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2135
3. Heppeler, A.; Froidevaux, S.; Macke, H. R.; Jermann, E.;
Behe, M.; Powell, P.; Hennig, H. Chem. Eur. J. 1999, 5, 1974.
4. Andre, J. P.; Macke, H. R.; Toth, E.; Merbach, A. JBIC
1999, 4, 341.
in 4 mL CHCl3. The mixture was stirred for 2 days at room
temperature and concentrated to a brown oil. The crude product
was puri®ed by column chromatography (silica gel 60; ethanol/
1
NH3 95:5), yield 920 mg (83%) of a colourless oil. H NMR
5. Kruper, W. J.; Rudolf, P. R.; Langho, C. A. J. Org.
Chem. 1993, 58, 3869.
6. Holmberg, C. Chem. Ber. 1927, 60, 2197.
7. Armstrong, A.; Brackenridge, I.; Jackson, R. R. W.; Kirk,
J. M. Tetrahedron Lett. 1988, 29, 2483.
(300 MHz, CDCl3, SiMe4): 7.35 (m, 5H, Ar); 5.1 (s, 2H, CH2-
Ph); 3.25 (dd, 1H, CHBr); 2.9±2.5 (m, 18H, NCH2, CH2
COOBzl); 2.2±1.85 (m, 2H, CHN-CH2-CH2); 1.45 (s, 9H,
C(CH3)3); 13C NMR (75 MHZ, CDCl3, SiMe4): 173.1 (COOBzl);
171.5 (COOtBu); 135.8 (CH2C(Ar)); 128.5, 128.3, 128.2 (C(Ar));
81.4 (C(CH3)3); 66.2 (O-CH2-Ar); 63.5 (HCNCH2); 48.8, 48.0,
46.5, 45.6 (NCH2CH2N); 30.6 (CH2COOBzl); 28.2 (C(CH3)3);
24.5 (HCN-CH2); EI±MS m/z: (intensity): 449.3 (56, [M+H]+);
245.8 (100, [M+ CH3CN+2H]++). Synthesis of 1-(1-carbo-
benzyloxy-3-carbotertbutoxypropyl)-4,7,10-(carbotertbutoxy-
methyl)-1,4,7,10-tetraazacyclododecane (5d): A suspension of
1.1 g (5.6 mmol) bromoacetic acid-tert-butylester, 1.02 g
(2.27 mmol) 1-(1-carbobenzyloxy-3-carbotertbutoxypropyl)-
1,4,7,10-tetraazacyclododecane (4d), and 2.63 g (19.1 mmol) of
dry potassium carbonate in 10 mL dry acetonitrile was stirred
for 18 h at rt and was ®ltrated afterwards over Celite and eva-
porated to dryness. The crude product was puri®ed by column
chromatographie (silica gel 60; CH2Cl2:EtOH 9:1 followed by
EtOH:NH3 95:5) yield 1.3 g (73%) of a yellow oil (5d). 1H
NMR (300 MHz, CDCl3, SiMe4): 7.35 (m, 5H, Ar); 5.1 (s, 2H,
CH2-Ph); 3.6±1.9 (m, 27H, CHN, NCH2, CH2COOBzl, CHN-
CH2-CH2, CH2COOC(CH3)3); 1.45 (s, 36H, C(CH3)3); 13C
NMR (75 MHZ, CDCl3, SiMe4): 174.6 (COOBzl); 172.9,
172.8, 172.6 (COOtBu); 135.6 (CH2C(Ar)); 128.5, 128.3, 128.2
(C(Ar)); 82.4, 81.8, 81.8 (C(CH3)3); 66.3 (O-CH2-Ar); 55.8,
55.7, 55.4, 52.6, 52.3, 50.3, 48.5, 48.1, 47.1, 44.3 (13C, HCN
CH2, NCH2CH2N, CH2COOtBu, CH2COOBzl); (NCHCH2
CH2); 28.0, 28.0, 27.8, 27.6 (C(CH3)3); EI±MS m/z (intensity):
813.6 (22, [M+Na]+); 791.6 (38, [M+H]+); 396.5 (100,
[M+2H]++). Synthesis of DOTAGA(tBu)4 (6d): 600 mg
(0.76 mmol) 5d was dissolved in methanol, and 30 mg Pd/C
suspended in 1 mL H2O was added. The mixture was hydro-
genated for 2 days, ®ltrated over Celite and evaporated to dry-
ness. The crude product was chromatographed on silica gel 60
(EtOH:NH3 95:5) to obtain 470 mg (84.6%) of a white solid
(6d). 1H NMR (300 MHz, CDCl3, SiMe4): 6.5 (br, 1H,
COOH); 3.6±2.0 (m, 27H, CHN, NCH2, CH2COOH, CHN-
CH2-CH2, CH2COOC(CH3)3); 1.45 (s, 36H, C(CH3)3); 13C
NMR (75 MHZ, CDCl3, SiMe4): 175.2 (COOH); 175.0, 172.9,
172.8, 172.6 (COOtBu); 82.4, 82.1, 81.9 (C(CH3)3); 55.8, 60.1
(NCHCOOtBu); 55.9, 55.8, 55.6, 52.7, 52.6, 52.5, 48.6, 48.5,
48.2, 47.1, 44.3 (12C, NCH2CH2N, CH2COOtBu, CH2CO
OH); 33.4 (NCHCH2CH2); 27.9, 27.8 (C(CH3)3); EI±MS m/z
(intensity): 723.5 (27, [M+Na]+); 701.5 (68, [M+H]+); 351.4
(100, [M+2H]++).
