2-(1-Trityl-1H-imidazol-4-yl)-ethylamine hydrate

Synthesis

Histamine dihydrochloride (20.47 g, 0.111 mol) was used as starting material and stirred with triethylamine (48 mL, 0.345 mol) in anhydrous methanol (400 mL) for 10 min at room temperature. Subsequently, a solution of ethyl trifluoroacetate (14.6 mL, 0.122 mol) in methanol (30 mL) was added slowly and dropwise over a period of 30 min at 0 °C. The reaction mixture was continued to be stirred at room temperature for 3.5 hours before the solvent was removed by vacuum evaporation. The residue was dissolved in dichloromethane (450 mL) and triethylamine (31 mL, 0.222 mol) was added. Next, triphenylmethyl chloride (34.1 g, 0.122 mol) was added in batches and the mixture was stirred overnight at room temperature. Upon completion of the reaction, chloroform (400 mL) and water (600 mL) were added to the mixture, the aqueous layer was separated and extracted with chloroform (3 x 400 mL). The organic layers were combined and dried with anhydrous magnesium sulfate. After evaporation of the solvent, the resulting beige solid was ground with hexane (1000 mL) and filtered to afford 2,2,2-trifluoro-N-[2-(1-trityl-1H-imidazol-4-yl)-ethyl]-acetamide as a white solid in a yield of 45.54 g (91% yield).1H NMR (300 MHz, CDCl3, δH): 8.44 (bs, 1H) , 7.43 (s, 1H), 7.41-7.33 (m, 9H), 7.19-7.10 (m, 6H), 6.65 (s, 1H), 3.66 (q, J = 5.9 Hz, 2H), 2.79 (t, J = 5.9 Hz, 2H). The above amide (45.54 g, 0.101 mol) was dissolved in tetrahydrofuran (1000 mL) and methanol (1200 mL) and a solution of sodium hydroxide (20.26 g, 0.507 mol) in water (500 mL) was added. The mixture was stirred at room temperature for 2 hours and then concentrated. The residue was partitioned between chloroform (1200 mL) and water (800 mL) and the aqueous layer was extracted with chloroform (3 x 400 mL). The organic layers were combined, dried with anhydrous magnesium sulfate and the solvent was evaporated to give a brown oil, which was dried for 3 days to give the title product 2-(1-trityl-1H-imidazol-4-yl)ethylamine as a beige solid in a yield of 32.23 g (90% yield), 82% total yield. Melting point: 111-113 °C. 1H NMR (300 MHz, CDCl3, δH): 7.39 (d, J = 1.3 Hz, 1H), 7.38-7.32 (m, 9H), 7.20-7.12 (m, 6H), 6.61 (s, 1H), 3.00 (t, J = 6.6 Hz, 2H), 2.70 (t, J = 6.5 Hz , 2H), 1.93 (bs, 2H).

References

[1] Bioorganic and Medicinal Chemistry Letters, 2002, vol. 12, # 9, p. 1269 - 1273
[2] Patent: EP3000482, 2016, A1. Location in patent: Paragraph 0261; 0263
[3] Patent: US2010/216854, 2010, A1. Location in patent: Page/Page column 24
[4] Patent: US6562823, 2003, B1
[5] Journal of Biological Inorganic Chemistry, 2016, vol. 21, # 5-6, p. 777 - 792