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J. Shirai et al. / Bioorg. Med. Chem. 20 (2012) 962–977
obtained oil (22.9 g, 0.066 mol) was dissolved in MeOH (210 mL),
and followed by 28% NaOMe in MeOH (25.2 mL). After the mixture
was heated under reflux for 3 h, 2 N NaOH (165 mL) and THF
(84.1 mL) were added. The mixture was stirred at 60 °C for 14 h,
cooled to room temperature and made neutral with 2 N HCl. The
product was extracted with EtOAc and the extract was washed
with water and brine, dried (Na2SO4) and concentrated to give
22f (18.8 g, 0.059 mol, 89%) as white crystals, mp 172–174 °C. 1H
NMR (CDCl3, d): 10.50–9.50 (br, 1H), 7.19–7.08 (m, 4H), 4.35–
4.22 (m, 1H), 4.16–4.03 (m, 1H), 3.15 (dt, J = 11.5 and 4.0 Hz, 1H),
2.90 (dt, J = 11.6 and 3.6 Hz, 1H), 2.79 (t, J = 12.9 Hz, 1H), 2.57 (t,
J = 12.3 Hz, 1H), 2.38 (s, 3H), 2.08–1.99 (m, 1H), 1.83–1.65 (m,
1H), 1.45 (s, 9H). Anal. Calcd for C18H25NO4: C, 67.69; H, 7.89; N,
4.39. Found: C, 67.48; H, 7.85; N, 4.32.
5.1.43. (3RS,4RS)-N4-[3,5-Bis(trifluoromethyl)benzyl]-3-(4-
fluoro-2-methylphenyl)-N1-methylpiperidine-1,4-
dicarboxamide (26)
This compound was prepared from 12e and 28% ammonia solu-
tion by the similar procedure as described for the synthesis of 25 in
67% yield as white crystals, mp 187–189 °C. 1H NMR (CDCl3, d):
7.84–7.73 (m, 1H), 7.45–7.35 (m, 2H), 7.08–7.00 (m, 1H), 6.86–
6.70 (m, 2H), 4.82 (d, J = 15.0 Hz, 1H), 4.60–4.40 (m, 2H), 4.21 (d,
J = 15.0 Hz, 1H), 4.30–4.10 (m, 1H), 3.90–3.80 (m, 1H), 3.55–3.40
(m, 1H), 3.20–2.75 (m, 6H), 2.47–2.34 (m, 3H), 2.10–1.90 (m,
2H). Anal. Calcd for C24H24N3O2F7ꢁ0.5H2O: C, 54.55; H, 4.77; N,
7.95. Found: C, 54.37; H, 4.54; N, 7.92. LC–MS m/z (ion): 520
(M+H)+.
5.1.44. (3RS,4RS)-N4-[3,5-Bis(trifluoromethyl)benzyl]-3-(4-
fluoro-2-methylphenyl)-N1-methoxy-N4-methylpiperidine-1,4-
dicarboxamide (27)
