Alkylation of tetraazacyclodecane (I) with ethyl 2-bromobutyrate (II) afforded the tetrasubstituted macrocycle (III) as a mixture of diastereoisomers. Subsequent hydrolysis of the ethyl ester groups of (III) using ethanolic NaOH gave the octacarboxylic acid (IV). Complexation of (IV) with either Gd2O3 or GdCl3 and NaOH generated the corresponding gadolinium chelate. The mixture of diastereoisomeric chelates was then isomerized under acidic conditions to furnish the racemic pair of R,R,R,R and S,S,S,S isomers (V).
Coupling between 4-nitrobenzoyl chloride (VI) and 4-aminobenzoic acid (VII) afforded nitrobenzamide (VIII), which was further reduced to amine (IX) by catalytic hydrogenation over Pd/C. Acylation of (IX) with phthalimidoacetyl chloride (X) yielded diamide (XI). The carboxyl group of (XI) was then activated as the corresponding acid chloride (XII) by treatment with SOCl2. Then, condensation of the glycylamide derivative (XIII) with acid chloride (XII) furnished amide (XIV).
Deprotection of the phthaloyl group of (XIV) by hydrazinolysis provided amine (XV). This was then coupled with the octaacid gadolinium chelate (V) in the presence of EDC and HOBt leading to the target amide.
In a related synthetic route, the glycinamide derivative (XV) was coupled to acid (IV), and the resultant macrocyclic tetramide was subsequently complexed with GdCl3 to form the title gadolinium chelate.