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

HRID 990701Notes

Reaction equation

HRID 990701 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 (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 (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 removed 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 removed in vacuo. The residue was treated with activated charcoal and recrystalized from diethyl ether/hexane. The product was isolated as a white solid in 70% yield (7 g); mp 103-105° C. 1H NMR (CDCl3) δ 6.12 (s, 2 H), 3.80-3.85 (m, 11 H), 2.74 (s, 2 H), 1.47 (s, 6 H). 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 removed 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 removed in vacuo
  10. additionThe residue was treated with activated charcoal
  11. customrecrystalized from diethyl ether/hexane
  12. customThe product was isolated as a white solid in 70% yield (7 g)

Sources & evidence

ORD record
ord-33f456498e1f4cdbb6c7c0dbc96f34a1
Source dataset
uspto-grants-2002_10
Patent number
US06462044B2

Reaction notes

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