Hydrochloric Acid → Iodixanol Impurity 25

HRID 1358852Notes

Reaction equation

HRID 1358852 reaction equation
[OH:1][CH:2]([CH2:29][OH:30])[CH2:3][NH:4][C:5](=[O:28])[C:6]1[C:19]([I:20])=[C:18]([NH:21][C:22](=[O:25])[CH2:23][Cl:24])[C:17]([I:26])=[C:8]([C:9]([NH:11][CH2:12][CH:13]([OH:16])[CH2:14][OH:15])=[O:10])[C:7]=1[I:27].[CH2:31]1[O:33][CH2:32]1.Cl>O>[OH:1][CH:2]([CH2:29][OH:30])[CH2:3][NH:4][C:5](=[O:28])[C:6]1[C:19]([I:20])=[C:18]([N:21]([CH2:31][CH2:32][OH:33])[C:22](=[O:25])[CH2:23][Cl:24])[C:17]([I:26])=[C:8]([C:9]([NH:11][CH2:12][CH:13]([OH:16])[CH2:14][OH:15])=[O:10])[C:7]=1[I:27]

Participants

5

Reactant 3

HCID 313Hydrochloric AcidHCID 6354Ethylene OxideHCID 111047205-(2-Chloroacetamido)-N1,N3-bis(2,3-dihydroxypropyl)-2,4,6-triiodoisophthalamide

Product 1

HCID 12082254Iodixanol Impurity 25

Reagents, catalysts & solvents 1

HCID 962WaterSolvent

Procedure

The general procedure for the process of the invention involves reacting 5-amino-N,N′-bis(2,3-dihydroxypropyl)-2,4,6-triiodoisophthalamide with N,N-dimethylacetamide and chloroacetyl chloride. The resulting product is hydrolyzed with a base (such as sodium hydroxide). A homogeneous solution is obtained by adding water. Precipitation is affected to yield N,N′-bis(2,3-dihydroxypropyl)-5-(2-chloroacetamido)-2,4,6-triiodoisophthalamide. Alternately, 5-amino-N,N′-bis(2,3-dihydroxypropyl)-2,4,6-triiodoisophthalamide is reacted with N,N-dimethylacetamide, acetonitrile, and chloroacetyl chloride. The resulting product is hydrolyzed with a base. A homogeneous solution is obtained by adding water. Precipitation is affected to yield N,N′-bis(2,3-dihydroxypropyl)-5-(2-chloroacetamido)-2,4,6-triiodoisophthalamide. This product is combined with an aqueous base and deionized water. 2-Chloroethanol is added followed by heating. The addition of hydrochloric acid yields N,N′-bis(2,3-dihydroxypropyl)-5-[N-(2-hydroxyethyl)(2-chloroacetamido)]-2,4,6-triiodoisophthalamide. Alternately, N,N′-bis(2,3-dihydroxypropyl)-5-(2-chloroacetamido)-2,4,6-triiodoisophthalamide plus metal halide and deionized water are combined. Ethylene oxide is added followed by heating. The addition of hydrochloric acid yields N,N′-bis(2,3-dihydroxypropyl)-5-[N-(2-hydroxyethyl)(2-chloroacetamido)]-2,4,6-triiodoisophthalamide. This product is suspended in water with acetate ions and hydrochloric acid added. This suspended solution can take place at or above atmospheric pressure. Generally about 1 to about 2 atmospheres above atmospheric pressure is used. After adding aqueous sodium hydroxide to, maintain the pH, the reaction yields N,N′-bis(2,3-dihydroxypropyl)-5-N-(2-hydroxyethyl)glycolamido-2,4,6-triiodoisopthalamide. Finally, salts and low molecular weight impurities are removed.

Workup

  1. temperatureby heating

Sources & evidence

ORD record
ord-09bb0308a96f4d78ac9dd38bf508dd2c
Source dataset
uspto-grants-2003_07
Patent number
US06596904B1

Reaction notes

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