Acetic Acid → methyl 2-(4-(benzyloxy)phenyl)-4-oxobutanoate

HRID 1835619Notes

Reaction equation

HRID 1835619 reaction equation
[CH3:1][O:2][C:3](=[O:22])[CH:4]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:10][CH:9]=1)[CH2:5][CH:6]=C.[O:23]=[O+][O-].C(O)(=O)C.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C.[Zn]>[CH3:1][O:2][C:3](=[O:22])[CH:4]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:10][CH:9]=1)[CH2:5][CH:6]=[O:23]

Participants

7

Reactant 4

HCID 176Acetic AcidHCID 24823OzoneHCID 516892Sodium BicarbonateHCID 11637943HCID 11637943, compound

Product 1

HCID 11609090methyl 2-(4-(benzyloxy)phenyl)-4-oxobutanoate

Reagents, catalysts & solvents 2

HCID 23994ZincCatalyst2×HCID 8857Ethyl AcetateSolvent

Conditions

Temperature
-70 °C

Procedure

Under a nitrogen atmosphere, 2-(4-benzyloxy-phenyl)-pent-4-enoic acid methyl ester (750 g; 2.53 mol) is dissolved in ethyl acetate (7.5 L), and the resulting mixture cooled to −70° C. Ozone is introduced subsurface into the reaction for 3 h causing the reaction mixture to turn blue. The reaction mass is purged subsurface with nitrogen for 0.5 h to displace any residual ozone. At this point HPLC analysis indicates complete consumption of the starting material. The reaction mixture is warmed to −30° C. and held. In a separate vessel, zinc (450 g; 6.88 mol) and aqueous acetic acid (500 mL in 500 mL water) are combined and cooled to 0° C. The contents of the ozonolysis reactor are added to the aqueous acidic zinc mixture at such a rate as to maintain a reaction temperature of ≦0° C. After the addition is complete and the mixture has been held for 2 h, HPLC indicates conversion of intermediates to the desired aldehyde. The reaction mixture is filtered through Celite®, washed with water (2×4.5 L), and water (4.5 L) is added to the organic phase. Sodium bicarbonate (150 g; 1.79 mol) is added to the mixture, and stirring for 0.25 h gives a pH of >7. The aqueous layer is removed, and the volume is reduced to 2.25 L by reduced pressure distillation. The mixture is held at 50° C., and heptane (3L) is added to slowly provide a precipitate. The resulting slurry is cooled to 20° C. over 2 h, the solids are filtered, washed with heptane (3 L), and dried to constant weight at 45° C. and ˜25″ Hg. The title aldehyde, compound A (513 g; 68% isolated yield) is afforded as a tan solid.

Workup

  1. custominto the reaction for 3 h
  2. customThe reaction mass is purged subsurface with nitrogen for 0.5 h
  3. customconsumption of the starting material
  4. temperatureThe reaction mixture is warmed to −30° C.
  5. temperaturecooled to 0° C
  6. temperatureto maintain a reaction temperature of ≦0° C
  7. additionAfter the addition
  8. filtrationThe reaction mixture is filtered through Celite®
  9. washwashed with water (2×4.5 L), and water (4.5 L)
  10. additionis added to the organic phase
  11. customgives a pH of >7
  12. customThe aqueous layer is removed
  13. distillationthe volume is reduced to 2.25 L by reduced pressure distillation
  14. customis held at 50° C.
  15. additionheptane (3L) is added
  16. customto slowly provide a precipitate
  17. temperatureThe resulting slurry is cooled to 20° C. over 2 h
  18. filtrationthe solids are filtered
  19. washwashed with heptane (3 L)
  20. customdried to constant weight at 45° C.

Sources & evidence

ORD record
ord-a641bd1afad847a1b51b719510e9f86f
Source dataset
uspto-grants-2004_08
Patent number
US06770763B2

Reaction notes

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