Citric Acid → 4-Acetyl-3-[(4-methoxyphenyl)methyl]-1,3-thiazolidin-2-one

HRID 551774Notes

Reaction equation

HRID 551774 reaction equation
[C:1]([C@@H:4]1[CH2:8][S:7][C:6](=[O:9])[N:5]1[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1)(=[O:3])[CH3:2].C[Mg]Cl.CON(C)C(C1CSC(=O)N1CC1C=CC(OC)=CC=1)=O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1.O>[C:1]([CH:4]1[CH2:8][S:7][C:6](=[O:9])[N:5]1[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1)(=[O:3])[CH3:2]

Participants

7

Reactant 4

HCID 311Citric AcidHCID 11346122(R)-3-(4-Methoxybenzyl)-4-acetylthiazolidin-2-oneHCID 733183603-(4-Methoxy-benzyl)-2-oxo-thiazolidine-4-carboxylic acid methoxy-methyl-amideHCID 178418332HCID 178418332, compound2×

Product 1

HCID 534204854-Acetyl-3-[(4-methoxyphenyl)methyl]-1,3-thiazolidin-2-oneYield 80%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
0 °C

Procedure

Preparation of (R)-4-acetyl-3-(4-methoxy-benzyl)-thiazolidin-2-one (A compound of Formula I): A dry three-necked round bottom flask fitted with an internal temperature probe and a mechanical stirrer was charged with 0.805 L of a 3 M solution of methylmagnesium chloride in THF. The solution was purged with nitrogen and cooled to 0° C. In a separate flask, 3-(4-methoxy-benzyl)-2-oxo-thiazolidine-4-carboxylic acid methoxy-methyl-amide (250.0 g, 0.805 mol) was dissolved in 1.00 L of dry THF. The resulting solution was added to the solution of methyl magnesium chloride at a rate that maintained an internal reaction temperature less than 5° C. The reaction was monitored by HPLC and was considered complete upon the disappearance of starting material. The reaction mixture was slowly added to 1.00 L of a 10% citric acid solution at a rate that maintained a temperature of less than 25° C. The mixture was diluted with 0.90 L of water. The THF was removed by distillation at atmospheric pressure. The product was extracted with 2.5 L of ethyl acetate. The organic phase was separated, concentrated to a final volume of ˜800 mL and cooled to room temperature. A suspension was formed by the addition of 16 L of n-heptane. The suspension was stirred for 30 minutes. The resulting solid was isolated by filtration and was dried in a vacuum oven at 40° C. for 12 hours. Approximately 170 g of 4-acetyl-3-(4-methoxy-benzyl)-thiazolidin-2-one was obtained (80% yield). 1H NMR (300 MHz, DMSO) δ 7.14 (d, 8.9 Hz, 2H), 6.88 (d, 8.9 Hz, 2H), 4.48 (dd, J=9.4, 2.6 Hz, 1H), 4.27 (AB, JAB=15.2 Hz, ΔνAB=267.3 Hz, 2H), 3.72 (s, 3H), 3.62 (dd, J=11.9, 10.0 Hz, 1H), 3.37 (dd, J=11.8, 2.6 Hz, 1H), 2.19 (s, 3H). 13C NMR (75 MHz, DMSO) δ 26.9, 27.9, 47.2, 55.8, 66.0, 114.7, 129.1, 130.0, 159.4, 171.7, 205.1; [α]26.5D-56.0° (c=1.39, EtOH).

Workup

  1. customfitted with an internal temperature probe and a mechanical stirrer
  2. customThe solution was purged with nitrogen
  3. temperaturemaintained an internal reaction temperature less than 5° C
  4. temperaturethat maintained a temperature of less than 25° C
  5. customThe THF was removed by distillation at atmospheric pressure
  6. extractionThe product was extracted with 2.5 L of ethyl acetate
  7. customThe organic phase was separated
  8. concentrationconcentrated to a final volume of ˜800 mL
  9. temperaturecooled to room temperature
  10. customA suspension was formed by the addition of 16 L of n-heptane
  11. customThe resulting solid was isolated by filtration
  12. customwas dried in a vacuum oven at 40° C. for 12 hours

Sources & evidence

ORD record
ord-b82f697cfa6f4368b9184c70d9d60a0a
Source dataset
uspto-grants-2011_05
Patent number
US07947850B2

Reaction notes

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