Practical Asymmetric Synthesis of Aprepitant
(dd, J ) 8.9, 8.6 Hz, 2H), 4.73 (d, J ) 6.9 Hz, 1H), 3.94-3.85
(m, 1H), 3.78 (q, J ) 6.9 Hz, 1H), 3.72 (td, J ) 11.2, 2.4 Hz,
1H), 3.47 (d, J ) 7.1 Hz, 1H), 3.41 (br, 1H), 2.56 (td, J ) 11.5,
3.3 Hz, 1H), 2.34 (dt, J ) 11.8, 2.0 Hz, 1H), 1.25 (d, J ) 6.9
Hz, 3H); 13C NMR (100.6 MHz) δ 162.4 [(C-F) d, J C-F ) 246.4
Hz], 143.0 (C), 134.3 [(C) d, J C-F ) 3.1 Hz], 130.3 [(CH) d,
J C-F ) 7.9 Hz], 128.0 (CH), 127.4 (CH), 126.6 (CH), 115.5 [(CH)
d, J C-F ) 21.1 Hz], 98.1 (CH), 69.0 (CH), 64.7 (CH2), 54.6 (CH),
42.7 (CH2), 8.5 (CH3); 19F NMR (376.6 MHz) δ -114.5; IR
(cm-1) 3381 (br), 2969, 2827, 1603, 1509, 1221, 1152, 1107,
698, 549. Anal. Calcd for C18H20FNO2: C, 71.74; H, 6.69; F,
6.30; N, 4.65. Found: C, 71.71; H, 6.70; F, 6.46; N, 4.65.
Tr ich lor oa cetim id a te 18. A mixture of crude lactol solu-
tion 17 (38 mL), K2CO3 (4.12 g, 1.0 equiv), and CCl3CN (4.47
mL, 1.5 equiv) was stirred at rt for 5 h (∼95% conversion by
1H NMR). The K2CO3 was filtered off and rinsed with toluene.
The filtrate was concentrated under vacuum to give the crude
18: 1H NMR (400 MHz) δ 8.40 (s, 1H), 7.58-7.52 (m, 2H),
7.42-7.22 (m, 6H), 7.08-7.00 (m, 2H), 5.85 (d, J ) 7.4 Hz,
1H), 4.04-3.98 (m, 1H), 3.91-3.80 (m, 3H), 2.67 (dt, J ) 11.4,
3.4 Hz, 1H), 2.41 (dt, J ) 11.4, 2.5 Hz, 1 H), 1.27 (d, J ) 6.9
Hz, 3H).
272.2 Hz], 121.7 (CH), 115.8 [(CH) d, J C-F ) 21.7 Hz], 98.6
(CH), 74.6 (CH), 61.4 (CH2), 60.6 (CH), 43.2 (CH2), 24.6 (CH3);
19F NMR (376.6 MHz, DMSO-d6) δ -61.7 (CF3), -112.8; IR
(cm-1) 2882, 2705, 2609, 2452, 1518, 1279, 1176, 1134, 1078,
841, 683. Anal. Calcd for C20H19ClF7NO2: C, 50.70; H, 4.04;
Cl, 7.48; F, 28.07, N, 2.96. Found: C, 50.54; H, 3.72; Cl, 7.74;
F, 27.97; N, 2.86.
Im in e 8. To a mixture of crude 20 (∼70 mL of solution, 25.3
mmol), DMF (20 mL), and K2CO3 (0.70 g, 0.20 equiv) was
added NCS (3.88 g, 29.1 mmol, 1.15 equiv) in portions at 0
°C. After the mixture was stirred for 0.5 h, DBU (4.81 g, 31.6
mmol, 1.25 equiv) was added (exothermic). The mixture was
allowed to warm to rt and stirred for 3 h. Water (40 mL) was
added, and the organic layer was separated and washed with
water. The solution of crude imine 8 was used for the
hydrogenation step directly. An analytical sample of 8 was
obtained by crystallization from a 10:1 heptane/toluene mix-
ture: mp 105-106.5 °C; [R]22D +13.1 (c 0.96, MeOH); 1H NMR
(400 MHz) δ 7.87 (s, 1H), 7.76 (s, 2H), 7.46-7.41 (dd, J ) 8.9,
5.4 Hz, 2H), 6.97 (dd, J ) 8.9, 8.6 Hz, 2H), 5.12 (q, J ) 6.6 Hz,
1 H), 5.10 (s, 1H), 4.11-4.04 (m, 1H), 3.91-3.88 (m, 2H), 3.83-
3.78 (m, 1H), 1.55 (d, J ) 6.6 Hz, 3H); 13C NMR (100.6 MHz)
δ 164.0 [(C-F) d, J C-F ) 250.5 Hz], 161.5 (CdN), 144.8 (C),
132.6 [(C) d, J C-F ) 3.2 Hz], 132.0 [(C) q, J C-F ) 33.4 Hz],
128.4 [(CH) d, J C-F ) 8.6 Hz], 127.1 (CH), 123.2 [(CF3) q,
J C-F ) 272.9 Hz], 122.1 [(CH) m, J C-F ) 3.8 Hz], 115.3 [(CH)
d, J C-F ) 21.8 Hz], 88.4 (CH), 73.1 (CH), 55.9 (CH2), 47.9 (CH2),
23.9 (CH3); 19F NMR (376.6 MHz) δ -63.3 (CF3), -110.8; IR
(cm-1) 2985, 1640, 1594, 1507, 1373, 1289, 1279, 1120, 1067,
927, 897, 847, 707, 683. Anal. Calcd for C20H16F7NO2: C, 55.18;
H, 3.70; F, 30.55; N, 3.22. Found: C, 55.07; H, 3.46; F, 30.46;
N, 3.18.
