Cesium carbonate → 3-{4-[3-(4-Chloro-2-cyclohexyl-phenoxy)-5-methyl-phenoxy]-2-methyl-phenyl}-propionic acid

HRID 1822253

Reaction equation

HRID 1822253 reaction equation
C[O:2][C:3](=[O:22])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]2[CH:18]=[C:17]([CH3:19])[CH:16]=[C:15](Br)[CH:14]=2)=[CH:8][C:7]=1[CH3:21].[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([OH:30])=[C:26]([CH:31]2[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]2)[CH:25]=1.CC(C)(C(=O)CC(=O)C(C)(C)C)C.C(=O)([O-])[O-].[Cs+].[Cs+].[OH-].[Na+]>CN1C(=O)CCC1.CO.[Cu]Cl>[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][C:15]2[CH:14]=[C:13]([CH:18]=[C:17]([CH3:19])[CH:16]=2)[O:12][C:9]2[CH:10]=[CH:11][C:6]([CH2:5][CH2:4][C:3]([OH:2])=[O:22])=[C:7]([CH3:21])[CH:8]=2)=[C:26]([CH:31]2[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]2)[CH:25]=1

Participants

9

Reactant 5

HCID 10796Cesium carbonateHCID 14798Sodium HydroxideHCID 707002,2,6,6-Tetramethyl-3,5-heptanedioneHCID 831204-Chloro-2-cyclohexylphenolHCID 578942123-[4-(3-Bromo-5-methyl-phenoxy)-2-methyl-phenyl]-propionic acid methyl ester

Product 1

HCID 112024153-{4-[3-(4-Chloro-2-cyclohexyl-phenoxy)-5-methyl-phenoxy]-2-methyl-phenyl}-propionic acidYield 38%

Reagents, catalysts & solvents 3

HCID 62652Cuprous chlorideCatalystHCID 887MethanolSolventHCID 13387N-methyl-2-pyrrolidoneSolvent

Procedure

A solution of 3-[4-(3-bromo-5-methyl-phenoxy)-2-methyl-phenyl]-propionic acid methyl ester (0.1 g, 0.27 mmol), 4-chloro-2-cyclohexyl-phenol (63 mg, 0.3 mmol), copper(I) chloride (13 mg, 0.13 mmol), 2,2,6,6-tetramethyl-3,5-heptanedione (0.01 mL, 0.07 mmol), and cesium carbonate (105 mg, 0.32 mmol) in NMP (3 mL) is heated to 120° C. The reaction is stirred overnight and cooled to rt. The reaction is quenched with 1N aqueous HCl and extracted with ethyl ether. The organic layer is washed with brine, dried over sodium sulfate, and filtered. The solvent is removed to afford the crude ester intermediate. The intermediate is treated with 5N NaOH (0.4 mL, 2.2 mmol) in MeOH (5 mL) and heated to reflux. The reaction stirred at reflux for 2 hours and then cooled. The reaction is quenched with 1N aqueous HCl to obtain pH=4. The aqueous layer is extracted with ethyl ether. The organic layer is washed with brine, dried over sodium sulfate, and filtered. The solvent is removed to afford the crude product. The crude is purified by HPLC to afford 49 mg (38%) of desired product. 1H NMR (400 MHz, CDCl3); MS (ES+) m/z mass calculated for C29H31ClO4 478, found 479 and 481 (M+1 and M+3, 100%).

Workup

  1. customThe reaction is quenched with 1N aqueous HCl
  2. extractionextracted with ethyl ether
  3. washThe organic layer is washed with brine
  4. dry with materialdried over sodium sulfate
  5. filtrationfiltered
  6. customThe solvent is removed
  7. customto afford the crude ester intermediate
  8. temperatureheated to reflux
  9. stirringThe reaction stirred
  10. temperatureat reflux for 2 hours
  11. temperaturecooled
  12. customThe reaction is quenched with 1N aqueous HCl
  13. customto obtain pH=4
  14. extractionThe aqueous layer is extracted with ethyl ether
  15. washThe organic layer is washed with brine
  16. dry with materialdried over sodium sulfate
  17. filtrationfiltered
  18. customThe solvent is removed
  19. customto afford the crude product
  20. customThe crude is purified by HPLC

Sources & evidence

ORD record
ord-e510c01daf424293b294850e22a1f045
Source dataset
uspto-grants-2009_10
Patent number
US07608639B2

Linked notes

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