Cesium carbonate → {4-[3-(4-Chloro-2-phenoxy-phenoxy)-phenoxy]-2-methyl-phenylsulfanyl}-acetic acid

HRID 1822251Notes

Reaction equation

HRID 1822251 reaction equation
Br[C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][CH:22]=1)[O:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][C:7]=1[O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C([O:25][C:26](=[O:37])[CH2:27][S:28][C:29]1[CH:34]=[CH:33][C:32]([OH:35])=[CH:31][C:30]=1[CH3:36])C.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:12][C:9]1[CH:10]=[CH:11][C:6]([O:5][C:4]2[CH:3]=[C:2]([CH:22]=[CH:21][CH:20]=2)[O:35][C:32]2[CH:33]=[CH:34][C:29]([S:28][CH2:27][C:26]([OH:37])=[O:25])=[C:30]([CH3:36])[CH:31]=2)=[C:7]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:8]=1

Participants

9

Reactant 5

HCID 10796Cesium carbonateHCID 14798Sodium HydroxideHCID 707002,2,6,6-Tetramethyl-3,5-heptanedioneHCID 578942271-(3-Bromo-phenoxy)-4-chloro-2-phenoxy-benzeneHCID 59164200(4-Hydroxy-2-methyl-phenylsulfanyl)-acetic acid ethyl ester

Product 1

HCID 11785199{4-[3-(4-Chloro-2-phenoxy-phenoxy)-phenoxy]-2-methyl-phenylsulfanyl}-acetic acidYield 40%

Reagents, catalysts & solvents 3

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

Procedure

A solution of 1-(3-bromo-phenoxy)-4-chloro-2-phenoxy-benzene (0.15 g, 0.4 mmol), (4-hydroxy-2-methyl-phenylsulfanyl)-acetic acid ethyl ester (99 mg, 0.44 mmol), copper(I) chloride (20 mg, 0.2 mmol), 2,2,6,6-tetramethyl-3,5-heptanedione (0.02 mL, 0.1 mmol), and cesium carbonate (156 mg, 0.48 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 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 is stirred at reflux for 2 hours and then cooled. The reaction is quenched with 1N aqueous HCl to give 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 prep HPLC to afford 78 mg (40%) of desired product. 1H NMR (400 MHz, CDCl3); MS (ES+) m/z mass calculated for C27H21ClO5S 492, found 493 and 495 (M+1 and M+3, 100%).

Workup

  1. customThe reaction is quenched with 1N aqueous HCl
  2. extractionextracted with ethyl ether
  3. washThe organic 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 is stirred
  10. temperatureat reflux for 2 hours
  11. temperaturecooled
  12. customThe reaction is quenched with 1N aqueous HCl
  13. customto give 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 prep HPLC

Sources & evidence

ORD record
ord-a6996c2bcfca4d48a9f36a3a5444bbfb
Source dataset
uspto-grants-2009_10
Patent number
US07608639B2

Reaction notes

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