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Synlett 2010(8): 1215-1218  
DOI: 10.1055/s-0029-1219813
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

A Rapid Microwave-Assisted Procedure for Easy Access to Nx Polydentate ­Ligands for Potential Application in α-RIT

Mathieu Mévela, Ewen Bodioa, Sylvain Grosjeana, Gilles Montavonb, Jean-Claude Meslina, Karine Juliennea, David Deniaud*a
a Université de Nantes, CEISAM, Chimie Et Interdisciplinarité, Synthèse, Analyse, Modélisation, UMR CNRS 6230, UFR des Sciences et des Techniques, 2, Rue de la Houssinière, BP 92208, 44322 Nantes Cedex 3, France
Fax: +33(2)51125402; e-Mail: david.deniaud@univ-nantes.fr;
b Université de Nantes, Laboratoire SUBATECH, UMR CNRS 6457, Ecole des Mines de Nantes, 4, Rue A. Kastler, BP 20722, 44307 Nantes Cedex 3, France
Further Information

Publication History

Received 5 February 2010
Publication Date:
07 April 2010 (online)

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Abstract

Heterocycles bearing a hydrazine moiety react with bisaldehydes or bisketones to afford new Nx polydentate ligands suitable for α-radioimmunotherapy. We developed a fast and efficient method using microwave-assisted technology to obtain chelators with variable size and number of coordination centers which were fully characterized. The complexation efficiency with astatine will be assessed.

Key words

astatine - radioimmunotherapy - pyrimidinone - triazin­one - chelating agent

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24

General Procedure for Ligands L 1-8
To a 10 mL microwave reaction vessel was placed heterocyclic ring 3 or 4 (0.5 mmol) and dialdehyde 5 or 8 or diketone 6 or 7 (0.25 mmol) in MeOH for L 1,2,7,8 (4 mL) or in AcOH for L 3-6 (4 mL). The vial was heated (internal temperature measured by fibre optic) in a microwave synthesizer (MultiSYNTH®, Milestone S.r.l.) to 110 ˚C [2 min (110 W) ramp + 15 min irradiation (80 W)] for L 1,2,7,8 or to 130 ˚C [2 min (300 W) ramp + 15 min irradiation (250 W)] for L 3-6 . The solvent was removed under vacuum, and the solid residue was washed with Et2O. The product was filtered and dried under vacuum to afford ligands L 1-8 .

