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

被引：42

作者：

MCMURRY, TJ ^{[1
]}

BRECHBIEL, M ^{[1
]}

WU, CC ^{[1
]}

GANSOW, OA ^{[1
]}

机构：

[1] NCI, RADIAT ONCOL BRANCH, BETHESDA, MD 20892 USA

来源：

BIOCONJUGATE CHEMISTRY | 1993年 / 4卷 / 03期

关键词：

D O I：

10.1021/bc00021a009

中图分类号：

Q5 [生物化学];

学科分类号：

071010 ; 081704 ;

摘要：

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)ethylenediamine with NN-bis[2-[(p-tolylsulfonyl)oxy]ethyl]-p-toluenesulfonamide gave 2-(p-benzamidobenzyl)-1,4,7-tris(p-tolylsulfonyl)-1,4,7-triazacyclononane 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-tetraazacyclododecane (11), 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-tetraaceticacid (V), 2-(p-nitrobenzyl)-1,4,8,11-tetraazatetradecane-1,4,8,11-tetraacetic acid (VI), and the acyclic ligand 1-(p-nitrobenzyl)-4-meth-yldiethylenetriamine-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 much less than VI much less than IV < V approximately II

引用

页码：236 / 245

页数：10

共 41 条

[1] SYNTHESIS AND COORDINATION CHEMISTRY OF THE HEXADENTATE LIGANDS 1,4,7-TRIS(2-HYDROXYBENZYL)-1,4,7-TRIAZACYCLONONANE (H3L1) AND 1,4,7-TRIS(3-TERT-BUTYL-2-HYDROXYBENZYL)-1,4,7-TRIAZACYCLONONANE (H3L2) - CRYSTAL-STRUCTURES OF [HL1CUII] AND [L2FEIII]ACACH [J].