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

HRID 348358Notes

Reaction equation

HRID 348358 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.[CH3:25][C:26]1[O:30][C:29]([C:31]2[CH:36]=[CH:35][C:34]([C:37]3[S:38][CH:39]=[CH:40][CH:41]=3)=[CH:33][CH:32]=2)=[N:28][C:27]=1[CH2:42][CH2:43]OS(C1C=CC(C)=CC=1)(=O)=O.C([O-])([O-])=O.[K+].[K+].[OH-].[Na+]>C(O)C>[F:23][C:18]1[CH:17]=[C:16]([CH:21]=[CH:20][C:19]=1[F:22])[O:15][C:5]([CH3:14])([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:43][CH2:42][C:27]2[N:28]=[C:29]([C:31]3[CH:36]=[CH:35][C:34]([C:37]4[S:38][CH:39]=[CH:40][CH:41]=4)=[CH:33][CH:32]=3)[O:30][C:26]=2[CH3:25])=[CH:9][CH:8]=1)[C:4]([OH:3])=[O:24]

Participants

6

Reactant 4

HCID 11430Potassium CarbonateHCID 14798Sodium HydroxideHCID 693198392-(3,4-Difluorophenoxy)-3-(4-hydroxyphenyl)-2-methyl-propionic acid ethyl esterHCID 86593515Toluene-4-sulfonic acid 2-(5-methyl-2-(4-thiophen-2-yl-phenyl)-oxazol-4-yl)ethyl ester

Product 1

HCID 101882962-(3,4-Difluoro-phenoxy)-2-methyl-3-(4-{2-[5-methyl-2-(4-thiophen-2-yl-phenyl)-oxazol-4-yl]-ethoxy}-phenyl)-propionic acid

Reagents, catalysts & solvents 1

HCID 702EthanolSolvent2×

Procedure

A mixture of 2-(3,4-difluoro-phenoxy)-3-(4-hydroxyphenyl)-2-methyl-propionic acid ethyl ester (0.030 mmol) (see Ex. 45, Part C), toluene-4-sulfonic acid 2-(5-methyl-2-(4-thiophen-2-yl-phenyl)-oxazol-4-yl)-ethyl ester (0.030 mmol) (see Ex. 3, Part B) 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 2-(3,4-difluoro-phenoxy)-2-methyl-3-(4-{2-[5-methyl-2-(4-thiophen-2-yl-phenyl)-oxazol-4-yl]-ethoxy}-phenyl)-propionic acid. 1H NMR (400 MHz, CDCl3) δ 7.99 (d, 2H, J=8.8 Hz), 7.98 (bs, 1H), 7.67 (d, 2H, J=8.8 Hz), 7.42 (dd, 1H, J=4.0, 1.0 Hz), 7.36 (d, 1H, J=4.8 Hz), 7.17 (d, 2H, J=8.8 Hz), 7.12 (dd, 1H, J=4.8, 4.0 Hz), 7.00 (q, 1H, J=9.2 Hz), 6.83 (d, 2H, J=8.8 Hz), 6.76 (ddd, 1H, J=11.6, 6.8, 3.2 Hz), 6.63–6.59 (m, 1H), 4.21 (t, 2H, J=6.6 Hz), 3.23 and 3.10 (d of ABq, 2H, J=14.2 Hz), 3.07 (t, 2H, J=6.6 Hz), 2.43 (s, 3H), 1.38 (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-c7249a4e8d4d4f839e4361da02711258
Source dataset
uspto-grants-2007_02
Patent number
US07176224B2

Reaction notes

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