In a related method for obtaining the precursor (V), epoxide (II) was condensed with the tosyl-protected tetraamine (XIII) in an autoclave at 170 C to give (XIV). The N-tosyl groups of (XIV) were then removed by treatment with lithium metal in liquid ammonia, yielding intermediate (III), which was then subjected to alkylation with bromoacetic acid, followed by acid hydrolysis
A different synthesis started from the previously reported tetraaza cyclopentaacenaphthylene (XV). Treatment of (XV) with a solution of piperazine at pH 6 gave rise to the bicyclic lactam (XVI). Alkylation of (XVI) with bromoacetic acid, followed by basic lactam hydrolysis furnished the tris(carboxymethyl) derivative (X), which was processed as in Scheme 3.
1,4,7,10-Tetraazacyclododecane (I) was condensed with 2,3-epoxy-1,4-butanediol acetonide (II) in boiling n-butanol to afford adduct (III). Subsequent acetonide (III) hydrolysis in the presence of HCl led to triol (IV). Alkylation of (IV) with chloroacetic acid furnished the tetraaminotricarboxylic acid (V). Alternatively, compound (V) was prepared by alkylation of (III) with chloroacetic acid, followed by acidic ketal hydrolysis. The title gadolinium complex was finally prepared by treatment of the cyclic tetraamine (V) with gadolinium oxide
Alternatively, the protected tetraamine (VIII) was condensed with epoxide (II) to afford (XII), which was further hydrolyzed to the mono-substituted tetraazacyclododecane (III) under basic conditions. Alkylation of (III) with chloracetic acid, followed by acidic ketal hydrolysis furnished the precursor (V), which was finally complexed with gadolinium oxide as above
In a similar procedure, condensation of (I) with epoxide (II) in isopropanol in the presence of LiCl furnished the corresponding adduct as a complex with LiCl (VI) (2). Condensation of (VI) with chloroacetic acid, followed by acidic hydrolysis provided the lithium complex (VII). Finally, treatment of (VII) with Gd2O3 and HCl afforded the title gadolinium compound
The macrocyclic tetraamine (I) was protected as the triaminomethane derivative (VIII) by treatment with either triethyl orthoformate (4) or with dimethylformamide dimethylacetal (5). Alkylation of (VIII) with bromoacetic acid gave rise to the N-formyl N',N'',N'''-tris(carboxymethyl) compound (IX). After basic hydrolysis of the formamide function of (IX), the resultant N-deprotected amine (X) was condensed with epoxide (II) to yield (XI). Further complexation with GdCl3 and ketal group hydrolysis led to the target compound