Journal of Medicinal Chemistry
Article
(200 mL) and filtered through a plug of Celite. The resultant solution
was washed with water (3 × 100 mL), washed with brine (200 mL),
dried (magnesium sulfate), absorbed onto silica gel (approximately
70 g), and purified by column chromatography (eluent 5% acetone in
hexanes increasing to 33% acetone) to afford crude 6 (40.6 g) as a
dark orange gel. This material was dissolved in ethyl acetate (250 mL),
adsorbed onto silica gel (approximately 50 g), and repurified by
column chromatography (eluent hexanes, then dichloromethane in
hexanes increasing to 100% dichloromethane) to afford 39.3 g of
semicrude material which was dissolved in the minimum volume of
boiling hexanes (1250 mL). Upon seeding with a spatula tip of purified
6 (from a previous experiment) and standing overnight at room tem-
perature, a solid formed. The solid material was filtered on a sinter
funnel under vacuum to afford 6 (25.5 g, 45%) as a light, pale yellow
solid. 1H NMR (CDCl3) 8.53 (d, J = 2.0 Hz, 1H), 8.31−8.39 (m, 1H),
7.59 (d, J = 2.8 Hz 1H), 7.41−7.49 (m, 2H), 6.65−6.73 (m, 2H), 6.68
(d, J = 8.4 Hz 2H), 6.61 (d, J = 9.2 Hz, 2H), 4.48−4.63 (m, 2H),
4.15−4.28 (m, 1H), 2.93−3.12 (m, 2H), 2.00−2.16 (m, 2H), 1.32−
1.50 (m, 2H); 13C NMR (101 MHz, CDCl3) 159.7, 150.5, 150.0,
147.5, 145.7, 139.1, 136.6, 134.6, 126.7, 125.0, 125.0, 124.4, 120.8,
115.7, 115.0, 105.5, 55.7, 44.4, 30.5; LCMS [M + H]+ = 467.5; mp
95−97 °C. Anal. Calcd for C23H20F6N4: C, 59.23; H, 4.32; N, 12.01.
Found: C, 59.49; H, 4.44; N, 12.06.
The mother liquor was concentrated to give a further 12.5 g of
material as a dark orange gel, which was subjected to cycles of the
solidification process with boiling hexanes to afford a further 7.3 g,
1.3 g, and 400 mg of 6. These batches were combined, dissolved in
diethyl ether (50 mL), and washed with 4 M hydrochloric acid
(180 mL). The aqueous layer was then extracted with more diethyl
ether (50 mL). The aqueous layer was then basified (to pH 13) using
2 M sodium hydroxide (approximately 350 mL). The resulting cloudy
white aqueous layer was extracted with ethyl acetate (2 × 100 mL) and
the organic layer separated. Activated carbon was added to the ethyl
acetate layer and the resulting suspension heated to 70 °C for 2 h.
Magnesium sulfate was added and the suspension filtered. The
solution was then concentrated to afford 6 (8.0 g) as a light, pale
yellow resin. Upon standing in the fridge for 12 days, the resin had
formed a white solid. This was further dried to give 6 (7.93g) as a
white solid.
fitted with a balloon containing nitrogen and the mixture heated to
110 °C and stirred overnight. The mixture was cooled to room
temperature and then washed with diethyl ether. The aqueous phase
was separated and treated with 4 M HCl (aq) to pH ∼5 (precipitation
observed) and extracted with ethyl acetate (×2). The combined
organic washings were dried (MgSO4), filtered, and concentrated
under vacuum to afford acid 12 as a pale yellow solid (4.4 g, 55%). 1H
NMR (400 MHz, DMSO-d6) 13.04 (br s, 1H), 8.54 (d, J = 1.2 Hz,
1H), 8.46 (d, J = 3.9 Hz, 1H), 7.68−7.78 (m, 1H), 7.30−7.48 (m,
5H), 5.21 (s, 1H).
