反应详情

温度

27.5 °C

To a stirred solution of (1R)-1-naphthyl ethylamine (2, 10 g, 0.058 mol) was added the benzaldehyde (3, 17.04 g, 0.058 mol) and stirred at 25-30° C. for 1-2 h. After completion of the reaction (by HPLC) N-methyl-2-pyrrolidinone (30 mL) was added to the mixture and stirred for 15-20 min followed by addition of 1-(3-bromopropyl)-3-methylbenzene (18.68 g, 0.087 mol). The temperature of reaction mass was raised to 125-130° C. and maintained until completion of the reaction (by HPLC). The reaction mass was quenched with water (100 mL), pH of the resulting solution was adjusted to 8-9 using aqueous ammonia, and the solution was extracted with toluene (100 mL). The toluene layer was separated, washed with water (100 mL) followed by 10% sodium metabisulphite (100 mL×2). Water (100 mL) was added into toluene layer, and the pH of the solution was adjusted to 0.5-1.5 using concentrated hydrochloric acid. The resulting solution was stirred, and the layers were separated. The organic layer was washed with water (100 mL×2) and concentrated under reduced pressure to provide thick syrup. Syrup was dissolved in n-heptane (60 mL) and stirred for 2 h, and the solid obtained was filtered. The wet solid was suspended in ethyl acetate (50 mL); the solution was heated at 55-60° C. for 30 min, cooled to 15-20° C., filtered, washed with ethyl acetate, and dried to afford des(trifluorocinacalcet), the title compound, as a white crystalline solid. Yield: 11.0 g (55.92%); HPLC purity: 99.60%; Chiral Purity: 99.90%; IR (KBr) cm−1: 3435, 3006, 2962, 2945, 2798, 1588, 1455, 799, 771, 702; MS: m/z=304.2 [M+H]+; 1H NMR (400 MHz, DMSO-d6): δ=1.66-1.68 (d, 3H), 1.93-1.96 (m, 2H), 2.22 (s, 3H), 2.52-2.54 (m, 2H), 2.71-2.74 (dt, 1H), 2.90-2.94 (dt, 1H), 5.29-5.31 (q, 1H), 6.89-6.97 (dd, J=8.0 Hz and 3.0 Hz, 3H), 7.11-7.13 (t, J=8.0 Hz, 1H), 7.59-7.63 (dd, J=8.0 Hz and 3.0 Hz, 3H), 7.97-8.02 (m, 3H), 8.23-8.25 (d, J=8.0 Hz, 1H), 9.24 (bs, 1H), 9.84 (s, 1H); 13C NMR (100 MHz, DMSO-d6): δ=20.13 (CH3), 21.02 (CH3), 27.16 (CH2), 31.92 (CH2), 44.88 (CH2), 52.07 (CH), 122.68, 124.51, 125.25, 125.62, 126.19, 126.64, 126.98, 128.64, 128.89, 130.36, 133.39, 134.22, 137.36, 140.59.

1. additionwas added to the mixture
2. stirringstirred for 15-20 min
3. customThe temperature of reaction mass
4. temperaturewas raised to 125-130° C.
5. temperaturemaintained until completion of the reaction (by HPLC)
6. customThe reaction mass was quenched with water (100 mL), pH of the resulting solution
7. extractionthe solution was extracted with toluene (100 mL)
8. customThe toluene layer was separated
9. washwashed with water (100 mL)
10. additionWater (100 mL) was added into toluene layer
11. stirringThe resulting solution was stirred
12. customthe layers were separated
13. washThe organic layer was washed with water (100 mL×2)
14. concentrationconcentrated under reduced pressure
15. customto provide thick syrup
16. stirringstirred for 2 h
17. customthe solid obtained
18. filtrationwas filtered
19. temperaturethe solution was heated at 55-60° C. for 30 min
20. temperaturecooled to 15-20° C.
21. filtrationfiltered
22. washwashed with ethyl acetate
23. customdried
24. customto afford des(trifluorocinacalcet)