Chlorination of 5-amino-2,4,6-triiodoisophthalic acid (I) with SOCl2 in EtOAc or toluene affords acid chloride (II). Yields have been improved with the addition of benzyltriethylammonium chloride as a catalyst. Acid chloride (II) is then condensed with 3-amino-1,2-propanediol (III) to produce diamide (IV). Compound (IV) is converted to the tetraacetate ester (V) employing acetic anhydride in pyridine. Subsequent acylation of the amino group of (V) with acetoxyacetyl chloride (VI) gives amide (VII). After saponification of the ester groups of (VII), the resultant hydroxy acetamide (VIII) is alkylated by 2-chloroethanol (IX) to furnish the title compound. Alternatively, amide (VIII) is alkylated by bromoethyl acetate (X), producing (XI). Hexa-ester (XI) is finally hydrolyzed with aqueous sulfuric acid. An improved procedure for this final hydrolysis step uses 1,1,2-trichloroethane as co-solvent.
In an alternative procedure, the intermediate amino tetraacetate (I) is acylated by chloroacetyl chloride (II), yielding chloroacetamide (III). The amide N is then alkylated with bromoethyl acetate (IV) to produce (V). Simultaneous hydrolysis of the acetate esters and the chloro group in aqueous sulfuric acid furnishes the title compound.
Similarly, the tetrahydroxy amine (I) is acylated by chloroacetyl chloride (II) to produce the tetraester amide (III). After amide alkylation with bromoethyl acetate (IV), the resultant penta-ester (V) is hydrolyzed to the title compound using aqueous sulfuric acid.
In a related method, the intermediate tetrahydroxy amine (I) is acylated by chloroacetyl chloride (II) to produce the penta(chloroacetyl) derivative (III). The chloroacetate ester groups are then hydrolyzed under basic conditions to afford the tetra-hydroxy chloroacetamide (IV). Conversion of (IV) to the hydroxy acetamide (V) is accomplished by treatment with sodium acetate and NaOH. Amide (V) is finally alkylated with either chloroetanol (VI) or with ethylene oxide (VII) to furnish the title N-(hydroxyethyl) amide.
A further synthetic variation for the title compound is based on the acylation of intermediate (I) with acetoxyacetyl chloride (II) to afford (III). Amide alkylation with bromoethyl acetate (IV) furnishes (V). The ester groups of (V) are finally hydrolyzed in aqueous sulfuric acid.
An improved method for the preparation of the iodinated precursor (II) has been reported. Thus, iodination of the amino isophthalamide (I) with iodine monochloride is performed with co-addition of phosphoric acid, to yield a higher purity triiodo derivative (II).
In an improved method, the acetamido isophthalamide (I) is treated with boric acid and KOH to form the cyclic diborate tripotassium salt (II). Subsequent alkylation of (II) with 1-chloro-3-methoxy-2-propanol (III) yields regioselectively the N-alkylated acetamide (IV). The borate groups of (IV) are finally removed upon quenching with diluted HCl.
In a different strategy, the acetamido isophthalamide (I) is treated with boric acid and KOH to form the cyclic diborate tripotassium salt (II). Subsequent condensation of (II) with epichlorohydrin (III) yields the dimeric adduct (IV). The borate groups of (IV) are finally removed upon quenching with diluted HCl.
In an improved method, the acetamido isophthalamide (I) is treated with boric acid and KOH to form the cyclic diborate tripotassium salt (II). Subsequent alkylation of (II) with 2-chloroethanol (III) yields regioselectively the N-alkylated acetamide (IV). The borate groups of (IV) are finally removed upon quenching with diluted HCl.
Treatment of 5-amino-2,4,6-triiodo-1,3-benzenedicarboxylic acid (I) with thionyl chloride yields the dichloride (II). Compound (II) is treated with acetoxyacetyl chloride to give compound (III), which is methylated with iodomethane. Condensation with 3-amino-1,2-propanediol of the N-methyl derivative (IV) thus obtained, followed by deacetylation with alkali metal hydroxide, yields iomeprol.
In a different strategy, the target N-aryl hydroxy acetamide has been obtained by Smiles rearrangement of the aryloxy acetamide (I) under basic conditions.