[NB: In other repeat preparations it has been observed that sig-
nificant precipitation of some product can occur during the acidifica-
tion process and will not dissolve in the ethyl acetate washings. This
material can be isolated by filtration and is of comparable purity or
higher purity than that isolated from the organic washings.]
2-(4-Chlorophenyl)-1-{4-[4-(trifluoromethyl)phenyl]piperazin-1-yl}-2-
(pyridin-3-yl)ethanone (7). Acid 12 (3.0 g, 12.1 mmol), HATU (4.60 g,
12.1 mmol), and 1-[4-(trifluoromethyl)phenyl]piperazine (13)
(2.78 g, 12.1 mmol) were dissolved in N,N-dimethylformamide
(30 mL) and treated with diisopropylethylamine (3.18 mL, 18.2 mmol).
The mixture was stirred at room temperature for 3 h and then
partitioned between ethyl acetate and water. The organic layer was
washed with water (×3) and then brine, dried (MgSO4), filtered, and
concentrated under vacuum, and the crude residue was purified by
column chromatography (Flashmaster II ethyl acetate/hexane/
1
methanol gradient) to give 7 as an off-white foam (4.2 g, 75%). H
NMR (400 MHz, CDCl3) 8.52 (dd, J = 1.2, 4.7 Hz, 1H), 8.48 (d, J =
1.6 Hz, 1H), 7.56−7.65 (m, 1H), 7.45−7.53 (m, 2H), 7.30−7.38 (m,
2H), 7.24−7.29 (m, 1H), 7.18−7.24 (m, 2H), 6.83−6.92 (m, 2H),
5.21 (s, 1H), 3.88−3.98 (m, 1H), 3.75−3.85 (m, 1H), 3.57−3.71 (m,
2H), 3.19−3.37 (m, 2H), 3.08−3.18 (m, 1H), 2.93−3.04 (m, 1H); 13C
NMR (101 MHz, CDCl3) 169.0, 152.6, 149.8, 148.8, 136.8, 136.6,
134.8, 133.7, 129.9, 129.3, 126.5, 124.7, 123.5, 121.3, 115.0, 51.6, 48.1,
47.9, 45.6, 41.9; LCMS [M + H] = 460.3; HPLC (water/ACN + 0.1%
TFA gradient) 99.5% at 254 nm. Anal. d for C24H21F3N3O: C, 62.68;
H, 4.60; N, 9.14. Found: C, 62.70; H, 4.71; N, 9.13.
Chiral Resolution of 2-(4-Chlorophenyl)-1-{4-[4-(trifluoromethyl)-
phenyl]piperazin-1-yl}-2-(pyridin-3-yl)ethanone (7) to Give (R)-7 and
(S)-7. Compound 7 was resolved by preparative chiral HPLC using the
following conditions. First eluted enantiomer = (R)-7 (98.6% ee),
second eluted enantiomer = (S)-7 (98.0% ee). Instrument: Thar 350
preparative SFC. Column: ChiralCel OJ, 10 μm, 300 mm × 50 mm i.d.
Mobile phase: A, CO2; B, methanol. Gradient: B, 45%. Flow rate:
240 mL/min. Back pressure: 100 bar. Column temperature: 38 °C.
Wavelength: 220 nm. Cycle time: 6 min. The NMR spectral data for
the separated enantiomers were identical with the data for the racemate.
Preparation of 1-[4-(Trifluoromethyl)phenyl]piperazine (13).
