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BioconJugate Chem. 1993, 4, 236-245
Synthesis of 2-(p-Thiocyanatobenzyl)-1,4,7-triazacyclononane1,4,7-triacetic Acid: Application of the 4-Methoxy-2,3,6trimethylbenzenesulfonamide Protecting Group in the Synthesis of Macrocyclic Polyamines Thomas J. McMurry," Martin Brechbiel, Chuanchu Wu, and Otto A. Gansow Radiation Oncology Branch, National Cancer Institute, National Institutes of Health, Building 10, Room B3-B69, Bethesda, Maryland 20892. Received December 30, 1992
A synthesis of the bifunctional chelator 2-@-thiocyanatobenzy1)-1,4,7-triazacyclononane-1,4,7-triacetic acid [2-@-NCS-Bz)-NOTAl is described which illustrates the especial utility of the (4-methoxy-2,3,6trimethylpheny1)sulfonyl (Mtr) protecting group as an alternative to the p-tolylsulfonyl (Ts) moiety commonly used for Richman-Atkins type cyclizations. Reaction of N,"- bis@-tolylsulfonyl)-1-(pbenzamidobenzy1)ethylenediaminewith N,N-bis[B- [(p-tolylsulfonyl)oxyl ethyl] -p-toluenesulfonamide gave 2-@-benzamidobenzyl)-1,4,7-tris@-tolylsulfonyl)-l,4,7-triazacyclononanein 557% yield, whereas the analogous reaction using the Mtr-protected starting materials gave the corresponding Mtr-protected macrocycle in 34 % yield. However, deprotection of the Ts- and Mtr-protected macrocycles (HzS04, 90 "C) afforded 2-@-benzamidobenzyl)-1,4,7-triazacyclononanein 23 % and 60 76 yield, respectively, illustrating the relatively facile cleavage of the Mtr moiety. A modest improvement in overall percent conversion of @-nitrobenzy1)ethylenediamine into substituted macrocyclic polyamine was observed when comparing the Mtr vs Ts protection (12.6 vs 10.6%1. The macrocyclic triamine was converted to 2-(p-NCS-Bz)-NOTA by alkylation with bromoacetic acid (pH 9,7376) followed by hydrolysis of the benzamide protecting group (6 M HC1,70 "C, 87%) and reaction with thiophosgene (90%). The serum stability of the 67Cucomplexes of 1,4,7-triazacyclononane (I), 2-@-nitrobenzyl)-1,4,7,10-tetraazacyclododecane (II),2-(p-nitrobenzyl)-l,4,8,1 l-tetraazacyclotetradecane(III),2-(p-PhCONH-Bz)-NOTA (IV),2- (p-nitrobenzyl)- 1,4,7,10-tetraazadodecane1,4,7,10-tetraaceticacid (V),2-@-nitrobenzyl)-l,4,8,11tetraazatetradecane-1,4,8,ll-tetraaceticacid (VI), and the acyclic ligand l-@-nitrobenzyl)-4-methyldiethylenetriamine-N,N,",N",N"-pentaacetic acid (VII) was measured at 37 "C (576 C02) and showed the following order of relative stability: I < VI1
