Synthesis of Two Novel Mixed Bifunctional Chelating Agents: DO2AP(tBu)₄ and DO3AP(tBu)₄

Abstract

A convenient synthesis of two novel macrocyclic bifunctional chelating agents (BFCAs), formally derived from the well-known ligands DO3A and DOTA by selective replacement of one carboxymethyl side arm with a phosphonomethyl residue, is reported.

Key words

bifunctional chelating agents - DO3A - DOTA - phosphonic group - protecting group

• References and Notes


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• 24 Di-tert-butyl 4-[[Di(tert-butoxy)phosphoryl]methyl]-1,4,7,10-tetrazacyclododecane-1,7-diacetate (3): A mixture of 7 (13.9 g, 26 mmol, 1 equiv), tri-tert-butyl phosphite (7.6 g, 28.6 mmol, 1.1 equiv) and paraformaldehyde (0.9 g, 30 mmol, 1.15 equiv) was stirred and heated at 70 °C. After 16 h, additional tri-tert-butyl phosphite (1 g, 3.8 mmol, 0.15 equiv) and paraformaldehyde (0.1 g, 3.3 mmol, 0.13 equiv) were added and the mixture was heated for a further 20 h. The mixture was evaporated under vacuum at 80 °C to eliminate volatile by-products. The oily residue was dissolved in methanol (145 mL), 5% Pd/C (2.6 g) was added and the mixture was stirred under hydrogen atmosphere at room temperature for 8 h. The mixture was filtered through a Millipore FT 0.45 μm filter, evaporated, and the residue was purified by flash chromatography (CH₂Cl₂ then CH₂Cl₂/MeOH = 9:1) to give compound 3 (10.3 g, 65% over two steps) as a brown oil. IR (neat): 2977, 2927, 1730, 1368, 1223, 1152, 973, 917, 849, 692 cm^–1. ¹H NMR (300 MHz, CDCl₃, 333 K): δ = 3.02–2.91 (m, 5 H), 2.71–2.38 (m, 18 H), 1.09 (s, 18 H), 1.04 (s, 18 H) ppm. ¹³C NMR (75 MHz, CDCl₃, 333 K): δ = 169.8 (C), 82.2 (d, J = 9.8 Hz, C), 80.6 (C), 57.5 (CH₂), 51.2 (CH₂), 50.9 (CH₂), 48.9 (CH₂), 46.8 (CH₂), 45.3 (d, J = 145 Hz, CH₂), 29.9 (d, J = 3.7 Hz, CH₃), 27.5 (CH₃) ppm. ³¹P NMR (121 MHz, CDCl₃, 333 K): δ = 18.1 (s) ppm. MS (ESI⁺): m/z (%) = 607.24 (100) [M + H]⁺, 551.20 (21), 495.16 (35), 439.15 (34), 383.18 (20). HRMS (ESI⁺): m/z calcd for C₂₉H₅₉N₄O₇P: 606.41214; found: 607.41886 (100) [M + H]⁺, 629.40094 (46) [M + Na]⁺.
• 25 7-[[Di(t-butoxy)phosphoryl]methyl]-1,4,7,10-tetrazacyclododecane-1,4,10-triacetic acid 4,10-di-t-butyl ester (4): A mixture of compound 8 (1.38 g, 1.83 mmol), 10% Pd/C (0.28 g) and MeOH (10 mL) was stirred under hydrogen atmosphere at room temperature for 10 h. The mixture was filtered through Celite and evaporated to give compound 4 (1.20 g, 99%) as a pale-yellow oil. IR (neat): 3381, 2975, 1725, 1650, 1367, 1151, 1070, 976, 567, 433 cm^–1. ¹H NMR (300 MHz, CD₃OD, 313 K): δ = 3.79–2.82 (m, 24 H), 1.52–1.48 (m, 36 H) ppm. ¹³C NMR (75 MHz, CD₃OD, 298 K): δ = 170.9 (C), 169.1 (C), 82.7 (C), 79.9 (d, J = 8.1 Hz, C), 57.4 (CH₂), 54.2 (CH₂), 52.4 (d, J = 140.6 Hz, CH₂), 52.3 (CH₂), 51.8 (6 CH₂), 30.1 (d, J = 3.8 Hz, CH₃), 27.6 (CH₃) ppm. ³¹P NMR (121 MHz, CD₃OD, 313 K): δ = 5.85 (s) ppm. MS (ESI⁺): m/z (%) = 703.2 (36) [M + K]⁺, 687.4 (100) [M + Na]⁺, 630.9 (12). HRMS (ESI⁺): m/z calcd for C₃₁H₆₁N₄O₉P: 664.41762; found: 665.42279 (100) [M + H]⁺, 687.40452 (55) [M + Na]⁺.
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