Journal of Medicinal Chemistry
ARTICLE
1H), 8.26 (dd, J = 2.4, 8.6 Hz, 1H), 8.04 (s, 1H), 7.87 (dt, J = 7.9, 2.0 Hz,
1H), 7.48 (s, 1H), 7.42ꢀ7.39 (m, 1H), 7.31 (d, J = 8.3 Hz, 2H),
7.10ꢀ7.04 (m, 3H), 3.67 (d, J = 13.2 Hz, 1H), 3.51 (t, J = 8.1 Hz, 1H),
3.20 (d, J = 13.2 Hz, 1H), 3.09ꢀ3.04 (m, 1H), 2.31ꢀ2.21 (m, 2H),
1.91ꢀ1.84 (m, 2H), 1.69ꢀ1.64 (m, 1H).
gel eluting with 2ꢀ20% (10% ammonium hydroxide (aq) in ethanol)
in 1:1 dichloromethane:hexanes to afford 3-chloro-4-[4-[[(2S)-2-
(3-pyridyl)pyrrolidin-1-yl]methyl]phenoxy]benzamide. Yield (68%).
HPLC = 100% at 1.39 min by HPLC method 2, mass spectrum (m/z):
408.2 (M + 1). Chiral HPLC = 99% at 3.69 min by chiral HPLC method
4. The retention time of this compound matches the retention time of
the first eluting peak from enantiomers previously separated by
3-Chloro-4-(4-formylphenoxy)benzonitrile (15). Compound 15 was
prepared from 4-hydroxybenzaldehyde and 3-chloro-4-fluoro-benzoni-
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trile using general procedure A. Yield (84%). H NMR (300 MHz,
preparative chiral HPLC. H NMR (399.83 MHz, DMSO): 8.55 (s,
DMSO): 9.97 (s, 1H), 8.31 (d, J = 1.8 Hz, 1H), 8.00ꢀ7.89 (m, 3H),
1H), 8.44ꢀ8.43 (m, 1H), 8.05 (s, 1H), 8.01 (s, 1H), 7.79 (d, J = 8.4 Hz,
2H), 7.42 (s, 1H), 7.33 (t, J = 5.9 Hz, 1H), 7.25 (d, J = 7.0 Hz, 2H),
6.94ꢀ6.91 (m, 3H), 3.60ꢀ3.57 (m, 1H), 3.45 (t, J = 8.1 Hz, 1H), 3.29
(s, 1H), 3.17 (d, J = 13.2 Hz, 1H), 3.00 (t, J = 8.1 Hz, 1H), 2.26ꢀ2.15
(m, 2H), 1.88ꢀ1.55 (m, 2H).
7.39ꢀ7.35 (m, 1H), 7.26ꢀ7.23 (m, 2H).
3-Chloro-4-(4-formylphenoxy)benzamide (16). Compound 16 was
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prepared from 15 using general procedure B. Yield (97%). H NMR
(300 MHz, DMSO): 9.95 (s, 1H), 8.14 (m, 2H), 7.97ꢀ7.91 (m, 3H),
7.58 (bs, 1H), 7.36 (d, J = 8.7 Hz, 1H), 7.18ꢀ7.13 (m, 2H).
3-Chloro-4-[4-[[(2R)-2-(3-pyridyl)pyrrolidin-1-yl]methyl]phenoxy]-
benzamide (19). Compound 19 was prepared from 17 using general
procedure E. Yield (38%). HPLC = 100% at 1.42 min, mass spectrum
(m/z): 408.2 (M + 1) by HPLC-MS method 2. Chiral HPLC = 100% at
5.246 min by chiral HPLC method 4. Specific rotation = [α]20D ꢀ23.87
(c 1.00, EtOH). 1H NMR (399.83 MHz, DMSO): 8.55 (d, J = 1.8 Hz,
1H), 8.43 (dd, J = 1.5, 4.6 Hz, 1H), 8.05 (d, J = 2.2 Hz, 1H), 8.03ꢀ8.01
(m, 1H), 7.79 (dd, J = 2.0, 8.6 Hz, 2H), 7.42 (s, 1H), 7.34 (dd, J = 4.6, 7.7
Hz, 1H), 7.25 (d, J = 8.4 Hz, 2H), 6.93 (dd, J = 5.9, 8.6 Hz, 3H), 3.59 (d,
J = 13.2 Hz, 1H), 3.45 (t, J = 8.1 Hz, 1H), 3.29 (m, 1H), 3.17 (d, J = 13.2
Hz, 1H), 3.03ꢀ2.98 (m, 1H), 2.27ꢀ2.15 (m, 2H), 1.87ꢀ1.55 (m, 2H).
