Potassium Carbonate → 3-{4-[2-(2-Biphenyl-3-yl-5-methyl-oxazol-4-yl)-ethoxy]-phenyl}-2-(3,4-difluoro-phenoxy)-2-methyl-propionic acid

HRID 348357Notes

Reaction equation

HRID 348357 reaction equation
C([O:3][C:4](=[O:24])[C:5]([O:15][C:16]1[CH:21]=[CH:20][C:19]([F:22])=[C:18]([F:23])[CH:17]=1)([CH3:14])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)C.[C:25]1([C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[CH:30]=[CH:29][CH:28]=[C:27]([C:31]2[O:32][C:33]([CH3:49])=[C:34]([CH2:36][CH2:37]OS(C3C=CC(C)=CC=3)(=O)=O)[N:35]=2)[CH:26]=1.C([O-])([O-])=O.[K+].[K+].[OH-].[Na+]>C(O)C>[C:25]1([C:50]2[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=2)[CH:30]=[CH:29][CH:28]=[C:27]([C:31]2[O:32][C:33]([CH3:49])=[C:34]([CH2:36][CH2:37][O:13][C:10]3[CH:11]=[CH:12][C:7]([CH2:6][C:5]([O:15][C:16]4[CH:21]=[CH:20][C:19]([F:22])=[C:18]([F:23])[CH:17]=4)([CH3:14])[C:4]([OH:3])=[O:24])=[CH:8][CH:9]=3)[N:35]=2)[CH:26]=1

Participants

6

Reactant 4

HCID 11430Potassium CarbonateHCID 14798Sodium HydroxideHCID 58979436Toluene-4-sulfonic acid 2-(2-biphenyl-3-yl-5-methyloxazol-4-yl)ethyl esterHCID 693198392-(3,4-Difluorophenoxy)-3-(4-hydroxyphenyl)-2-methyl-propionic acid ethyl ester

Product 1

HCID 101206603-{4-[2-(2-Biphenyl-3-yl-5-methyl-oxazol-4-yl)-ethoxy]-phenyl}-2-(3,4-difluoro-phenoxy)-2-methyl-propionic acid

Reagents, catalysts & solvents 1

HCID 702EthanolSolvent2×

Procedure

A mixture of 2-(3,4-difluorophenoxy)-3-(4-hydroxyphenyl)-2-methyl-propionic acid ethyl ester (0.030 mmol) (see Ex. 45, Part C), toluene-4-sulfonic acid 2-(2-biphenyl-3-yl-5-methyloxazol-4-yl)ethyl ester (0.030 mmol) (see Ex. 2, Part F) and 325 mesh K2CO3 (0.084 g, 0.60 mmol) in ethanol (2 mL) was heated to reflux for 24 h under N2. Aqueous 5N NaOH (0.5 mL) and additional ethanol (1 mL) was added to the reaction mixture and it was heated at reflux for an additional 2 h. The reaction was cooled and the solvent removed in vacuo. The residue was acidified with aqueous 1 N HCl (5 mL), extracted with water and CH2Cl2 and the organic layer dried by passing it through a Varian Chem Elut 1003 cartridge. The solvent was removed in vacuo to give 3-{4-[2-(2-biphenyl-3-yl-5-methyl-oxazol-4-yl)-ethoxy]-phenyl}-2-(3,4-difluoro-phenoxy)-2-methyl-propionic acid. 1H NMR (400 MHz, CDCl3) δ 8.24 (s, 1H), 8.23 (bs, 1H), 7.94 (d, 1H, J=8.0 Hz), 7.71 (d, 1H, J=8.0 Hz), 7.65 (d, 2H, J=7.6 Hz), 7.53 (t, 1H, J=7.6 Hz), 7.48–7.43 (m, 2H), 7.40–7.35 (m, 1H), 7.17 (d, 2H, J=8.4 Hz), 6.97 (q, 1H, J=9.6 Hz), 6.83 (d, 2H, J=8.4 Hz), 6.72 (ddd, 1H, J=12.0, 7.2, 3.2 Hz), 6.62–6.58 (m, 1H), 4.22 (t, 2H, J=6.4 Hz), 3.23 and 3.10 (d of ABq, 2H, J=14.0 Hz), 3.08 (t, 2H, J=6.4 Hz), 2.44 (s, 3H), 1.37 (s, 3H).

Workup

  1. temperaturewas heated
  2. temperatureto reflux for 24 h under N2
  3. temperaturewas heated
  4. temperatureat reflux for an additional 2 h
  5. temperatureThe reaction was cooled
  6. customthe solvent removed in vacuo
  7. extractionextracted with water and CH2Cl2
  8. customthe organic layer dried
  9. customThe solvent was removed in vacuo

Sources & evidence

ORD record
ord-d703d5496e1a40b2ba632e9aa3ddfb76
Source dataset
uspto-grants-2007_02
Patent number
US07176224B2

Reaction notes

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