Acetic Acid → HCID 15512565, compound

HRID 324585Notes

Reaction equation

HRID 324585 reaction equation
[CH:1]1[C:6]([CH:7]=[O:8])=[CH:5][C:4]2[O:9][CH2:10][O:11][C:3]=2[CH:2]=1.O[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH:20]([CH3:22])[CH3:21])=[CH:15][C:14]=1[C:23](=[O:29])[CH2:24][C:25]([O:27][CH3:28])=[O:26].N1CCCCC1.C(O)(=O)C>C1(C)C=CC=CC=1>[O:11]1[C:3]2[CH:2]=[CH:1][C:6]([CH:7]3[CH:24]([C:25]([O:27][CH3:28])=[O:26])[C:23](=[O:29])[C:14]4[C:13](=[CH:18][CH:17]=[C:16]([O:19][CH:20]([CH3:22])[CH3:21])[CH:15]=4)[O:8]3)=[CH:5][C:4]=2[O:9][CH2:10]1

Participants

6

Reactant 4

HCID 176Acetic AcidHCID 8082PiperidineHCID 8438PiperonalHCID 15512564HCID 15512564, compound

Product 1

HCID 15512565HCID 15512565, compound

Reagents, catalysts & solvents 1

HCID 1140TolueneSolvent2×

Procedure

A solution of piperonal (182.4 g, 1.22 mol) in toluene (1 L) was heated to reflux in a flask equipped with a Dean Stark dehydration apparatus to which a mixture of methyl 3-(2-hydroxy-5-isopropoxy-phenyl)-3-oxo-propionate (VIII-2) (151 g, 0.61 mol) synthesized by the method described in Reference Example 4, piperidine (1.55 g, 0,018 mol), acetic acid (3.65 g, 0.061 mol) in toluene (1.3 L) was added dropwise over a period of 1 h and the solution was refluxed for another 1 h. After cooling, the reaction mixture was poured into ice water (3 L) and extracted with toluene. The organic layer was washed with water, dried, and concentrated under reduced pressure. The residue was treated with Girard T reagent (143 g) in methanol (500 ml) and toluene (2 L) for 2 h. Brine (3.5 L) was added and the organic layer was separated and the aqueous layer was further extracted with toluene. The combined organic layers were washed with water, dried, and concentrated. The residue was subjected to a chromatographed on silica gel (toluene). During the elution, the products gradually cyclized to give compound (IV-2) (102 g, 44%) as an oil. The oil was clarified a keto-enol tautomeric mixture as shown by NMR. NMR(CDCl3):1.3 l(d, J=6.0), 1.32*(d, J=6.2), 3.67*(s), 3.76(s), 4.02*(d, J=12.0), 4.46(m), 4.53*(m), 5.55*(d, J=12.0), 5.91*(s), 6.00(s),6.10(s), 6.67-7.36(m) (* are signals derived from a major product)

Workup

  1. temperatureto reflux in a flask
  2. customequipped with a Dean Stark dehydration apparatus to which
  3. customsynthesized by the method
  4. additionwas added dropwise over a period of 1 h
  5. temperaturethe solution was refluxed for another 1 h
  6. temperatureAfter cooling
  7. extractionextracted with toluene
  8. washThe organic layer was washed with water
  9. customdried
  10. concentrationconcentrated under reduced pressure
  11. additionThe residue was treated with Girard T reagent (143 g) in methanol (500 ml) and toluene (2 L) for 2 h
  12. additionBrine (3.5 L) was added
  13. customthe organic layer was separated
  14. extractionthe aqueous layer was further extracted with toluene
  15. washThe combined organic layers were washed with water
  16. customdried
  17. concentrationconcentrated
  18. customa chromatographed on silica gel (toluene)
  19. washDuring the elution
  20. customto give compound (IV-2) (102 g, 44%) as an oil

Sources & evidence

ORD record
ord-b2a35a227bf6430aa34ee6ec6dd2885d
Source dataset
uspto-grants-2001_04
Patent number
US06218427B1

Reaction notes

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