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S. GANGULA ET AL.
(d, J ¼ 10.0 Hz, 1H), 3.70 (dt, J ¼ 1.6, 1.6, 2.0 Hz, 1H), 3.41 (d, J ¼ 14.4 Hz, 1H), 2.95
(d, J ¼ 14.4 Hz, 1H), 2.75 (d, J ¼ 11.6 Hz, 1H), 2.41 (dt, J ¼ 2.4, 3.2, 2.4 Hz, 1H),
0.95 (d, J ¼ 6.4 Hz, 3H); MS calcd. for C23H21F7N4O3 (Mþ) 534.43; found (MHþ)
535; ent-3 in 98.6% yield (600 mg) with 97.0% ee (98.5% purity by chiral HPLC)
25
and 98.60% purity by HPLC; ½aꢃD ¼ ðꢄÞ 35:20ꢀ (c ¼ 0.68 MeOH); DSC ¼ 253.8 ꢀC;
1H NMR (400 M Hz, DMSO-d6 & CDCl3): d 11.3 (s, 1H), 11.2 (s, 1H), 7.90–7.84 (m,
3H), 7.65–7.55 (m, 1H), 7.22–7.0 (m, 2H), 4.73 (q, J ¼ 6.4 Hz, 1H), 4.57 (d,
J ¼ 7.2 Hz, 1H), 3.95 (m, 1H), 3.86 (d, J ¼ 10.0 Hz, 1H), 3.70 (dt, J ¼ 1.6, 1.6,
2.0 Hz, 1H), 3.41 (d, J ¼ 14.4 Hz, 1H), 2.95 (d, J ¼ 14.4 Hz, 1H), 2.75 (d, J ¼ 11.6 Hz,
1H), 2.41 (dt, J ¼ 2.4, 3.2, 2.4 Hz, 1H), 0.95 (d, J ¼ 6.4 Hz, 3H); 13C NMR (100 MHz,
DMSO-d6): d 162.8, 160.4, 156.2, 146.4, 143.7, 133.1, 130.9, 129.9, 127.0, 124.3,
121.6, 114.6, 95.4, 71.5, 67.6, 58.6, 51.4, 50.3, 24.3; MS calcd. for C23H21F7N4O3
(Mþ) 534.43; found (MHþ) 535; 4 in 98% yield (590.0 mg) with 96.8% ee (98.0%
25
purity by chiral HPLC) and 98.4% purity by HPLC; ½aꢃD ¼ ðþÞ 39:52ꢀ (c ¼ 0.68
MeOH); DSC ¼ 254.8 ꢀC;1H NMR (400 MHz, DMSO-d6 & CDCl3) d 11.36 (s,
1H), 11.25 (s, 1H), 7.98–7.91(m, 3H), 7.62–7.59 (m, 2H), 7.15 (t, J ¼ 8.8 Hz, 2H),
4.87 (d, J ¼ 2.8 Hz, 1H), 4.74 (q, J ¼ 6.4 Hz, 1H), 3.87 (t, J ¼ 9.2, 9.2 Hz, 1H), 3.61
(d, J ¼ 2.8 Hz, 1H), 3.48 (d, J ¼ 11.2 Hz, 1H), 3.35 (d, 1H, J ¼ 14.4 Hz), 2.85 (d,
J ¼ 14.0 Hz, 1H), 2.72 (d, J ¼ 11.6 Hz, 1H), 2.36 (t, J ¼ 2.0, 2.8 Hz, 1H), 1.02 (d,
J ¼ 6.4 Hz, 3H); MS calcd. for C23H21F7N4O3 (Mþ) 534.43; found (MHþ) 535;
ent-4 in 98.2% yield (600.0 mg) with 97.4% ee (98.7% purity by chiral HPLC) and
25
1
99.1% purity by HPLC; ½aꢃD ¼ ðꢄÞ 38:52ꢀ (c ¼ 0.68 MeOH); DSC ¼ 254.8 ꢀC; H
NMR (400 M Hz, DMSO-d6) d 11.36 (s, 1H), 11.25 (s, 1H), 7.98–7.91 (m, 3H),
7.62–7.59 (m, 2H), 7.15 (t, J ¼ 8.8 Hz, 2H), 4.87 (d, J ¼ 2.8 Hz, 1H), 4.74 (q,
J ¼ 6.4 Hz, 1H), 3.87 (t, J ¼ 9.6, 9.6 Hz, 1H), 3.61 (d, J ¼ 2.8 Hz, 1H), 3.48 (d,
J ¼ 11.6 Hz, 1H), 3.40 (d, J ¼ 14.4 Hz, 1H), 2.98 (d, J ¼ 14.0 Hz, 1H), 2.73 (d,
J ¼ 11.6 Hz, 1H), 2.37 (dt, J ¼ 3.2, 2.8, 3.2 Hz, 1H), 1.02 (d, J ¼ 6.4 Hz, 3H); 13C
NMR (50 MHz, DMSO-d6) d 159.0, 156.1, 147.5, 143.7, 133.4, 131.4, 130.3, 126.5,
125.9, 120.7, 114.5, 96.4, 73.3, 67.4, 59.2, 50.6, 50.2, 21.4; MS calcd. for
C23H21F7N4O3 (Mþ) 534.43; found (MHþ) 535.
2R-[1R-(3, 5-Bistrifluromethyl-phenyl)-ethoxy]-3S-(4-fluoro-phenyl)-
morpholine 12[3]
N-chlorosuccinimide (NCS) (1.1 kg, 8.23 mol) was added in portions to a mix-
ture of sec-amine 8 (3.26 kg, 7.45 mol), DMF (18.6 L), and K2CO3 (0.4 kg, 2.9 mol)
at 0–5 ꢀC. After the mixture was stirred for 30–45 min, 1,8-diazabicyclo[5.4.0]undec-
7-ene (DBU) (1.35 kg, 8.9 mol) was added. The mixture was allowed to warm to room
temperature and stirred for 3 h. Water (50 L) and toluene (31 L) were added, and the
organic layer was separated and washed with water (10 L). The resulting organic layer
was distilled off below 50 ꢀC to afford 3.1 kg of imine compound 10. Crude imine
compound (3.1 kg, 7.12 mol) was dissolved in methanol (24.8 L), and sodium borohy-
dride (0.46 kg, 12.2 mol) was added lotwise at 0–5 ꢀC. The reaction mixture was stir-
red for 1.5–2.0 h at 0–5 ꢀC. After completion of the reaction, it was distilled off
completely, water (31 L) and toluene (15.5 L) were added, and the organic layer
was separated and washed with water (2 ꢂ 9.3 L). The organic layer was distilled
off completely under vacuum to afford 12 as thick syrup in 85.6% yield (2.8 kg).