A synthetic route to 3‐(dialkylamino)phenothiazin‐5‐ium salts and 3,7‐disubstituted derivatives containing two different amino groups

Abstract

Phenothiazin‐5‐ium tetraiodide hydrate (2), the suggested oxidation product of phenothiazine with iodine, is treated with two equivalents of a dialkylamine to give 3‐(dialkylamino)phenothiazin‐5‐ium triiodides, 3‐6. 3,7‐Disubstituted phenothiazin‐5‐ium iodides, 7‐9, are obtained by the reaction of 3‐6 with an amine.

Design and Synthesis of Novel Phenothiazinium Photosensitiser Derivatives

“…[14] In addition to the latter, we selected a commercially available tether 5 designed for the synthesis of N-(2-aminoethyl)-Azure B (8), a compound reported to be a suitable precursor in dye-peptide conjugates. [15] We expected that attack of the aromatic π-electrons at the methylated terminal of the tether 5 would be most favorable owing to the N-atom's nucleophilicity and thus set out to synthesise compound 8 by the methodology developed by Strekowski et al towards 3,7-disubstituted phenothiazin-5-ium salts containing two different amino groups (Scheme 1). [7] We were delighted that coupling 7 to the amino tether 5, at room temperature in anhydrous MeOH followed by preparative HPLC purification of the crude mixture, gave the Azure B derivative 8 in 84 % yield, the highest reported to date for the synthesis of this compound.…”

“…Thus, following the literature synthesis of protected Ornithine octamer 20, [7] coupling to the butylamine dye 14 occurred readily following optimized conditions, furnishing protected octa-orn-dye 25 in a satisfactory 70 % yield. Nevertheless, as we had already encountered, "post" perguanidylation towards 30 did not give any products in the "therapeutic" PDT window i.e.…”

“…All structural assignments were in agreement with 1 H NMR spectroscopic data available from the literature. [7] 3-(Dimethylamino)phenothiazin-5-ium Triiodide (7): The compound was synthesized from 6 in accordance with known literature protocol. [7] The desired product 8 was obtained as a dark solid (340 mg, 28 %).…”

“…[14] Phenothiazin-5-ium Tetraiodide Hydrate (6): The compound was synthesized in accordance with known literature protocol. [7] A solution of iodine (8.4 g, 33 mmol) in chloroform (175 mL) was added dropwise to a stirred solution of phenothiazine (2.1 g, 11 mmol) in chloroform (75 mL) within 1 h at room temperature. The reaction mixture was then stirred for a further 30 min at 5°C and the resultant precipitate was filtered, washed with chloroform (2 ϫ 500 mL) and then dried at room temperature for 3 h give the phenothiazine tetraiodide (6.8 g, 74 %) as a black solid.…”

“…In our studies, a modified version of the method described by Strekowski et al is utilized for their synthesis. [7,8] The potential therapeutic efficacy of several synthetic drug analogs can be limited due to their unfavorable properties. These include: poor solubility, absorption, or distribution and poor cell penetration.…”