Citric Acid → (R)-dimethyl 2-(3-(4-methoxybenzyl)-2-oxothiazolidin-4-yl)-2-oxoethylphosphonate

HRID 2219795Notes

Reaction equation

HRID 2219795 reaction equation
[CH3:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4].CON(C)[C:11]([CH:13]1[CH2:17][S:16][C:15](=[O:18])[N:14]1[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1)=[O:12].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1.O>[CH3:27][O:26][C:23]1[CH:22]=[CH:21][C:20]([CH2:19][N:14]2[C@H:13]([C:11](=[O:12])[CH2:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4])[CH2:17][S:16][C:15]2=[O:18])=[CH:25][CH:24]=1

Participants

6

Reactant 3

HCID 311Citric AcidHCID 12958Dimethyl methylphosphonate2×HCID 733183603-(4-Methoxy-benzyl)-2-oxo-thiazolidine-4-carboxylic acid methoxy-methyl-amide

Product 1

HCID 11164670(R)-dimethyl 2-(3-(4-methoxybenzyl)-2-oxothiazolidin-4-yl)-2-oxoethylphosphonateYield 94.8%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
-70 °C

Procedure

A dry three-necked round bottom flask fitted with an internal temperature probe and a mechanical stirrer was charged with dimethyl methylphosphonate (36.7 mL, 0.338 mol) and 0.5 L of THF. The solution was purged with nitrogen and cooled to −70° C. 126 mL of a 2.55 M solution of n-butyllithium was added dropwise maintaining an internal reaction temperature less than −60° C. In a separate flask, 3-(4-methoxy-benzyl)-2-oxo-thiazolidine-4-carboxylic acid methoxy-methyl-amide (50.0 g, 0.161 mol) was dissolved in 300 mL of dry THF. The resulting solution was added to the solution of dimethyl methylphosphonate anion at a rate maintaining an internal reaction temperature less than −60° C. The reaction was monitored by HPLC and was considered complete upon the disappearance of starting material. The reaction mixture was slowly added to 50 mL of a 10% citric acid solution at a rate that maintained a temperature of less than 5° C. The mixture was diluted with 0.35 L of water. The THF was removed by distillation at atmospheric pressure. The product was extracted with 300 mL of ethyl acetate. The organic phase was separated and a suspension was formed by the addition of 250 mL 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 57 g of (R)-dimethyl 2-(3-(4-methoxybenzyl)-2-oxothiazolidin-4-yl)-2-oxoethylphosphonate was obtained (94% yield). 1H NMR (300 MHz, DMSO) δ 7.16 (d, 8.5 Hz, 2H), 6.89 (d, 8.5 Hz, 2H), 4.78 (d, J=15.2 Hz, 1H), 4.69-4.61 (m, 1H), 3.79-3.55 (m, 11H), 3.51-3.27 (m, 3H). 13C NMR (75 MHz, DMSO) δ 36.3, 38.0, 46.9, 53.5, 55.08, 66.1, 114.7, 129.0, 129.9, 159.4, 171.9, 199.0; [α]25.0D-29.60 (c=1.00, EtOH).

Workup

  1. customA dry three-necked round bottom flask fitted with an internal temperature probe and a mechanical stirrer
  2. customThe solution was purged with nitrogen
  3. addition126 mL of a 2.55 M solution of n-butyllithium was added dropwise
  4. temperaturemaintaining an internal reaction temperature less than −60° C
  5. temperaturemaintaining an internal reaction temperature less than −60° C
  6. temperaturemaintained a temperature of less than 5° C
  7. customThe THF was removed by distillation at atmospheric pressure
  8. extractionThe product was extracted with 300 mL of ethyl acetate
  9. customThe organic phase was separated
  10. customa suspension was formed by the addition of 250 mL 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-f5eb3100220d4c17b5d5c687553d10e6
Source dataset
uspto-grants-2008_08
Patent number
US07414137B2

Reaction notes

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