PAPER
Synthesis of Fluorinated Macrocyclic Chelators
219
Alcohol 11
HRMS (MALDI-TOF): m/z calcd for C45H62F27N4O13: 1379.3882;
found: 1379.3902.
A suspension of compound 10 (6.0 g, 5.7 mmol) and Pd(OH)2
(10%, 1.2 g) in MeOH (80 mL) was stirred under H2 for 2 h. After
filtration, the mixture was concentrated under vacuum and purified
by flash chromatography on silica gel (n-hexane–EtOAc, 8:1) to
give the alcohol 11 as a clear oil; yield: 5.3 g (97%).
1H NMR (400 MHz, CDCl3): d = 3.99 (s, 6 H), 3.53–3.60 (m, 16
H), 3.39 (s, 2 H).
F-DOTA 2 = 2,2¢,2¢¢-{10-[18,18,18-trifluoro-14,14-bis{[(2,2,2-
trifluoro-1,1-bis(trifluoromethyl)ethoxy]methyl}-17,17-bis(tri-
fluoromethyl)-3,6,9,12,16-pentaoxaoctadec-1-yl]-1,4,7,10-tetra-
azacyclododecane-1,4,7-triyl}triacetic Acid
LiOH (0.9 g, 37.0 mmol) was added to a solution of compound 14
(5.1 g, 3.7 mmol) in MeOH (100 mL) and H2O (10 mL). The result-
ing mixture was stirred for 8 h at r.t. Then aq 1 N HCl was added to
adjust the solution to pH 1. After removing the solvent under vacu-
um, the residue was purified by flash column chromatography on
neutral aluminum oxide (CH2Cl2–MeOH, 10:1) to give the com-
pound 2 as a white solid; yield: 4.7 g (99%).
Mesylate 12
To a stirred solution of alcohol 11 (5.1 g, 5.3 mmol) and Et3N (3.2
g, 31.8 mmol) in CH2Cl2 (80 mL) at 0 °C was added MsCl (1.9 g,
15.9 mmol). The resulting mixture was stirred for 1 h at r.t. and
quenched with H2O (50 mL). The organic phase was collected and
the aqueous phase was extracted with EtOAc (3 × 30 mL). The com-
bined organic phases were dried (MgSO4). After concentration un-
der vacuum, the residue was purified by flash chromatography on
silica gel (n-hexane–EtOAc, 10:1) to give the mesylate 12 as a clear
oil; yield: 5.5 g (99%).
1H NMR (400 MHz, acetone-d6): d = 4.20 (s, 6 H), 3.53–3.59 (m,
16 H), 2.2–3.2 (m, 24 H).
13C NMR (100.7 MHz, CD3OD): d = 180.9, 179.6, 175.3, 175.1,
121.5 (q, J = 292.6 Hz), 80.5–81.4 (m), 71.9, 71.6, 71.5, 71.4, 71.3,
69.9, 68.8, 67.5, 67.1, 60.6, 59.2, 53.9, 52.4, 51.9, 47.4.
19F NMR (376 MHz, CD3OD): d = –71.15 (s).
MS (MALDI-TOF): m/z = 1295 ([M + H]+, 100).
1H NMR (400 MHz, CDCl3): d = 4.34–437 (m, 2 H), 4.04 (s, 6 H),
3.73–3.76 (m, 2 H), 3.53–3.67 (m, 12 H), 3.43 (s, 2 H), 3.04 (s, 3 H).
Amine 13
HRMS (MALDI-TOF): m/z calcd for C39H50F27N4O13: 1295.2943;
A suspension of mesylate 12 (5.3 g, 5.1 mmol) and cyclen (1.8 g,
10.2 mmol) in DMF (50 mL) was stirred overnight at 60 °C. After
concentrating the mixture to dryness under vacuum, the residue was
found: 1295.2953.
purified by solid-phase extraction on FluoroFlash® silica gel. After Acknowledgment
loading the sample to fluorous silica gel, it was washed first with
This research was supported by the National Institutes of Health un-
der grants EB002880 and EB004416. We wish to thank G. Mahika
Weerasekare for her kind help with NMR experiments.
MeOH–H2O (4:1, 200 mL) and then with MeOH (400 mL). The
product was obtained as a clear oil by concentrating the MeOH elu-
ent; yield: 5.2 g (93%).
1H NMR (400 MHz, CD3OD): d = 4.14 (s, 6 H), 3.57–3.69 (m, 14
H), 3.49 (s, 2 H), 2.95–3.04 (m, 7 H), 2.85–2.89 (m, 5 H), 2.76–2.82
(m, 2 H), 2.69 (s, 4 H).