Tr a n s Aceta liza tion to 19. Crude 18 (29.8 mmol) was
slowly added to a solution of chiral alcohol 3 (7.69 g, 29.8
mmol) and BF3‚Et2O (0.51 g, 12 mol %) in dry THF (70 mL)
at <-20 °C. The mixture was stirred for 1 h, and then the
reaction was quenched with a mixture of 10% Na2CO3/brine
(6/24 mL). The organic layer was separated and concentrated
and the solvent switched to EtOH (final volume ∼80 mL).
Water (20 mL) was added slowly over 2 h at 50 °C, and the
mixture was cooled to rt and stirred for 2 h. The product was
filtered and washed with 3/1 EtOH/water. The wet cake was
used directly for the next step or air-dried to give 14.3 g of
cis-sec-Am in e 9‚HCl. To the crude solution of imine 8 were
added EtOH (25 mL) and 5% Pd/C (0.50 g). The mixture was
hydrogenated under 40 psi of H2 at rt for 2 h. The catalyst
was filtered off and rinsed with toluene. TsOH‚H2O (4.55 g,
1.0 equiv) was added to the filtrate, and the mixture was
azeotropically distilled to ∼60 mL under a slight vacuum at
60-80 °C. The mixture was slowly cooled to 20 °C, and then
heptane (20 mL) was added. The product was collected by
filtration and dried at 40 °C to give 15.3 g of the tosylate salt
of the cis-sec-amine 9. HPLC indicated ∼94% purity and ∼4-
5% residue toluene. The overall isolated yield of 9 from the
acetalization product 19 was 94% corrected for purity. Alter-
natively, the HCl salt was isolated by using 1.0 equiv of
concentrated HCl instead of TsOH, and then the solvent was
switched to MEK. Adding 0.5 volume of heptane completed
the product 19, 85% yield from 16: mp 109-110.5 °C; [R]22
D
+97.4 (c 0.89, MeOH); 1H NMR (400 MHz) δ 7.70 (s, 1H), 7.40-
7.17 (m, 9H), 7.03-6.97 (m, 2H), 4.94 (q, J ) 6.6 Hz, 1H), 4.22
(d, J ) 7.3 Hz, 1H), 3.90 (ddd, J ) 11.2, 3.1, 1.5 Hz, 1H), 3.74
(q, J ) 6.9 Hz, 1H), 3.60 (td, J ) 11.4, 2.4 Hz, 1H), 3.57 (d,
J ) 7.3 Hz, 1H), 2.59 (td, J ) 11.6, 3.2 Hz, 1H), 2.30 (dt, J )
11.6, 1.8 Hz, 1H), 1.40 (d, J ) 6.6 Hz, 3H), 1.22 (d, J ) 6.9 Hz,
3H); 13C NMR (100.6 MHz) δ 162.4 [(C) d, J C-F ) 246.9 Hz],
145.4 (C), 142.9 (C), 133.8 [(C) d, J C-F ) 3.3 Hz], 131.5 [(C) q,
J C-F ) 33.3 Hz], 130.0 [(CH) d, J C-F ) 7.9 Hz], 128.0 (CH),
127.5 (CH), 126.6 (CH) 126.2 [(CH) d, J C-F ) 2.9 Hz], 123.1
[(CF3) q, J C-F ) 272.8 Hz], 121.5 [(CH) m, J C-F ) 3.7 Hz], 115.5
[(CH) d, J C-F ) 21.4 Hz], 101.6 (CH), 73.9 (CH), 67.5 (CH),
64.8 (CH2), 54.4 (CH), 42.7 (CH2), 24.3 (CH3), 7.9 (CH3); 19F
NMR (376.6 MHz) δ -63.1 (CF3), -114.4; IR (cm-1) 2973, 1606,
1510, 1375, 1279, 1176, 1132, 898, 838, 698, 682, 503. Anal.
