p-Toluenesulfonic acid → Iopamidol ep impurity C

HRID 1590528Notes

Reaction equation

HRID 1590528 reaction equation
[NH2:1][C:2]1[C:3]([I:26])=[C:4]([C:18]([NH:20][CH:21]([CH2:24][OH:25])[CH2:22][OH:23])=[O:19])[C:5]([I:17])=[C:6]([C:15]=1[I:16])[C:7]([NH:9][CH:10]([CH2:13][OH:14])[CH2:11][OH:12])=[O:8].C1(C)C=CC(S(O)(=O)=O)=CC=1.[C:38](OC(=O)C)(=[O:40])[CH3:39]>>[C:38]([NH:1][C:2]1[C:15]([I:16])=[C:6]([C:7]([NH:9][CH:10]([CH2:13][OH:14])[CH2:11][OH:12])=[O:8])[C:5]([I:17])=[C:4]([C:3]=1[I:26])[C:18]([NH:20][CH:21]([CH2:24][OH:25])[CH2:22][OH:23])=[O:19])(=[O:40])[CH3:39]

Participants

4

Reactant 3

HCID 6101p-Toluenesulfonic acidHCID 7918Acetic AnhydrideHCID 10439744N,N'-Bis-(1,3-dihydroxy-2-propyl)-5-amino-2,4,6-triiodoisophthalamide

Product 1

HCID 13140687Iopamidol ep impurity C

Procedure

5-Amino-N,N'-bis(1,3-dihydroxy-2-propyl)-2,4,6-triiodoisophthalamide (300 g) was suspended in acetic anhydride (1.5 1) at 90° (in an oil bath) and then p-toluenesulphonic acid (3 g) was added. The mixture was heated for 41/2 hours and then cooled slowly to room temperature. The product was collected on a filter and washed with small amounts of acetic anhydride. Yield: 353 g. The product was suspended in a mixture of methanol (600 ml) and water (300 ml) at room temperature and the pH was adjusted to about 11.5 by adding 5N sodium hydroxide (200 ml). This mixture was heated at 50° C. and more 5 N sodium hydroxide (235 ml) was added dropwise in such a manner that the pH was kept at about 10.5. After 2-3 hours the pH did not decrease, and the hydrolysis was completed. After cooling to room temperature the mixture was acidified with 6 N hydrochloric acid to about pH 6. After stirring for two hours at room temperature, the mixture was cooled to 3° for 2-3 days. The product was collected on a filter, suspended in water (500 ml) and filtered again. Yield: 257 g. Melting point: above 270°. (Found: C 25.68; H 2.85; I 51.0; N 6.03. Calc. for C16H20I3N3O7 : C 25.72;H 2.70; I 50.96; N 5.62) TLC (precoated TLC Plates Silica Gel 60 F-254 from Merck A.G. and developed in CHCl3 : MeOH=70:30) showed one spot with Rf value 0.38.

Workup

  1. temperatureThe mixture was heated for 41/2 hours
  2. customThe product was collected on
  3. filtrationa filter
  4. washwashed with small amounts of acetic anhydride
  5. additionThe product was suspended in a mixture of methanol (600 ml) and water (300 ml) at room temperature
  6. additionby adding 5N sodium hydroxide (200 ml)
  7. temperatureThis mixture was heated at 50° C.
  8. additionmore 5 N sodium hydroxide (235 ml) was added dropwise in such a manner that the pH
  9. temperatureAfter cooling to room temperature the mixture
  10. temperaturethe mixture was cooled to 3° for 2-3 days
  11. customThe product was collected on a filter
  12. filtrationfiltered again

Sources & evidence

ORD record
ord-8124928175404c25943c9020e8fb3f3d
Source dataset
uspto-grants-1993_04
Patent number
US05204086

Reaction notes

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