反应详情

To a solution of triphosgene (0.714 g, 2.405 mmol) at 0° C. in dry ethyl acetate (5.5 ml) was slowly added a solution of phenylmethyl [(2R,4S)-2-(4-fluoro-2-methylphenyl)-4-(2-propen-1-yl)-4-piperidinyl]carbamate (Intermediate 18, 2 g, 5.23 mmol) and TEA (1.8 ml) in dry ethyl Acetate (10 ml) and the mixture was stirred for 5 minutes at the same temperature. Then a solution of {[3,5-bis(trifluoromethyl)phenyl]methyl}methylamine (WO 2007107818, 27 Sep. 2007) (1.479 g, 5.75 mmol) and TEA (1.63 ml) in dry Ethyl acetate (10 ml) was added in 5 minutes at 0° C. The resulting suspension was refluxed for 5 hours. After cooling, NaHCO3 sat. aq. solution and ethyl acetate were added to the reaction mixture and two phases were separated. The aqueous phase was extracted with ethyl acetate (3×) and the combined organic phases were dried (Na2SO4), filtered and evaporated to dryness. The residue was purified by flash chromatography with Biotage SP1 (from 1:0 to 7:3 Cyclohexane/EtOAc; 40 M) to give two batches of the title compound: 1st batch (1.6 g, 2.40 mmol, 46.0% yield); 1H NMR (500 MHz, DMSO-d6) δ ppm 7.94 (s, 1H) 7.61 (s, 2H) 7.27-7.38 (m, 5H) 7.24 (dd, 1H) 7.18 (br. s., 1H) 6.91 (dd, 1H) 6.76-6.83 (m, 1H) 5.68-5.81 (m, 1H) 5.06-5.18 (m, 2H) 4.88-5.00 (m, 2H) 4.60 (d, 1H) 4.36-4.44 (m, 1H) 4.36 (d, 1H) 3.36-3.47 (m, 1H) 2.94-3.06 (m, 1H) 2.88 (s, 3H) 2.63-2.72 (m, 2H) 2.31 (s, 3H) 1.84-2.05 (m, 3H) 1.64 (t, 1H); UPLC: Rt=1.02 mins; m/z=666 [MH]+. The 2nd batch was purified again by flash chromatography via Biotage SP1 (from 1:0 to 7:3 Cyclohexane/EtOAc; 40 M) to give further two batches of the title compound (0.8 g and 0.15 g).

1. temperatureThe resulting suspension was refluxed for 5 hours
2. temperatureAfter cooling
3. customwere separated
4. extractionThe aqueous phase was extracted with ethyl acetate (3×)
5. dry with materialthe combined organic phases were dried (Na2SO4)
6. filtrationfiltered
7. customevaporated to dryness
8. customThe residue was purified by flash chromatography with Biotage SP1 (from 1:0 to 7:3 Cyclohexane/EtOAc; 40 M)