This compound was prepared from 12e and O-methylhydroxyl-
amine hydrochloride by the similar procedure as described for the
synthesis of 25 in 56% yield as white amorphous. 1H NMR (CDCl3,
d): 7.83–7.72 (m, 1H), 7.42–7.35 (m, 2H), 6.98–6.70 (m, 4H),
4.84–4.45 (m, 1H), 4.30–3.90 (m, 3H), 3.72 (s, 3H), 3.54–2.30 (m,
10H), 2.00–1.85 (m, 2H). Anal. Calcd for C25H26N3O3F7ꢁ0.1diisopro-
pyl ether: C, 54.94; H, 4.93; N, 7.51. Found: C, 54.75; H, 5.02; N,
7.31. LC–MS m/z (ion): 550 (M+H)+.
5.1.39. (3RS,4RS)-1-(tert-Butoxycarbonyl)-3-[2-(1-
methylethyl)phenyl]piperidine-4-carboxylic acid (22g)
This compound was prepared from 21g in a manner similar to
that described for 22f as white crystals, mp 163–165 °C. 1H NMR
(CDCl3, d): 7.28–7.10 (m, 4H), 4.40–4.00 (m, 2H), 3.40–3.20 (m,
2H), 3.00–2.55 (m, 4H), 2.10–1.95 (m, 1H), 1.85–1.65 (m, 1H),
1.44 (s, 9H), 1.24 (d, J = 6.9 Hz, 3H), 1.18 (d, J = 6.9 Hz, 3H). Anal.
Calcd for C20H29NO4: C, 69.14; H, 8.41; N, 4.03. Found: C, 68.93;
H, 8.37; N, 3.91.
5.1.40. 1-Benzyl-5-phenyl-1,2,3,6-tetrahydropyridine-4-
carboxylic acid hydrochloride (23)
5.1.45. [(3RS,4RS)-4-{[3,5-bis(trifluoromethyl)benzyl]
A mixture of 21h (2.00 g, 6.22 mmol) in acetic acid (5 mL) and
hydrochloric acid (5 mL) was heated at 100 °C for 14 h and concen-
trated. The residue was crystallized from EtOAc, IPE and hexane to
give 23 (1.03 g, 3.12 mmol, 50%) as white crystals. 1H NMR (CDCl3,
d): 11.23 (br, 1H), 7.70–7.60 (m, 2H), 7.50–7.30 (m, 6H), 7.24–7.15
(m, 2H), 4.39 (m, 2H), 3.91 (s, 2H), 3.37 (m, 2H), 2.52 (m, 2H), HCl
peak was not observed. LC–MS m/z (ion): 294 (M–HCl+H)+. Chem-
ical purity: 94.8%.
(methyl)carbamoyl}-3-(4-fluoro-2-methylphenyl)piperidin-1-
yl](oxo)acetate (28)
To a cooled solution of 12e (0.30 g, 0.59 mmol) and Et3N
(0.082 mL, 0.59 mmol) in CH2Cl2 (10 mL) was added ethyl oxalyl
chloride (0.10 mL, 0.89 mmol) at 0 °C, and the mixture was allowed
to warm to room temperature. After stirring for 14 h, additional
ethyl oxalyl chloride (0.10 mL, 0.89 mmol) was added, and the
mixture was stirred for further 14 h and poured into H2O and
EtOAc. The organic layer was washed with aqueous saturated
NH4Cl and brine, dried over MgSO4, and concentrated to give 28
(0.33 g, 0.57 mmol, 97%) as white crystals, mp 184–186 °C. 1H
NMR (CDCl3, d): 7.85–7.34 (m, 1H), 7.10–7.00 (m, 2H), 6.96–6.75
(m, 2H), 4.92–2.35 (m, 16H), 2.05–1.90 (m, 2H), 1.45–1.30 (m,
3H). Anal. Calcd for C27H27N2O4F7: C, 56.25; H, 4.72; N, 4.86. Found:
C, 56.00; H, 4.75; N, 4.57. LC–MS m/z (ion): 577 (M+H)+.
5.1.41. (3RS,4RS)-1-(N-Acetylglycyl)-N-[3,5-bis(trifluoro
methyl)benzyl]-3-(4-fluoro-2-methylphenyl)-N-methylpiperi
dine-4-carboxamide (24)
This compound was prepared from 12e and N-acetylglycine by
the same procedure as described for the synthesis of 16 in 76%
yield as white amorphous. 1H NMR (CDCl3, d): 7.85–7.73 (m, 1H),
7.46–7.34 (m, 2H), 7.10–6.60 (m, 4H), 4.90–4.45 (m, 2H), 4.25–
2.35 (m, 14H), 2.10–1.80 (m, 5H). Anal. Calcd for C27H28N3O3F7:
C, 56.35; H, 4.90; N, 7.30. Found: C, 56.23; H, 5.03; N, 7.14. LC–
MS m/z (ion): 576 (M+H)+.
