The general procedure for the synthesis of N-(2-(6-fluoro-1H-indol-3-yl)ethyl)-3-(2,2,3,3-tetrafluoropropoxy)benzylamine hydrochloride using 6-fluorotryptophan and 3-(2,2,3,3-tetrafluoropropoxy)benzaldehyde was as follows: a mixture of 6-fluorotryptophan (11.0 g, 62 mmol) and 3-(2,2,3,3-tetrafluoropropoxy)benzaldehyde Formaldehyde (14.4 g, 59 mmol) were dissolved in toluene (120 mL) and isopropanol (96 mL), and the reaction was heated at 75°C for 3 hours. After completion of the reaction, the mixture was cooled to room temperature and 3% Pt/C catalyst (Evonik Noblyst P8080 type, 61.2% w/w water content, 3.06 g, 0.183 mmol) was added. The hydrogenation reaction was carried out at 70-75 °C and 5 bar pressure for 6 hours. At the end of the reaction, the mixture was cooled, the catalyst was removed by filtration, and the filtrate was concentrated to dryness to afford the crude product N-(2-(6-fluoro-1H-indol-3-yl)ethyl)-3-(2,2,3,3-tetrafluoropropoxy)benzylamine (25.7 g). The crude product (24.7 g, 1 g was retained for analysis) was dissolved in toluene (205 mL) and washed sequentially twice with 2% sodium hydroxide solution (79 mL) and then with a mixture of 3% ammonium chloride solution (74 mL) and water (74 mL). A dilute hydrochloric acid solution (10 mL) prepared from 6.4 mL of 37% w/w aqueous hydrochloric acid and 21.3 mL of water was slowly added, followed by the addition of acetonitrile (20 mL) and the mixture was heated to 50 °C. At this point, the target compound precipitated as hydrochloride (1:1), which was separated by filtration and washed with a mixture of toluene/acetonitrile, dilute hydrochloric acid and water. The wet product was dried in vacuum at 65 °C overnight to afford dry N-(2-(6-fluoro-1H-indol-3-yl)ethyl)-3-(2,2,3,3-tetrafluoropropoxy)benzylamine hydrochloride (20.4 g, 47 mmol, corrected yield 83%), which was analyzed by HPLC and showed a UV purity of 99.1%.
