反应详情

A 2 L Erlenmeyer flask was charged with piperazine (185.1 g, 2.15 mol), 2,2-difluoro-benzo[1,3]dioxole-5-carbaldehyde (100.0 g, 0.537 mol), and methanol (1.08 L). The solution was stirred at room temperature for 18 h then passed twice through an H-Cube Midi™ (ThalesNano, Budapest, Hungary) with a new 20% Pd(OH)2/C MidiCart cartridge, at the following settings: 70° C., 1 atm pressure, 6 mL/min flow rate, and 10% excess H2 production. The aldehyde starting material was >90% consumed after the first pass, and completely consumed after the second pass as indicated by HPLC analysis. The methanol was evaporated, toluene (1.20 L) was added and the mixture was stirred at room temperature for 18 h. The resulting white suspension was filtered and the solid was rinsed with toluene (200 mL). The combined filtrate was washed with water (2×300 mL), dried over Na2SO4, filtered, and concentrated to afford the product as a colorless oil. The oil was dissolved in heptane (100 mL) and the product was allowed to crystallize at room temperature. For subsequent synthesis experiments, addition of a small amount of seed crystals was used to quicken the crystallization process. The suspension was cooled to 0° C., filtered and the solid was dried in vacuum oven at 50° C. for 24 h to give the title compound as a white solid (108.0 g, 78%). The heptane filtrate was concentrated to approximately 20 mL followed by addition of product seed crystals. The solution then was stirred overnight. The second batch of the title compound was obtained as a white solid after filtration and drying (6.7 g, 5%). The combined yield was (115 g, 83%). MS (ESI+): calcd for C12H14F2N2O2 m/z 256.1. found 256.9 (M+H)+. 1H NMR (400 MHz, CDCl3) δ: 7.11 (d, J=0.9 Hz, 1H), 6.99 (dd, J=9.0, 0.9 Hz, 1H), 6.95 (d, J=9.0 Hz, 1H), 3.45 (s, 2H), 2.92-2.83 (m, 4H), 2.39 (s, 4H); 13C NMR (101 MHz, CDCl3) δ: 143.89, 142.72, 134.68, 131.65 (t, JC-F=255.3), 123.88, 110.13, 108.82, 63.10, 54.38, 46.07.

1. custom70° C., 1 atm pressure, 6 mL/min flow rate, and 10% excess H2 production
2. customconsumed after the first pass
3. customcompletely consumed after the second pass
4. customThe methanol was evaporated
5. additiontoluene (1.20 L) was added
6. stirringthe mixture was stirred at room temperature for 18 h
7. filtrationThe resulting white suspension was filtered
8. washthe solid was rinsed with toluene (200 mL)
9. washThe combined filtrate was washed with water (2×300 mL)
10. dry with materialdried over Na2SO4
11. filtrationfiltered
12. concentrationconcentrated