Trifluoroacetic acid → 3-Methyl-3(2,4,6-trimethoxyphenylmethylthio)butyric acid

HRID 1604210Notes

Reaction equation

HRID 1604210 reaction equation
[SH:1][C:2]([CH3:8])([CH3:7])[CH2:3][C:4]([OH:6])=[O:5].FC(F)(F)C(O)=O.[CH3:16][O:17][C:18]1[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[C:22]([O:28][CH3:29])[C:19]=1[CH2:20]O>C(Cl)Cl>[CH3:7][C:2]([S:1][CH2:20][C:19]1[C:22]([O:28][CH3:29])=[CH:23][C:24]([O:26][CH3:27])=[CH:25][C:18]=1[O:17][CH3:16])([CH3:8])[CH2:3][C:4]([OH:6])=[O:5]

Participants

5

Reactant 3

HCID 6422Trifluoroacetic acidHCID 6025152,4,6-Trimethoxybenzyl alcoholHCID 98127863-Methyl-3-sulfanylbutanoic acid

Product 1

HCID 154581393-Methyl-3(2,4,6-trimethoxyphenylmethylthio)butyric acidYield 70%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent2×

Conditions

Temperature
5 °C

Procedure

To a solution of 3-mercapto-3-methylbutyric acid (B. J. Sweetman et al. J. Med Chem., 14, 868 (1971)) (4.6 g, 34 mmol) in methylene chloride (250 mL) under nitrogen and cooled over ice/salt to 5° C. (internal temperature) was added trifluoroacetic acid (82 g, 0.72 mol). No significant temperature rise was noted during the addition. To this was then added dropwise a solution of 2,4,6-trimethoxybenzyl alcohol (M. C. Munson et al., J. Org. Chem. 57, 3013 (1992)) (6.45 g, 32 mmol) in methylene chloride (150 mL) such that the reaction temperature does not rise above 5° C. After the addition was complete, the mixture was stirred for an additional 5 minutes at 5° C. and the volatiles were evaporated in vacuo (toluene or ethyl acetate can be used to assist in the removal of volatile material). The residue was partitioned between diethyl ether and water and the organic phase dried over anhydrous sodium sulfate, filtered and the volatile material evaporated in vacuo. The residue was treated with activated charcoal and recrystalised from diethyl ether/hexane. The product was isolated as an white solid in 70% yield (7 g) mp 103-105° C. 1H NMR (CDCl3) δ 6.12 (s, 2H), 3.80-3.85 (m, 11H), 2.74 (s, 2H), 1.47 (s, 6H). 13C NMR (CDCl3) δ 173.9, 160.6, 158.6, 105.6, 90.5, 55.7, 55.3, 45.9, 43.6, 28.4, 21.0.

Workup

  1. additionNo significant temperature rise was noted during the addition
  2. customdoes not rise above 5° C
  3. additionAfter the addition
  4. customthe volatiles were evaporated in vacuo (toluene or ethyl acetate
  5. customto assist in the removal of volatile material)
  6. customThe residue was partitioned between diethyl ether and water
  7. dry with materialthe organic phase dried over anhydrous sodium sulfate
  8. filtrationfiltered
  9. customthe volatile material evaporated in vacuo
  10. additionThe residue was treated with activated charcoal
  11. customrecrystalised from diethyl ether/hexane
  12. customThe product was isolated as an white solid in 70% yield (7 g) mp 103-105° C

Sources & evidence

ORD record
ord-fd65a875549e4f909bc1b1044f0dd489
Source dataset
uspto-grants-1999_11
Patent number
US05994294

Reaction notes

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