8. Typical procedure for the reaction of 1 to 2: To a solution
of 6 g (25.9 mmol) l-glutamic acid-5-benzylester (1d) and 9.1 g
(88.5 mmol) sodium bromide in 45 mL aqueous 1N hydro-
bromic acid (46 mmol) cooled to 0 ꢀC was added portionwise
3.175 g (46 mmol) sodium nitrite. After stirring for 2 h at 0 ꢀC
2.25 mL, concd sulfuric acid was added followed by diethyl-
ether. The water phase was extracted three times with diethyl-
ether. The combined organic phases were extracted four times
with brine, dried over Na2SO4 and concentrated. The crude
product was puri®ed by chromatography (silica gel 60; hex-
ane:EtOAc 3:1 to 2:1) and obtained as a yellow oil in a yield of
4.8 g (63%). 1H NMR (300 MHz, CDCl3, SiMe4): 10.1 (1H,
COOH); 7.3 (m, 5H, Ar); 5.15 (s, 2 H, CH2-Ph); 4.4 (dd,
3
3J=5.7, 1H, CHBr); 2.6 (t, J=6.8, 2H, CH2-COOBzl); 2.5±
2.2 (m, 2H, CHBr-CH2-CH2); 13C NMR (75 MHZ, CDCl3,
SiMe4): 174.5 (COOH); 171.9 (COOBzl); 135.5 (CH2C(Ar));
128.6, 128.4, 128.3 (C(Ar)); 66.8 (O-CH2-Ar); 44.1 (HCBr);
31.4 (HCBr-CH2); 29.4 (CH2COOBzl; EI±MS m/z (intensity):
302, 300 (12, [M]+); 91 (100, [Bzl]+). Reaction of 2 to 3: To a
solution of 4.8 g (15.9 mmol) 2d in 20 mL CHCl3 a solution of
6.26 mL (34.1 mmol) TBTA (tert-butyltrichloroacetimidate) in
20 mL cyclohexane was added dropwise over 20 min. During
the addition a white precipitate formed, which was dissolved
by the addition of 3.5 mL of dimethylacetamide (DMA) fol-
lowed by 320 ml boron tri¯uoride ethyl etherate as catalyst.
The reaction mixture was stirred for 3 days at rt. The mixture
was concentrated and the remaining DMA phase was extrac-
ted three times with 30 mL hexane. The hexane phase was
evaporated and the residue chromatographed over silica gel 60
(Hexane:EtOAc 20:1 later 9:1) aording 3.5 g (61%) of a col-
ourless liquid. 1H NMR (300 MHz, CDCl3, SiMe4): 7.4 (m,
5H, Ar); 5.15 (s, 2H, CH2-Ph); 4.35 (dd, 1H, CHBr); 2.6 (td,
2H, CH2-COOBzl); 2.5±2.2 (m, 2H, CHBr-CH2-CH2); 1.5 (s,
9H, C(CH3)3). 13C NMR (75 MHZ, CDCl3, SiMe4): 172.4
(COOBzl); 168.7 (COOtBu); 136.1 (CH2C(Ar)); 129.0, 128.8,
128.7 (C(Ar)); 83.1 (C(CH3)3); 67.0 (O-CH2-Ar); 47.1 (HCBr);
32.0 (HCBr-CH2); 30.1 (CH2 COOBzl); 28.1 (C(CH3)3); EI±MS
m/z (intensity): 302, 300 (18, [M-C4H9]+); 57 (100, [C4H9]+).
9. Andre, J. P.; Toth, E.; Fischer, H.; Seelig, A.; Macke, H.
R.; Merbach, A. E. Chem. Eur. J. 1999, 5, 2977.
10. General procedure of the monoalkylation of cyclen: A
solution of 870 mg (2.44 mmol) a-bromoglutaric acid-1-tert-
butylester-5-benzylester (3d) in CHCl3 was added dropwise
over a period of 1 h to a solution of 885 mg (4.9 mmol) cyclen
11. Data of DOTAGA-CCK-B analogue (DOTAGA-7): Yield:
12.7mg, HPLC purity >95%, (+) EI±MS m/z (intensity):
1486.1 (48, [M+H]+); 743.7 (60, [M+2H]++); ( ) EI±MS m/z
(intensity): 1484.0 (28, [M+H] ); 741.8 (90, [M+2H] )