The acylation of O-benzyltyrosine (I) with ethyl trifluoroacetate in methanol gives O-benzyl-N-trifluroacetyltyrosine (II), which is condensed with N-(2-aminoethyl)carbamic acid benzyl ester (III) by means of ethyl chloroformate in THF, yielding the tyrosinamide (IV). The deacylation of (IV) by means of NaBH4 in ethanol affords the N-deprotected tyrosinamide (V), which is submitted to hydrogenolysis with H2 over Pd/C in methanol to provide tyrosine 2-aminoethylamide (VI). The reduction of (VI) with diborane gives 3-aza-1-(4-hydroxybenzyl)pentane-1,5-diamine (VII), which is alkylated with bromoacetic acid tert-butyl ester (VIII) and NaHCO3 to yield the 1-(4-hydroxybenzyl)-3-azapentane-1,5-diamine N,N,N'.N'',N''-pentaacetate penta-tert-butyl ester (IX) (1). The alkylation of the OH group of (IX) with ethyl iodide and NaH in THF affords the corresponding ethoxybenzyl derivative (X), which is treated with TFA to provide the pentaacetic acid derivative (XI). Finally, this compound is complexed with Gd2O3 and NaOH in hot water to furnish the target gadolinium complex.
The title complex was prepared starting from the previously described diethylenetriamino pentaacetate ester (I). Alkylation of the phenolic hydroxyl with iodoethane and NaH gave the ethyl ether (II). Subsequent trifluoroacetic acid-promoted cleavage of the tert-butyl esters yielded the penta-carboxylic acid (III). Finally, complexation of (III) with Gd2O3, followed by neutralization with NaOH furnished the target compound