Lithium hydroxide, monohydrate → Tesaglitazar

HRID 432080Notes

Reaction equation

HRID 432080 reaction equation
O.[OH-].[Li+].C([O:6][C:7](=[O:33])[C@@H:8]([O:30][CH2:31][CH3:32])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][S:26]([CH3:29])(=[O:28])=[O:27])=[CH:21][CH:20]=2)=[CH:12][CH:11]=1)C>O.O1CCCC1>[CH2:31]([O:30][C@@H:8]([CH2:9][C:10]1[CH:11]=[CH:12][C:13]([O:16][CH2:17][CH2:18][C:19]2[CH:20]=[CH:21][C:22]([O:25][S:26]([CH3:29])(=[O:27])=[O:28])=[CH:23][CH:24]=2)=[CH:14][CH:15]=1)[C:7]([OH:33])=[O:6])[CH3:32]

Participants

5

Reactant 2

HCID 168937Lithium hydroxide, monohydrate3×HCID 11293498ethyl (S)-2-ethoxy-3-[4-[[4-(methylsulfonyloxy)phenethyl]oxy]phenyl]propanoate

Product 1

HCID 208901TesaglitazarYield 88.8%

Reagents, catalysts & solvents 2

HCID 962WaterSolvent4×HCID 8028TetrahydrofuranSolvent

Conditions

Temperature
20 °C

Procedure

Lithium hydroxide hydrate (0.229 g; 5.45 mmole) dissolved in water (6 ml) was slowly added to a mixture of (S)-2-ethoxy-3-[4-(2-{4-methanesulfonyloxyphenyl} ethoxy)phenyl]-propanoic acid ethyl ester (2.29 g; 5.24 mmole) in tetrahydrofuran (50 ml) and water (10 ml) at 5° C. The reaction mixture was stirred at 5° C. for 2.5 hours, at 20° C. for 3 hours, at 0° C. for 15 hours and at 20° C. for 3,5 hours. More lithium hydroxide hydrate (44 mg, 1.05 mmole) dissolved in water (1 ml) was added at 10° C. After another 21.5 hours of stirring at 10° C., more lithium hydroxide hydrate (44 mg; 1.05 mmole) dissolved in water (1 ml) was added. The reaction mixture was stirred at 25° C. for 3 hours and then kept at 2° C. for 67 hours. Tetrahydrofuran was evaporated in vacuo and then water and ethyl acetate were added. Insoluble material was filtered off and the phases of the filtrate were separated. The water phase was washed twice with ethyl acetate, acidified with hydrochloric acid (2 M; 3.2 ml) and extracted with ethyl acetate (30 ml). The organic phase was washed twice with water, dried (magnesium sulfate), filtered and the solvent was evaporated in vacuo to give 1.9 g (yield 72% in 2 steps) of (S)-2-ethoxy-3-[4-(2-{4-methanesulfonyloxyphenyl}-ethoxy)phenyl]propanoic acid.

Workup

  1. additionwas added at 10° C
  2. stirringAfter another 21.5 hours of stirring at 10° C.
  3. additionwas added
  4. stirringThe reaction mixture was stirred at 25° C. for 3 hours
  5. waitkept at 2° C. for 67 hours
  6. customTetrahydrofuran was evaporated in vacuo
  7. additionwater and ethyl acetate were added
  8. filtrationInsoluble material was filtered off
  9. customthe phases of the filtrate were separated
  10. washThe water phase was washed twice with ethyl acetate
  11. extractionextracted with ethyl acetate (30 ml)
  12. washThe organic phase was washed twice with water
  13. dry with materialdried (magnesium sulfate)
  14. filtrationfiltered
  15. customthe solvent was evaporated in vacuo

Sources & evidence

ORD record
ord-66b3d145d490417e9deedad51c76b392
Source dataset
uspto-grants-2003_12
Patent number
US06660879B2

Reaction notes

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