Efficient Synthesis of Aminoquinolinium and Aminoquinazolinium Salt Series: Amination or N-Alkylation First?

Abstract

The pharmacokinetic properties and, in particular, the poor solubilities of lead drug compounds are often a major impediment to their future clinical development. One common and effective solution is generally to use salt forms. Efficient strategies for the synthesis of quinolinium and quinazolinium salt series with promising therapeutic activities are thus of major interest. This study compares different synthetic routes for the rapid preparation of monomeric and dimeric aminoquinolinium and aminoquinazolinium salts. The advantages and limitations of the different processes, especially the importance of step order, are discussed.

Key words

aminoquinolinium salts - aminoquinazolinium salts - N,N′-bridging alkylation - amination - nucleophilic aromatic substitution

Publication History

Received: 17 March 2023

Accepted after revision: 15 May 2023

Article published online:
27 June 2023

• References and Notes

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• 17 1,1′-Propane-1,3-diylbis[4-(diethylamino)-6,7-dimethoxyquinolinium] Diiodide (21); Method 1, Typical ProcedureA solution of N,N-diethyl-6,7-dimethoxyquinolin-4-amine (4; 50 mg, 0.19 mmol, 1 equiv) and 1,3-diiodopropane (10 μL, 0.086 mmol, 0.45 equiv) in anhyd MeCN (5 mL) was stirred for 24 h at 110 °C in a sealed microwave vial. Et₂O (25 mL) was then added to the cooled suspension to induce precipitation of a solid that was collected by filtration, washed with Et₂O (3 × 10 mL), and dried under a vacuum. The solid was crystallized from EtOH to give a pale-yellow solid; yield: 61 mg (87%).¹H NMR (400 MHz, DMSO-d ₆): δ = 1.38 (t, J = 6.9 Hz, 12 H, 4 CH₃), 2.44–2.46 (m, 2 H, CH₂), 3.72 (q, J = 6.9 Hz, 8 H, 4 NCH₂), 3.96 (s, 6 H, 2 OCH₃), 3.98 (s, 6 H, 2 OCH₃), 4.79 (br t, J = 7.2 Hz, 4 H, 2 N⁺CH₂), 7.02 (d, J = 7.5 Hz, 2 H, 2 H³), 7.27 (s, 2 H, 2 H⁸), 7.31 (s, 2 H, 2 H⁵), 8.45 (d, J = 7.5 Hz, 2 H, 2 H²).¹³C APT NMR (100 MHz, DMSO-d ₆): δ = 12.4 (CH₃), 27.9 (CH₂), 46.8 (NCH₂), 51.2 (N⁺CH₂), 55.9 (OCH₃), 56.7 (OCH₃), 98.7 (CH³), 103.7 (CH⁵), 106.0 (CH⁸), 113.7 (C^4a), 135.8 (C^8a), 142.8 (CH²), 147.4 (C⁶), 154.3 (C⁷), 157.4 (C⁴). HRMS (ESI): m/z [M²⁺] calcd for C₃₃H₄₆N₄O₄: 281.1754; found: 281.1752.1,1′-Propane-1,3-diylbis[4-(diethylamino)-6,7-dimethoxyquinolinium] Dihexafluorophosphate (21-PF₆)A solution of the diiodide 21 (40 mg, 0.048 mmol, 1 equiv) and KPF₆ (0.135 g, 0.73 mmol, 15 equiv) in 1:1 MeOH–H₂O (5 mL) was stirred for 2 h at 60 °C under reflux. H₂O (20 mL) was added to the cooled suspension to precipitate a solid that was collected by filtration, washed with H₂O (3 × 10 mL), and dried under vacuum to give a pale-yellow solid; yield: 24 mg (59%); mp 240–245 °C (dec.).¹H NMR (400 MHz, DMSO-d ₆): δ = 1.37 (t, J = 6.9 Hz, 12 H, 4 CH₃), 2.41–2.49 (m, 2 H, CH₂), 3.72 (q, J = 6.9 Hz, 8 H, 4 NCH₂), 3.95 (s, 6 H, 2 OCH₃), 3.96 (s, 6 H, 2 OCH₃), 4.74 (br t, J = 7.2 Hz, 4 H, 2 N⁺CH₂), 7.01 (d, J = 7.6 Hz, 2 H, 2 H³), 7.25 (s, 2 H, 2 H⁸), 7.31 (s, 2 H, 2 H⁵), 8.41 (d, J = 7.6 Hz, 2 H, 2 H²). ¹³C APT NMR (100 MHz, DMSO-d ₆): δ = 12.4 (CH₃), 27.8 (CH₂), 46.8 (NCH₂), 51.2 (N⁺CH₂), 55.9 (OCH₃), 56.6 (OCH₃), 98.7 (CH³), 103.7 (CH⁵), 106.0 (CH⁸), 113.7 (C^4a), 135.8 (C^8a), 142.9 (CH²), 147.4 (C⁶), 154.3 (C⁷), 157.5 (C⁴). ¹⁹F NMR (376 MHz, DMSO-d ₆): δ = –70 (d, J = 711 Hz). ³¹P NMR (162 MHz, DMSO-d ₆): δ = –144 (sept, J = 711 Hz). HRMS (ESI): m/z [M²⁺] calcd for C₃₃H₄₆N₄O₄: 281.1754; found: 281.1754; m/z [M²⁺ + PF₆ ^–]⁺ calcd for C₃₃H₄₆F₆N₄O₄P: 707.3153; found: 707.3155.