Synthesis of 2-(p-thiocyanatobenzyl)-1,4,7-triazacyclononane-1,4,7-triacetic acid: application of the 4-methoxy-2,3,6-trimethylbenzenesulfonamide protecting group in the synthesis of macrocyclic polyamines.
A synthesis of the bifunctional chelator 2-(p-thiocyanatobenzyl)-1,4,7-triazacyclononane-1,4,7-triacetic acid [2-(p-NCS-Bz)-NOTA] is described which illustrates the especial utility of the (4-methoxy-2,3,6-trimethylphenyl)sulfonyl (Mtr) protecting group as an alternative to the p-tolylsulfonyl (Ts) moiety commonly used for Richman-Atkins type cyclizations. Reaction of N,N'-bis(p-tolylsulfonyl)-1-(p-benzamidobenzyl)ethylenediami ne with N,N-bis[2-[(p-tolylsulfonyl)oxy]ethyl]-p-toluenesulfonamide gave 2-(p-benzamidobenzyl)-1,4,7-tris(p-tolylsulfonyl)-1,4,7-tria zacyclononane in 55% 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 (H2SO4, 90 degrees C) afforded 2-(p-benzamidobenzyl)-1,4,7-triazacyclononane in 23% and 60% yield, respectively, illustrating the relatively facile cleavage of the Mtr moiety. A modest improvement in overall percent conversion of (p-nitrobenzyl)ethylenediamine into substituted macrocyclic polyamine was observed when comparing the Mtr vs Ts protection (12.6 vs 10.6%). The macrocyclic triamine was converted to 2-(p-NCS-Bz)-NOTA by alkylation with bromoacetic acid (pH 9, 73%) followed by hydrolysis of the benzamide protecting group (6 M HCl, 70 degrees C, 87%) and reaction with thiophosgene (90%). The serum stability of the 67Cu complexes of 1,4,7-triazacyclononane (I), 2-(p-nitrobenzyl)-1,4,7,10-tetraazacy-clododecane (II), 2-(p-nitrobenzyl)-1,4,8,11-tetraazacyclotetradecane (III), 2-(p-PhCONH-Bz)-NOTA (IV), 2-(p-nitrobenzyl)-1,4,7,10-tetraazadodecane-1,4,7,10-tetraacetic acid (V), 2-(p-nitrobenzyl)-1,4,8,11-tetraazatetradecane-1,4,8,11-tetraaceti c acid (VI), and the acyclic ligand 1-(p-nitrobenzyl)-4-methyldiethylenetriamine-N,N,N',N", N"-pentaacetic acid (VII) was measured at 37 degrees C (5% CO2) and showed the following order of relative stability: I < VII << VI << IV < V approximately equal to II approximately equal to III.
McMurry
T J
TJ
Radiation Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892.
Brechbiel
M
M
Wu
C
C
Gansow
O A
OA
D000818:Animals; D001798:Blood Proteins / Q000378:metabolism; D002417:Cattle; D002614:Chelating Agents / Q000138:chemical synthesis / Q000737:chemistry*; D003301:Copper Radioisotopes; D003485:Cyanates / Q000138:chemical synthesis*; D004355:Drug Stability; D006571:Heterocyclic Compounds / Q000097:blood / Q000138:chemical synthesis*; D006573:Heterocyclic Compounds, 1-Ring; D017879:Isothiocyanates; D008024:Ligands; D046911:Macromolecular Substances; D011073:Polyamines / Q000138:chemical synthesis*; D013449:Sulfonamides / Q000737:chemistry*; D000096926:Benzenesulfonamides
D001798:Blood Proteins; D002614:Chelating Agents; D003301:Copper Radioisotopes; D003485:Cyanates; D006571:Heterocyclic Compounds; D006573:Heterocyclic Compounds, 1-Ring; D017879:Isothiocyanates; D008024:Ligands; D046911:Macromolecular Substances; D011073:Polyamines; D013449:Sulfonamides; C082059:N,N-bis(2-((4-tolylsulfonyl)oxy)ethyl)-4-methoxy-2,3,6-trimethylbenzenesulfonamide; D000096926:Benzenesulfonamides; C082060:2-(4-isothiocyanatobenzyl)-1,4,7-triazacyclononane-1,4,7-triacetic acid; C048993:1,4,7-triazacyclononane-N,N',N''-triacetic acid