反应详情

Following a method similar as described in Example 484, using 2-trifluoromethyl-4,9-dihydro-3-thia-1,4,9-triaza-benzo[f]azulene-10-thione (4.025 g, 13.36 mmol) and methyl trifluoromethanesulfonate (2.27 mL, 20.0 mmol), to formed the methylated intermediate. Take 1.38 g of this intermediate (3.0 mmol), combine and then (S)-2-[2-(3-fluoro-phenyl)-ethyl]-piperazine (0.62 g, 3.0 mmol), followed by two chromatographic purifications, the first with a pre-packed silica gel column, eluting with a gradient of a 3.5% solution of 2M ammonia in methanol, in dichloromethane (0–100% in dichloromethane); and the second with a pre-packed cation exchange column, loading with methanol, and then eluting the product with increasing concentrations of 2M ammonia in methanol, in dichloromethane gives the title compound (0.754 g): mass spectrum (APCI+, m/e): 476 (M+1); 1H NMR (300 MHz, DMSO-d6), δ (ppm): 8.45 (s, 1H), 7.33–7.23 (m, 1H), 7.05–6.80 (m, 6H), 6.74–6.68 (m, 1H), 4.06–3.80 (br. m, 2.94–2.76 (m, 2H), 2.74–2.52 (m, 5H), 2.35 (br. s, 1H), 1.67–1.49 (m, 2H).

1. customto formed the methylated intermediate
2. washthe first with a pre-packed silica gel column, eluting with a gradient of a 3.5% solution of 2M ammonia in methanol, in dichloromethane (0–100% in dichloromethane)
3. washeluting the product
4. temperaturewith increasing concentrations of 2M ammonia in methanol