反应详情

温度

0 °C

(R)-3-(1-(naphthalen-1-yl)ethylamino)-1-(3-(trifluoromethyl)phenyl)propan-1-one hydrochloride (V) (100.0 g, 245.182 mmol) is suspended in cold methanol (50 ml) at −10° C. and, subsequently, a solution of sodium borohydride (4.6 g, 121.597 mmol), 30% w/w aqueous sodium hydroxide (35.5 g, 266.250 mmol) and water (30 ml) is added slowly in order to keep the internal temperature below 0° C. The reaction mixture is stirred at 0° C. for 0.5 hrs, then quenched by addition of acetic acid (36.7 g, 611.157 mmol), allowed to reach room temperature and added with water (280 ml). The volatile solvent is distilled off under vacuum at 40° C., then MTBE is charged (400 ml). The organic layer is separated and washed with water (3×50 ml). Then the free base is liberated by addition of sodium hydroxide (aq. 30% w/w; 48.8 g, 366.0 mmol) up to pH=12-13, and the organic layer is washed with water (3×50 ml). MTBE is distilled off under vacuum and flushed with toluene. The reaction mixture is then cooled down to 20° C. and a solution of thionyl chloride (30.5 g, 256.367 mmol) in toluene (60 ml) is charged drop-wise over two hours. The mixture is then stirred at 30° C. for 3 hours and once reaction goes to completion the volatiles are removed under vacuum at 60° C. Then toluene is restored and the reaction mixture is cooled to 20° C. Diisopropyl ether (200 ml) is added and the reaction mixture is refluxed at 80° C. for 1 hour, then cooled down to 20° C. The resulting thick suspension is filtered, the solid is washed with a 2:1 vol/vol toluene/diisopropyl ether (60 ml), followed by MTBE (3×60 ml). The so-formed thick suspension is heated up to 50° C., stirred for 20 minutes and then cooled down to 5° C. 65.0 g of a 98.4:1.6 (HPLC % area) mixture of (R)-3-chloro-N-(1-(naphthalen-1-yl)ethyl)-3-(3-(trifluoromethyl)phenyl)propan-1-amine hydro-chloride (X) and (R,E)-N-(1-(naphthalen-1-yl)ethyl)-3-(3-(trifluoromethyl)phenyl)-prop-2-en-1-amine hydrochloride (XI) is obtained as a white powder after exsiccation at 55° C. under vacuum.

1. customthe internal temperature below 0° C
2. customto reach room temperature
3. distillationThe volatile solvent is distilled off under vacuum at 40° C.
4. additionMTBE is charged (400 ml)
5. customThe organic layer is separated
6. washwashed with water (3×50 ml)
7. washthe organic layer is washed with water (3×50 ml)
8. distillationMTBE is distilled off under vacuum
9. customflushed with toluene
10. temperatureThe reaction mixture is then cooled down to 20° C.
11. stirringThe mixture is then stirred at 30° C. for 3 hours
12. customonce reaction
13. customare removed under vacuum at 60° C
14. temperaturethe reaction mixture is cooled to 20° C
15. additionDiisopropyl ether (200 ml) is added
16. temperaturethe reaction mixture is refluxed at 80° C. for 1 hour
17. temperaturecooled down to 20° C
18. filtrationThe resulting thick suspension is filtered
19. washthe solid is washed with a 2:1 vol/vol toluene/diisopropyl ether (60 ml)
20. temperatureThe so-formed thick suspension is heated up to 50° C.
21. stirringstirred for 20 minutes
22. temperaturecooled down to 5° C
23. addition65.0 g of a 98.4:1.6 (HPLC % area) mixture of (R)-3-chloro-N-(1-(naphthalen-1-yl)ethyl)-3-(3-(trifluoromethyl)phenyl)propan-1-amine hydro-chloride (X)