Calcd for C28H26F7NO2: C, 62.11; H, 4.84; F, 24.56, N, 2.59.
Found: C, 62.00; H, 4.47; F, 24.61; N, 2.43.
the crystallization. 9‚HCl: mp 246 °C (dec); [R]22 +78.3 (c
D
0.78, MeOH); 1H NMR (400 MHz) δ 10.89 (br d, J ) 9 Hz,
1H), 10.48 (br d, J ) 10 Hz, 1H), 7.67 (s, 1H), 7.57 (dd, J )
8.7, 5.0 Hz, 2H), 7.23 (s, 2H), 7.06 (dd, J ) 8.5, 8.5 Hz, 2H),
4.94 (q, J ) 6.6 Hz, 1H), 4.55-4.49 (m, 2H), 4.24 (d, J ) 11.5
Hz, 1H), 3.84 (dd, J ) 12.5, 3.4 Hz, 1H), 3.48 (d, J ) 12.2 Hz,
1H), 3.30-3.20 (m, 1H), 0.93 (d, J ) 6.6 Hz, 3H); 13C NMR
(100.6 MHz) δ 163.4 [(C-F) d, J C-F ) 250.5 Hz], 144.2 (C),
131.9 [(C) q, J C-F ) 33.6 Hz], 130.0 [(CH) d, J C-F ) 8.3 Hz],
127.3 [(C) d, J C-F ) 3.2 Hz], 126.2 (CH), 122.9 [(CF3) q,
J C-F ) 272.8 Hz], 121.9 (CH), 116.1 [(CH) d, J C-F ) 22.0 Hz],
93.0 (CH), 73.0 (CH), 60.7 (CH), 55.2 (CH2), 44.0 (CH2), 24.2
tr a n s-sec-Am in e 20. A solution of 19 (14.3 g, 25.3 mmol)
and TsOH‚H2O (4.94 g, 1.02 equiv) in 1/1 toluene/EtOH (70
mL) was hydrogenated at 30 °C and 40 psi for 3 h in the
presence of 5% Pd/C (0.7 g). The catalyst was filtered off and
then rinsed with 1/1 toluene/EtOH. The filtrate was washed
with 5% Na2CO3 and water and then used directly for the next
step. Alternatively, the HCl salt was isolated by carrying out
the reaction in MeOH (200 mL) in the presence of 2.50 mL of
concentrated HCl (1.0 equiv). The filtrate was concentrated
and the solvent switched to methyl ethyl ketone. Heptane was
added until the ratio of MEK/heptane was ∼2/1 to crystallize
(CH3); 19F NMR (376.6 MHz) δ -63.2 (CF3), -111.3; IR (cm-1
)
3600-3100 (brd), 2919, 1610, 1518, 1442, 1280, 1180, 1128,
1026, 1007, 900, 838, 708, 682. Anal. Calcd for C20H19ClF7-
NO2: C, 50.70; H, 4.04; Cl, 7.48; F, 28.07; N, 2.96. Found: C,
50.73; H, 3.60; Cl, 7.78; F, 28.11; N, 2.88.
the HCl salt of 20 in 94% yield: mp 241 °C (dec); [R]22 +60.4
D
1
(c 0.97, MeOH); H NMR (400 MHz, DMSO-d6) δ 11-10 (br,
2H), 7.88 (s, 1H), 7.63 (dd, J ) 8.8, 5.3 Hz, 2H), 7.43 (s, 2H),
7.13 (t, J ) 8.8 Hz, 2H), 5.15 (q, J ) 6.5 Hz, 1H), 4.86 (d, J )
8.3 Hz, 1H), 4.25 (d, J ) 8.3 Hz, 1H), 4.24-4.11 (m, 2H), 3.23-
3.15 (m, 2H), 1.33 (d, J ) 6.5 Hz, 3H); 13C NMR (100.6 MHz,
DMSO-d6) δ 163.0 [(C-F) d, J C-F ) 246.5 Hz], 146.2 (C), 131.4
[(CH) d, J C-F ) 8.4 Hz], 130.6 [(C) q, J C-F ) 32.8 Hz], 129.4
Su p p or t in g In for m a t ion Ava ila b le: 1H and 13C NMR
and IR spectra for all new compounds and 19F NMR for most
new compounds. This material is available free of charge via
the Internet at http://pubs.acs.org.
[(CH) d, J C-F ) 2.8 Hz], 126.8 (CH), 123.5 [(CF3) q, J C-F
)
J O0203793
J . Org. Chem, Vol. 67, No. 19, 2002 6747