Diisopropylethylamine → N-(3,5-diamino-6-chloropyrazine-2-carbonyl)-N-(12-oxo-12-piperazin-1-yl-dodecyl)guanidine

Participants

Reaction Conditions

Reaction Steps

Diisopropylethylamine (1.67 mL, 9.59 mmol) was added to a suspension of 12-amino-1-piperazin-1-yl-dodecan-1-one dihydrochloride (11) (342 mg, 0.96 mmol) in absolute ethanol (10 mL). The resulting solution was stirred at 70° C. (oil bath) for 10 min and then 1-(3,5-diamino-6-chloropyrazine-2-carbonyl)-2-methylisothiourea hydriodide (380 mg, 0.98 mmol) added in one portion. The reaction mixture was then stirred at this temperature for 3 hours and cooled to room temperature. The solvent was removed by rotary evaporation and the resulting residue was dissolved in small volume of methanol, and the solution passed through an ion exchange resin column (Dowex 550A OH type). The resin column was rinsed thoroughly with methanol and the methanol solution was concentrated in vacuo. The resulting residue was purified by Biotage silica gel column chromatography, eluting with 0% to 20% of 9:1 methanol/ammonium hydroxide in dichloromethane to give N-(3,5-diamino-6-chloropyrazine-2-carbonyl)-N-(12-oxo-12-piperazin-1-yl-dodecyl)guanidine as a yellow solid. About half of this material was further purified by preparative HPLC using acetonitrile/water/0.05% TFA. The TFA salt obtained was co-evaporated twice with aqueous 2N HCl and further dried under high vacuum to give the desired compound 12 (123 mg, 45%) as a yellow solid: 1H NMR (500 MHz, DMSO-d6) δ 1.28 (m, 14H), 1.52 (m, 4H), 2.29 (t, 2H), 3.00 (m, 4H), 3.30 (m, 2H), 3.68 (m, 4H), 7.40 (br, 4H), 8.96 (m, 2H), 9.25 (m, 11H), 9.50 (br, 2H), 10.50 (s, 1H). m/z (ESI) 496 [C22H38ClN9O2+H]+. mp 148-150° C.

Provenance & Evidence