5.1.46. (3RS,4RS)-N-[3,5-Bis(trifluoromethyl)benzyl]-3-(4-
fluoro-2-methylphenyl)-N-methyl-1-[(methylamino)(oxo)
acetyl]piperidine-4-carboxamide (29)
A solution of 28 (0.10 g, 0.17 mmol) and 40% aqueous MeNH2
(1 mL) in EtOH (1.5 mL) was heated in a sealed tube at 100 °C for
4 h and poured into H2O and EtOAc. The organic layer was washed
with aqueous saturated NH4Cl and brine, dried over MgSO4, and
concentrated. The residue was purified by silica gel chromatogra-
phy with a gradient elution of 50% EtOAc/hexanes then 10%
MeOH/EtOAc to give 29 (0.028 g, 0.050 mmol, 29%) as white amor-
phous. 1H NMR (CDCl3, d): 7.85–7.73 (m, 1H), 7.46–7.35 (m, 2H),
7.30–6.70 (m, 2H), 5.42–5.09 (m, 1H), 4.84 (d, J = 15.0 Hz, 1H),
4.80–4.50 (m, 1H), 4.20 (d, J = 15.0 Hz, 1H), 3.65–2.60 (m, 11H),
2.50–2.40 (m, 3H), 2.10–1.80 (m, 2H), The NH peak was not ob-
served. LC–MS m/z (ion): 562 (M+H)+. Chemical purity: 92.1%.
5.1.42. (3RS,4RS)-N4-[3,5-Bis(trifluoromethyl)benzyl]-3-(4-
fluoro-2-methylphenyl)-N1,N4-dimethylpiperidine-1,4-
dicarboxamide (25)
To a cooled solution of 12e (0.15 g, 0.29 mmol) and Et3N
(0.082 mL, 0.59 mmol) in THF (5 mL) was added bis(trichloro-
methyl)carbonate (0.17 g, 0.57 mmol) at 0 °C, and the mixture was
allowed to warm to room temperature. After stirring for 1 h, 40%
aqueous MeNH2 (1 mL, 12.9 mmol) was added thereto. The mixture
was stirred for 14 h and poured into H2O and EtOAc. The organic
layer was washed with aqueous saturated NH4Cl and brine, dried
over MgSO4, and concentrated. The residue was purified by silica
gel chromatography with a gradient elution of 50% EtOAc/hexanes
then 10% MeOH/EtOAc to give 25 (0.11 g, 0.21 mmol, 72%) as white
crystals, mp 118–120 °C. 1H NMR (CDCl3, d): 7.83–7.71 (m, 1H),
7.46–7.32 (m, 2H), 7.09–6.98 (m, 1H), 6.94–6.70 (m, 2H), 4.82–
4.40 (m, 2H), 4.30–4.05 (m, 2H), 4.00–3.80 (m, 1H), 3.50–3.40 (m,
1H), 3.25–2.70 (m, 9H), 2.50–2.35 (m, 3H), 2.00–1.80 (m, 2H). Anal.
Calcd for C25H26N3O2F7: C, 56.28; H, 4.91; N, 7.88. Found: C, 56.24; H,
4.94; N, 7.85. LC–MS m/z (ion): 534 (M+H)+.
5.1.47. (3RS,4RS)-1-[Amino(oxo)acetyl]-N-[3,5-bis(trifluoro
methyl)benzyl]-3-(4-fluoro-2-methylphenyl)-N-methylpi
peridine-4-carboxamide (30)
A solution of 28 (0.53 g, 0.92 mmol) and 28% ammonia solution
(10 mL) in EtOH (5 mL) was stirred at room temperature for 6 h
and poured into H2O and EtOAc. The organic layer was washed
with aqueous saturated NH4Cl and brine, dried over MgSO4, and