Ethyl Acetate → 4'-Fluoro-2'-methoxy-5'-(1-methylethyl)-4-(trifluoromethyl)(1,1'-biphenyl)-2-methanol

HRID 1994570Notes

Reaction equation

HRID 1994570 reaction equation
I[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[CH2:12][OH:13].[F:14][C:15]1[C:20]([CH:21]([CH3:23])[CH3:22])=[CH:19][C:18](B(O)O)=[C:17]([O:27][CH3:28])[CH:16]=1.C([O-])([O-])=O.[Na+].[Na+].CCOC(C)=O>C1C=CC=CC=1.CCO.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:14][C:15]1[C:20]([CH:21]([CH3:23])[CH3:22])=[CH:19][C:18]([C:2]2[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=2[CH2:12][OH:13])=[C:17]([O:27][CH3:28])[CH:16]=1

Participants

7

Reactant 4

HCID 8857Ethyl AcetateHCID 10340Sodium CarbonateHCID 23160665(2-Iodo-5-(trifluoromethyl)phenyl)methanolHCID 53363739(4-Fluoro-5-isopropyl-2-methoxyphenyl)boronic acid

Product 1

HCID 533638284'-Fluoro-2'-methoxy-5'-(1-methylethyl)-4-(trifluoromethyl)(1,1'-biphenyl)-2-methanol

Reagents, catalysts & solvents 2

HCID 178418397HCID 178418397, compoundCatalystHCID 66847609Benzene ethanol waterSolvent

Procedure

A mixture of [2-iodo-5-(trifluoromethyl)phenyl]methanol (EXAMPLE 69) (3.09 g, 10.2 mmol), (4-fluoro-5-isopropyl-2-methoxyphenyl)boronic acid (4.34 g, 20.5 mmol), (Ph3P)4Pd (1.42 g, 1.23 mmol) and Na2CO3 (9.11 g, 85.9 mmol) in benzene/EtOH/H2O (7:1:3, 250 mL) was heated at reflux for 24 h under N2. After cooling to room temperature, the aqueous phase was separated and extracted with CH2Cl2 (3×50 mL). The combined organic layers were dried (Na2SO4) and concentrated in vacuo to give the crude product. This was purified by flash chromatography (Si, 65×200 mm, 0-20% EtOAc in hexanes gradient) to afford 4′-fluoro-5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methanol. Rf=0.50 (20% EtOAc in hexanes). 1H NMR (500 MHz, CDCl3) δ 7.86 (s, 1H), 7.59 (d, J=6.7 Hz, 1H), 7.30 (d, J=7.9 Hz, 1H), 6.99 (d, J=8.6 Hz, 1H), 6.68 (d, J=12.0 Hz, 1H), 4.52 (br s, 1H), 4.46 (br s, 1H), 3.73 (s, 3H), 3.25-3.17 (m, 1H), 1.82 (br s, 1H), 1.24 (d, J=6.8 Hz, 6H).

Workup

  1. temperaturewas heated
  2. temperatureat reflux for 24 h under N2
  3. customthe aqueous phase was separated
  4. extractionextracted with CH2Cl2 (3×50 mL)
  5. dry with materialThe combined organic layers were dried (Na2SO4)
  6. concentrationconcentrated in vacuo
  7. customto give the crude product
  8. customThis was purified by flash chromatography (Si, 65×200 mm, 0-20% EtOAc in hexanes gradient)
  9. customto afford 4′-fluoro-5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methanol

Sources & evidence

ORD record
ord-d420662298994e0191964c10fa1d1fae
Source dataset
uspto-grants-2010_01
Patent number
US07652049B2

Reaction notes

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