3,5-Pyridinedicarboxylic acid → Edaglitazone

HRID 854418Notes

Reaction equation

HRID 854418 reaction equation
N1C=C(C(O)=O)C=C(C(O)=O)C=1.[CH3:13][C:14]1[O:18][C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[N:16][C:15]=1[CH2:25][CH2:26][O:27][C:28]1[C:36]2[CH:35]=[CH:34][S:33][C:32]=2[C:31]([CH:37]=[C:38]2[S:42][C:41](=[O:43])[NH:40][C:39]2=[O:44])=[CH:30][CH:29]=1>>[CH3:13][C:14]1[O:18][C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[N:16][C:15]=1[CH2:25][CH2:26][O:27][C:28]1[C:36]2[CH:35]=[CH:34][S:33][C:32]=2[C:31]([CH2:37][CH:38]2[S:42][C:41](=[O:43])[NH:40][C:39]2=[O:44])=[CH:30][CH:29]=1

Participants

3

Reactant 2

HCID 103663,5-Pyridinedicarboxylic acidHCID 853192475-[[4-[2-(5-Methyl-2-phenyl-4-oxazolyl)ethoxy]-benzo[b]thien-7-yl]methylene]-2,4-thiazolidinedione2×

Product 1

HCID 9825701EdaglitazoneYield 92.5%

Conditions

Temperature
260 °C

Procedure

The content of the 1500 ml glass reactor was heated to 260° C. with a metal bath, while the content of the 1000 ml glass flask was heated to 145° C. The solution of 3,5-pyridinedicarboxylic acid, 1,4-dihydro-2,6-dimethyl-, diethyl ester was transferred within 1 to 2 minutes to the stirred solution of 5-[[4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]-benzo[b]thien-7-yl]methylene]-2,4-thiazolidinedione. The temperature dropped to 220-230° C. and the mixture was heated again to 260° C. After 10 to 15 minutes 5-[[4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]benzo[b]thien-7-yl]methylene]-2,4-thiazolidinedione was completely converted, and the metal bath removed. When the reaction mixture reached a temperature of 90° C., 650 ml of a mixture of n-heptane and ethanol (9:1) was added via a dropping funnel within 10 minutes. The mixture was seeded with 5-{[4-[2-(5-methyl-2-phenyl-oxazol-4-yl)ethoxy]benzo[b]thiophen-7-yl]methyl}-2,4-thiazolidinedione and crystallization started at 50° C. The suspension was cooled to 0° C. and stirred at that temperature for 5 h. The crystals were filtered off and washed with 4 portions of ethanol each 125 ml. The wet material was dried at 140° C., 10 mbar for 15 h, which afforded 89.1 g of white crystalline 5-{[4-[2-(5-methyl-2-phenyl-oxazol-4-yl)ethoxy]benzo[b]thiophen-7-yl]methyl}-2,4-thiazolidinedione with a purity of 96.5% according to HPLC analysis, corresponding to a corrected yield of 92.5%.

Workup

  1. temperaturewas heated to 145° C
  2. additionThe temperature dropped to 220-230° C.
  3. temperaturethe mixture was heated again to 260° C
  4. customthe metal bath removed
  5. customa temperature of 90° C., 650 ml of a mixture of n-heptane and ethanol (9:1)
  6. additionwas added via a dropping funnel within 10 minutes
  7. customThe mixture was seeded with 5-{[4-[2-(5-methyl-2-phenyl-oxazol-4-yl)ethoxy]benzo[b]thiophen-7-yl]methyl}-2,4-thiazolidinedione and crystallization
  8. customstarted at 50° C
  9. temperatureThe suspension was cooled to 0° C.
  10. filtrationThe crystals were filtered off
  11. washwashed with 4 portions of ethanol each 125 ml
  12. customThe wet material was dried at 140° C.
  13. wait10 mbar for 15 h

Sources & evidence

ORD record
ord-88d33353a9d04009b6db96520f08e778
Source dataset
uspto-grants-2007_08
Patent number
US07259176B2

Reaction notes

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