified by flash chromatography (Si, 12×160 mm, 0-40% EtOAc in hexanes gradient)

Sources & evidence

ORD record
ord-a4d4c6bd4b4b4a45a4e12f23dde3241e
Source dataset
uspto-grants-2010_01
Patent number
US07652049B2

Reaction notes

Loading…