13C NMR (100.7 MHz, CD3OD): d = 121.6 (q, J = 292.5 Hz), 80.5–
81.4 (m), 78.3, 72.0, 71.9, 71.73, 71.7, 71.67, 71.6, 71.56, 71.5,
71.4, 71.41, 71.4, 71.2, 69.6, 67.5, 67.2, 50.9, 46.4, 44.4.
19F NMR (376 MHz, CD3OD): d = –71.14 (s).
MS (MALDI-TOF): m/z = 1121 ([M + H]+, 100).
References
(1) Yu, Y. B. J. Drug Targeting 2006, 14, 663.
(2) (a) Jiang, Z.-X.; Yu, Y. B. Tetrahedron 2007, 63, 3982.
(b) Jiang, Z.-X.; Yu, Y. B. J. Org. Chem. 2007, 72, 1464.
(3) Bianchi, A.; Calabi, L.; Corana, F.; Fontana, S.; Losi, P.;
Maiocchi, A.; Paleari, L.; Valtancoli, B. Coord. Chem. Rev.
2000, 204, 309.
(4) (a) Otte, A.; Jermann, E.; Behe, M.; Goetze, M.; Buche, H.
C.; Roser, H. C.; Heppeler, A.; Mueller-Brand, J.; Maecke,
H. R. Eur. J. Nucl. Med. 1997, 24, 792. (b) Smith, M. C.;
Liu, J.; Chen, T.; Schran, H.; Yeh, C.-M.; Jamar, F.;
Valkema, R.; Bakker, W.; Kvols, L.; Krenning, E.; Pauwels,
S. Digestion 2000, 62 (Suppl 1), 69.
HRMS (MALDI-TOF): m/z calcd for C33H44F27N7O4: 1021.2779;
found: 1021.2790.
Triethyl Ester 14
To a stirred solution of amine 13 (5.1 g, 4.6 mmol) in THF (25 mL)
and DMF (25 mL) was added powdered anhyd K2CO3 (6.3 g, 46.0
mmol) and ethyl bromoacetate (2.6 mL, 3.8 g, 23.0 mmol). The re-
sulting mixture was stirred overnight at 60 °C. After filtration, the
solvent was removed under vacuum and the residue was purified by
flash chromatography on neutral aluminum oxide (CH2Cl2–
MeOH, 10:1) to give the product 14 as a clear oil; yield: 5.2 g
(82%).
1H NMR (400 MHz, CD3OD): d = 4.16–4.29 (m, 8 H), 4.14 (s, 6 H),
3.56–3.67 (m, 16 H), 3.48 (s, 4 H), 2.70–3.45 (m, 4 H), 2.41–2.76
(m, 14 H), 1.27–1.30 (m, 9 H).
(5) Grobelny, Z.; Stolarzewicz, A.; Czaja, M.; Demuth, W.;
Maercker, A. J. Org. Chem. 1999, 64, 8990.
(6) Gladysz, J. A.; Curran, D. P. Handbook of Fluorous
Chemistry; Wiley-VCH: Weinheim, 2003, ; and references
cited therein.
(7) (a) Kimura, A.; Narazaki, M.; Kanazawa, Y.; Fujiwara, H.
Magn. Reson. Imag. 2004, 22, 855. (b) Singh, M.; Waluch,
V. Adv. Drug Del. Rev. 2000, 41, 7.
(8) Lipinski, C. A.; Lombardo, F.; Dominy, B. W.; Feeney, P. J.
Adv. Drug Del. Rev. 1997, 23, 3.
(9) Since F-DOTA 1 and F-DOTA 2 each contains three
carboxylic groups, the protonation status of which is pH-
dependent, the 1-octanol/H2O partition measurements were
conducted with physiological saline buffer (PBS, 50 mM
phosphate, 100 mM NaCl, 1 mM EDTA, pH 7.0) as the
aqueous phase. Specifically, F-DOTA 1 or F-DOTA 2 (5
mg) was dissolved in mixture of PBS buffer (0.5 mL) and
1-octanol (0.5 mL). The sample was put into an Eppendorf®
13C NMR (100.7 MHz, CD3OD): d = 175.3, 175.1, 121.6 (q,
J = 292.6 Hz), 80.7–81.5 (m), 71.9, 71.5, 71.4, 71.3, 71.2, 70.8,
68.5, 67.4, 67.1, 62.3, 62.26, 56.4, 56.1, 53.6, 51.9, 51.1, 48.4, 47.4,
14.5, 14.3.
19F NMR (376 MHz, CD3OD): d = –71.12 (s).
MS (MALDI-TOF): m/z = 1379 ([M + H]+, 100).
Synthesis 2008, No. 2, 215–220 © Thieme Stuttgart · New York