26

Spectroscopic Data of Ligands L 1-8
L 1 : mp 243-244 ˚C. IR (KBr): 3245, 1733, 1628, 1480, 1193, 1147 cm-¹. ¹H NMR (TFA): δ = 1.23 [s, 9 H, C(CH3)3], 3.61 (s, 6 H, NCH3), 3.87 (s, 6 H, OCH3), 7.78 (s, 2 H, Har), 8.02 (s, 1 H, Har), 8.52 (s, 2 H, CH), 8.59 (s, 2 H, CHpyr). ¹³C NMR (TFA): δ = 27.3, 28.4, 33.4, 52.1, 106.5, 122.4, 130.3, 145.6, 148.9, 153.8, 155.7, 156.4, 162.7. MS (MALDI): m/z = 551.42 [M + H]+, 573.31 [M + Na]+.
L 2 : mp 245-247 ˚C. IR (KBr): 3302, 1674, 1493, 1429, 1303, 1193 cm-¹. ¹H NMR (TFA): δ = 1.37 [s, 9 H, C(CH3)3], 3.68 (s, 6 H, NCH3), 8.12 (s, 2 H, Har), 8.30 (s, 1 H, Har), 8.50 (s, 2 H, CH), 8.52 (s, 2 H, CHtri). ¹³C NMR (TFA): δ = 28.5, 33.6, 33.7, 125.7, 130.1, 130.9, 146.3, 153.9, 154.4, 157.0, 161.3. MS (CI-): m/z = 436.2 [M]+.
L 3 : mp 197-199 ˚C. IR (KBr): 3304, 1723, 1652, 1480, 1189, 1149 cm-¹. ¹H NMR (TFA): δ = 2.40 (s, 6 H, CH3), 3.66 (s, 6 H, NCH3), 3.87 (s, 6 H, OCH3), 8.57 (s, 2 H, CHpyr). ¹³C NMR (TFA): δ = 10.7, 27.5, 52.3, 108.4, 145.0, 149.8, 155.1, 160.1, 162.3. MS (CI+): m/z = 447.3 [M + H]+.
L 4 : mp >250 ˚C. IR (KBr): 3434, 3071, 1691, 1622, 1494, 1291 cm-¹. ¹H NMR (TFA): δ = 2.52 (s, 6 H, CH3), 3.61 (s, 6 H, NCH3), 8.53 (s, 2 H, CHtri). ¹³C NMR (TFA): δ = 10.7, 33.9, 146.4, 155.8, 161.0, 162.2; MS (CI+): m/z = 333.0
[M + H]+.
L 5 : mp 247-249 ˚C. IR (KBr): 3216, 1734, 1627, 1481, 1189, 1148 cm-¹. ¹H NMR (TFA): δ = 2.73 (s, 6 H, CH3), 3.75 (s, 6 H, NCH3), 3.95 (s, 6 H, OCH3), 8.45 (d, 2 H, J = 8.0 Hz, Har), 8.64 (s, 1 H, Hpyr), 8.81 (t, 1 H, J = 8.0 Hz, Har). ¹³C NMR (TFA): δ = 12.8, 27.9, 52.2, 104.9, 126.4, 146.3, 146.5, 148.1, 150.1, 154.1, 157.7, 163.4. MS (MALDI): m/z = 524.52 [M + H]+, 546.33 [M + Na]+. L 6 : mp 211-213 ˚C. IR (KBr): 3220, 1634, 1489, 1303, 1187 cm-¹. ¹H NMR (TFA): δ = 2.74 (s, 6 H, CH3), 3.66 (s, 6 H, NCH3), 8.55 (d, 2 H, J = 8.0 Hz, Har), 8.65 (s, 1 H, Htri), 8.85 (t, 1 H, J = 8.0 Hz, Har). ¹³C NMR (TFA): δ = 12.4, 34.0, 126.9, 145.0, 146.1, 148.6, 150.9, 157.5, 162.9. MS (CI-): m/z = 409.2 [M]+.
L 7 : mp >250 ˚C. IR (KBr): 1733, 1627, 1495, 1191, 1146 cm-¹. ¹H NMR (TFA): δ = 3.66 (s, 6 H, NCH3), 3.86 (s, 6 H, OCH3), 8.18 (s, 2 H, Har), 8.69 (s, 2 H, Hpyr), 8.72 (d, 2 H, J = 8.5 Hz, Har), 8.84 (d, 2 H, J = 8.5 Hz, Har), 9.15 (s, 2H, CH). ¹³C NMR (TFA): δ = 28.7, 53.2, 107.8, 123.7, 129.0, 131.9, 137.5, 143.2, 146.4, 147.7, 150.0, 150.9, 151.0, 163.4. MS (MALDI): m/z = 597.41 [M + H]+, 619.22 [M + Na]+.
L 8 : mp >250 ˚C. IR (KBr): 3212, 1623, 14932, 1306, 1186 cm-¹. ¹H NMR (TFA): δ = 3.69 (s, 6 H, NCH3), 8.27 (s, 2 H, Har), 8.69 (s, 2 H, Har), 8.61 (s, 2 H, Htri), 8.89 (d, 2 H, J = 8.6 Hz, Har), 9.06 (s, 2 H, CH), 9.29 (d, 2 H, J = 8.6 Hz, Har). ¹³C NMR (TFA): δ = 33.9, 123.2, 128.0, 130.9, 136.3, 141.8, 147.1, 147.3, 149.7, 156.1, 162.7. MS (CI-): m/z = 482.2 [M]+.