To a stirred, degassed (with N2) solution of 1-(tert-butoxycarbonyl)-
piperazine (15 g, 80 mmol), 4-bromobenzotrifluoride (19 g, 84 mmol),
palladium acetate (1.1 g, 2 mol %), and BINAP (2.5 g, 5 mol %) in a 1:1
mixture of ethyl acetate (80 mL) and 1,4-dioxane (80 mL) was added
cesium carbonate (52 g, 160 mmol), and the mixture was heated to
reflux under an N2 atmosphere. After 1 h, precipitation of palladium
black had occurred and TLC analysis indicated consumption of the
piperazine starting material. The mixture was cooled to room
temperature and quenched with 10% NH4Cl (aq) (5 mL) and passed
through a small plug of silica gel, which was washed with
dichloromethane. The collected filtrate was concentrated under
vacuum and the residue purified by column chromatography (eluent
dichloromethane) to afford intermediate tert-butyl 4-[4-(trifluoromethyl)-
2-(4-Chlorophenyl)-1-{4-[4-(trifluoromethyl)phenyl]piperazin-1-
yl}-2-(pyridin-3-yl)ethanone (7) and (R)- and (S)-7. (4-Chlorophenyl)-
(pyridin-3-yl)acetonitrile (11). 4-Chlorophenylacetonitrile (27.6 g,
182 mmol) and 3-fluoropyridine (9.00 g, 91.8 mmol) were dissolved
in N-methyl-2-pyrrolidone (80 mL), and the solution was to 0 °C
(ice/water bath). Potassium tert-butoxide (28.0 g, 250 mmol) was
added in portions (the mixture became red/purple/orange in color),
and then the reaction vessel was placed in an oil bath and heated to
85 °C and stirred overnight. The flask was removed from the heat and
cooled to 0 °C, quenched with 1 M HCl (aq) to approximately pH
6−7, and diluted with ethyl acetate. A white solid material was present
and removed by filtration through a sinter funnel, and the phases were
separated. The organic layer was washed again with water (×2), dried
(MgSO4), filtered, and concentrated under vacuum and the oily
residue was purified by column chromatography (10% ethyl acetate in
hexanes increasing to 30% ethyl acetate in hexanes) to obtain the
desired product still contaminated with unreacted 4-chlorophenylace-
tonitrile and an unknown impurity. This material was partitioned into
2 M HCl (aq) and diethyl ether, and the phases were separated. The
aqueous layer was washed again with diethyl ether and then treated
with 2 M NaOH (aq) to pH ∼8 and extracted with ethyl acetate (×2).
The ethyl acetate extracts were washed with brine, dried (MgSO4),
filtered, and concentrated under vacuum and the residue was repurified
by column chromatography (10% ethyl acetate in hexanes increasing
to 30% ethyl acetate in hexanes) to provide intermediate nitrile 11 as
1
phenyl]piperazine-1-carboxylate as an off-white solid (24.7 g, 93%). H
NMR (400 MHz, CDCl3) 7.45−7.53 (m, 2H), 6.89−6.96 (m, 2H),
3.54−3.64 (m, 4H), 3.19−3.29 (m, 4H), 1.49 (s, 9H).
tert-Butyl 4-[4-(trifluoromethyl)phenyl]piperazine-1-carboxylate
(24.7 g, 74.5 mmol) was taken up in dichloromethane (100 mL)
and methanol (5.5 mL) and then treated with trifluoroacetic acid
(250 mL). The mixture was stirred overnight at room temperature.
Then the volatiles were removed under vacuum and the was treated
with 2 M NaOH(aq). The aqueous phase was extracted with ethyl
acetate (×2), and the combined organic washings were dried
1
an amber oil (15.4 g, 73%). H NMR (400 MHz, CDCl3) 8.60−8.62
(m, 2H), 7.65−7.69 (m, 1H), 7.37−7.41 (m, 2H), 7.32−7.36 (m, 1H),
7.27−7.31 (m, 2H), 5.16 (s, 1H).)
(4-Chlorophenyl)(pyridin-3-yl)acetic Acid (12). Nitrile 11 (7.5 g,
32.3 mmol) was suspended in 2 M NaOH (aq) (75 mL) and the sus-
pension degassed with nitrogen for approximately 5 min. The flask was
10168
dx.doi.org/10.1021/jm401610c | J. Med. Chem. 2013, 56, 10158−10170