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

Abstract

Heterocycles bearing a hydrazine moiety react with bisaldehydes or bisketones to afford new N_x 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.

astatine - radioimmunotherapy - pyrimidinone - triazin­one - chelating agent

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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 .

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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, H_ar), 8.02 (s, 1 H, H_ar), 8.52 (s, 2 H, CH), 8.59 (s, 2 H, CH_pyr). ^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, H_ar), 8.30 (s, 1 H, H_ar), 8.50 (s, 2 H, CH), 8.52 (s, 2 H, CH_tri). ^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, CH_pyr). ^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, CH_tri). ^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, H_ar), 8.64 (s, 1 H, H_pyr), 8.81 (t, 1 H, J = 8.0 Hz, H_ar). ^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, H_ar), 8.65 (s, 1 H, H_tri), 8.85 (t, 1 H, J = 8.0 Hz, H_ar). ^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, H_ar), 8.69 (s, 2 H, H_pyr), 8.72 (d, 2 H, J = 8.5 Hz, H_ar), 8.84 (d, 2 H, J = 8.5 Hz, H_ar), 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, H_ar), 8.69 (s, 2 H, H_ar), 8.61 (s, 2 H, H_tri), 8.89 (d, 2 H, J = 8.6 Hz, H_ar), 9.06 (s, 2 H, CH), 9.29 (d, 2 H, J = 8.6 Hz, H_ar). ^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]⁺.