Water → Tesaglitazar

HRID 6978Notes

Reaction equation

HRID 6978 reaction equation
[CH2:1]([O:3][C@@H:4]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][S:27]([CH3:30])(=[O:29])=[O:28])=[CH:22][CH:21]=2)=[CH:13][CH:12]=1)[C:5]([O:7]CC)=[O:6])[CH3:2].O1CCCC1.O.[OH-].[Li+]>C(OCC)(=O)C>[CH2:1]([O:3][C@@H:4]([CH2:10][C:11]1[CH:12]=[CH:13][C:14]([O:17][CH2:18][CH2:19][C:20]2[CH:21]=[CH:22][C:23]([O:26][S:27]([CH3:30])(=[O:28])=[O:29])=[CH:24][CH:25]=2)=[CH:15][CH:16]=1)[C:5]([OH:7])=[O:6])[CH3:2]

Participants

6

Reactant 4

HCID 962WaterHCID 3939Lithium HydroxideHCID 8028TetrahydrofuranHCID 11293498ethyl (S)-2-ethoxy-3-[4-[[4-(methylsulfonyloxy)phenethyl]oxy]phenyl]propanoate

Product 1

HCID 208901Tesaglitazar

Reagents, catalysts & solvents 1

HCID 8857Ethyl AcetateSolvent

Procedure

To the oil of ethyl (S)-2-ethoxy-3-[4-[[4-(methylsulfonyloxy)phenethyl]oxy]phenyl]propanoate (723 g(71.2% assay), 1.18 mol, 1.0 eq) was added tetrahydrofuran (THF) (3900 ml). When a homogenous solution was formed, water (900 ml) was added. The mixture was cooled to +10° C. Lithium hydroxide solution (390 ml, 4 M, 1.45 eq) was added over 1 hour. The temperature was then raised to +30° C. and the reaction allowed to proceed at this temperature for 2–3 hours. The reaction was stopped when the conversion was >99%. Ethyl acetate (500 ml) was added and the mixture cooled to room temperature. The solution was stirred for about 30 minutes and the THF was evaporated off. When about 80–90% of the THF was evaporated water (1900 ml) was added. The evaporation was continued until no THF remained in the mixture. The alkali water solution was then washed with ethyl acetate (1000 ml, 2×1250 ml, and 950 ml). The pH of the water solution of (S)-2-ethoxy-3-[4-[[4-(methylsulphonyloxy)phenethyl]oxy]phenyl]propanoic acid was then adjusted to 2.0–2.5 with HCl (aq) (550 ml, 3.0 M). Ethyl acetate (2500 ml) was added and the phases separated. The ethyl acetate solution of (S)-2-ethoxy-3-[4-[[4-(methylsulphonyloxy)phenethyl]oxy]phenyl]propanoic acid was then washed with water (700 ml) and after separation evaporated to dryness. The remaining oil was then used in the following crystallisation

Workup

  1. customWhen a homogenous solution was formed
  2. temperatureThe mixture was cooled to +10° C
  3. temperatureThe temperature was then raised to +30° C.
  4. waitto proceed at this temperature for 2–3 hours
  5. customthe THF was evaporated off
  6. customWhen about 80–90% of the THF was evaporated water (1900 ml)
  7. additionwas added
  8. customThe evaporation
  9. washThe alkali water solution was then washed with ethyl acetate (1000 ml, 2×1250 ml, and 950 ml)
  10. additionEthyl acetate (2500 ml) was added
  11. customthe phases separated
  12. washThe ethyl acetate solution of (S)-2-ethoxy-3-[4-[[4-(methylsulphonyloxy)phenethyl]oxy]phenyl]propanoic acid was then washed with water (700 ml)
  13. customafter separation
  14. customevaporated to dryness
  15. customThe remaining oil was then used in the following crystallisation

Sources & evidence

ORD record
ord-cc6cc8363cff42a4af4528dcc64a7236
Source dataset
uspto-grants-2006_08
Patent number
US07084177B2

Reaction notes

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