88% |
With sulfuric acid; acetic acid; at 20℃; for 20.0h;Inert atmosphere; |
To a mixture of acetic acid (9.5 mL, 165.83 mmol), sulfuric acid (6.4 mL, 204.1 mmol) was added 2,2,2-trifluoro-N-[2-(4-fluorophenyl)ethyl]acetamide (3 g, 12.76 mmol) followed by Paraformaldehyde (0.64 g, 12.76 mmol) at room temperature under argon. The resulting viscous cloudy reaction mixture allowed to stir for ~20 h at room temperature. The reaction mixture was then poured onto 100 mL of cold water, extracted with ethyl acetate (2 X 100 mL). The organic extracts were then combined, washed with saturated aq. NaHCO3 (2 X 100 mL), brine (2X100 mL), dried over anhydrous sodium sulfate, filtered and (0751) concentrated under reduced pressure. The residue is then absorbed onto silica gel for purification. The desired product was obtained as a colorless viscous oil in 88% yield (2.77 g). 1H NMR (400 MHz, Chloroform-d) delta 7.17- 7.09 (m, 1H), 6.99- 6.81 (m, 2H), 4.79- 4.70 (m, 2H), 3.91- 3.81 (m, 2H), 2.92 (h, J = 5.4 Hz, 2H). Yield: 88% |
71% |
With sulfuric acid; acetic acid; at 20℃; for 20.0h;Inert atmosphere; |
Step 2: N-trifluoroacetyl-7-fluoro-1,2,3,4-tetrahydroisoquinoline N-(4-fluorophenethyl) trifluoroacetamide (2.66g, 11.3mmol), paraformaldehyde (0.56g) and concentrated sulfuric acid / acetic acid (5.5mL/8.2mL) were added to a 150ml reaction flask. The reaction was stirred for 20 hours under the protection of nitrogen at room temperature. The reaction solution was poured into water (50ml), and extracted three times with ethyl acetate. The organic phases were combined, washed sequentially with saturated aqueous sodium bicarbonate solution and saturated brine, dried, concentrated, and the obtained crude product was separated and purified by column chromatography (silica gel column, eluent: ethyl acetate/petroleum ether, gradient: 0?30%) to obtain the title compound (1.98g, 71%). (MS: [M+1] none) |
49% |
With sulfuric acid; acetic acid; In dichloromethane; at 20℃; for 8.0h;Inert atmosphere; |
The A23-2 (500mg, 2.13mmol) and paraformaldehyde (109mg, 3.40mmol) was dissolved in glacial acetic acid (2.9mL), was slowly added dropwise under ice-conc.Sulfuric acid (1.88mL), followed by stirring at room temperature for 8h. The reaction solution was poured into 10mL of ice water, and extracted three times with ethyl acetate, the combined organic phases are washed with saturatedAqueous solution of sodium bicarbonate until no bubbles, then washed once with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and the solvent was evaporated, purified by column chromatography (petroleumEther: ethyl acetate = 1: 0-200: 1) to give a colorless oil (260mg, 49%). |