Reaction Steps
To a mixture of crude material containing (5S,6R)-3-amino-6-methyl-1-(2,2,2-trifluoroethyl)-5-(2,3,6-trifluorophenyl)piperidin-2-one (24, 2.00 g, 5.88 mmol), prepared according to the same method as the previous example, and 3,5-dichloro-2-hydroxybenzaldehyde (0.011 g, 0.059 mmol) in isopropyl acetate (15.0 ml) at 55-60° C. under nitrogen was slowly added a solution of diphenylacetic acid (1.26 g, 5.88 mmol) in THF (10.0 ml) over 2 h. Upon completion of acid addition, a thick salt suspension was agitated at 55-60° C. for another 18 h and then was allowed to cool to ambient temperature. The salt was filtered and washed with isopropyl acetate. After drying at 60° C. in a vacuum oven with nitrogen purge for 8 hours, 25 (2.97 g, 91.4%) was obtained as crystals. 1H NMR (500 MHz, DMSO-d6): δ 7.48 (qd, J=9.4, 4.9 Hz, 1H), 7.32 (d, J=7.7 Hz, 4H), 7.25-7.26 (m, 4H), 7.19-7.17 (m, 3H), 6.79 (br, 3H), 4.95 (s, 1H), 4.67 (dq, J=15.3, 9.7 Hz, 1H), 3.81-3.79 (m, 3H), 3.62 (dd, J=11.6, 6.5 Hz, 1H), 2.66-2.62 (m, 1H), 2.25 (dd, J=12.9, 6.4 Hz, 1H), 1.11 (d, J=6.5 Hz, 3H); 13C NMR (100 MHz, DMSO-d6): δ 174.4, 171.8, 156.9 (ddd, J=244, 7.0, 2.5 Hz), 149.1 (ddd, J=249, 14.4, 8.5 Hz), 147.2 (ddd, J=246, 13.9, 3.2 Hz), 141.4, 129.0, 128.5, 126.7, 125.5 (q, J=281 Hz), 118.0 (dd, J=19.8, 13.8 Hz), 117.1 (dd, J=19.2, 10.6 Hz), 112.3 (ddd, J=26.1, 6.7, 3.3 Hz), 58.5, 57.1, 51.7, 44.8 (q, J=32.7 Hz), 35.3, 27.5 (br t, J=4.6 Hz), 14.5.
