反应详情

温度

-2.5 °C

5,5,5-Trifluoro-2-(1-phenylethylamino)pentanenitrile (crude mixture of diastereomers from Step B, 1.10 kg) was dissolved in dichloromethane (5.5 L) in a suitable vessel equipped with mechanical stirring, ice bath for cooling and maintained under a blanket of nitrogen. Stirring was started and the reaction mixture was cooled to 0 to −5° C. Concentrated sulfuric acid (1.75 L) was added dropwise over a period of 1 hour into the above mixture, maintaining the temperature below 0° C.; a clear solution was obtained after the addition was complete. The temperature of the reaction mixture was raised to 25 to 27° C. and stirred overnight (12-14 h). Completion of the reaction was determined by HPLC. The reaction mixture was poured slowly over crushed ice (˜15.0 kg) and was neutralized with aqueous ammonia (˜25% by volume). The aqueous layer was separated and extracted with dichloromethane (2×3.0 L). The combined dichloromethane layer was washed with water (1×12.0 L) followed by brine (1×3.0 L). The product rich organic layer was dried over sodium sulfate and concentrated under reduced pressure to yield 0.85 kg (72.0%) of the crude title compound 1H NMR (CDCl3) (400 MHz) (Mixture of diasteromers) δ 1.36 (d&m, 41-1, CH3 (J=8.0 Hz & 1H of CH2), 1.90 (m, 1H of CH2), 2.15 & 2.35 (two m, 1H each of CH2—CF3), 2.80-2.90 (m, 1-H, CH-Ph), 3.60-3.70 (m, 1H, —(CONH2)CH(NH), 5.90 & 6.45 (111 each of CONH2 with minor peaks for other diasteromer), 7.20-7.40 (m, 6H, Ar+NH).

1. customequipped with mechanical stirring, ice bath
2. temperaturefor cooling
3. temperaturemaintained under a blanket of nitrogen
4. temperaturemaintaining the temperature below 0° C.
5. customa clear solution was obtained
6. additionafter the addition
7. temperatureThe temperature of the reaction mixture was raised to 25 to 27° C.
8. stirringstirred overnight (12-14 h)
9. additionThe reaction mixture was poured slowly
10. customThe aqueous layer was separated
11. extractionextracted with dichloromethane (2×3.0 L)
12. washThe combined dichloromethane layer was washed with water (1×12.0 L)
13. dry with materialThe product rich organic layer was dried over sodium sulfate
14. concentrationconcentrated under reduced pressure
15. customto yield