3-Chloro-4-[4-[[(2R)-2-(3-pyridyl)pyrrolidin-1-yl]methyl]phenoxy]-
benzamide (19). Compound 19 was prepared from 3-[(2R)-pyrrolidin-
2-yl]pyridine using procedure for the preparation of 18. Yield (59%).
HPLC = 100% at 1.38 min by HPLC method 2, mass spectrum (m/z):
408.2 (M+1). Chiral HPLC = 100% at 5.44 min by chiral HPLC method
4. The retention time of this compound matches the retention time of
the second eluting peak from enantiomers previously separated by
3-Chloro-4-[4-[[2-(3-pyridyl)pyrrolidin-1-yl]methyl]phenoxy]benzamide
(17). Compound 17 was prepared from 16 using general procedure C.
Yield (73%). HPLC = 100% at 1.44 min, mass spectrum (m/z): 408.2
(M + 1) by HPLC-MS method 2. 1H NMR (300 MHz, DMSO): 8.59
(d, J = 1.3 Hz, 1H), 8.47 (dd, J = 1.3, 4.9 Hz, 1H), 8.08 (d, J = 1.8 Hz,
1H), 8.04 (bs, 1H), 7.85ꢀ7.80 (m, 2H), 7.46 (bs, 1H), 7.37 (dd, J = 4.3,
7.3, 1H), 7.29 (d, J = 8.5 Hz, 2H), 7.00ꢀ6.93 (m, 3H), 3.62 (d, J = 12.8
Hz, 1H), 3.49 (t, J = 8.5 Hz, 1H), 3.21 (d, J = 12.8 Hz, 1H), 3.04 (m, 1H),
2.31ꢀ2.16 (m, 2H), 1.91ꢀ1.73 (m, 2H), 1.68ꢀ1.55 (m, 1H).
3-[(2R)-Pyrrolidin-2-yl]pyridine and 3-[(2S)-Pyrrolidin-2-yl]pyridine.
Enantiomers of racemic 3-pyrrolidin-2-ylpyridine (0.5 g, 3.4 mmol)
were separated by supercritical fluid chromatography(SFC) utilizing a
Berger Multigram Supercritical Fluid chromatograph with a Chiralpak
AD-H column (2.1 cm ꢂ 25 cm ꢂ 5 μm). The components were eluted
with 15% methanol (containing 0.2% DMEA) in CO2 at 70 mL/min
monitoring at λ = 225 nM. Fractions containing each separated isomer
were combined and evaporated to yield isomer 1, compound X2, and
isomer 2, compound X3. Optical purity was determined by chiral super
critical fluid chromatography on a Berger Minigram Supercritical Fluid
chromatograph with a Chiralpak AD-H column (4.6 mm ꢂ 150 mm ꢂ 5
μm). The components were eluted with 10% methanol (containing
0.2% DMEA) in CO2 at 5 mL/min monitoring at λ = 230 nM. Absolute
configuration of the separated enantiomers of 3-pyrrolidin-2-ylpyridine
were determined by specific rotation as reported in ref 20. 3-[(2R)-
pyrrolidin-2-yl]pyridine: Yield =25%. Chiral HPLC = 100% at 2.18
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preparative chiral HPLC. H NMR (399.83 MHz, DMSO): 8.55 (s,
1H), 8.44ꢀ8.43 (m, 1H), 8.29ꢀ8.25 (m, 0H), 8.03 (d, J = 17.6 Hz, 2H),
7.79 (d, J = 8.4 Hz, 2H), 7.42ꢀ7.39 (m, 1H), 7.33 (t, J = 5.7 Hz, 1H),
7.25 (d, J = 7.0 Hz, 2H), 6.94ꢀ6.91 (m, 3H), 3.60ꢀ3.57 (m, 1H), 3.45
(t, J = 8.1 Hz, 1H), 3.28 (s, 1H), 3.17 (d, J = 13.2 Hz, 1H), 3.02ꢀ2.98
(m, 1H), 2.26ꢀ2.15 (m, 2H), 1.88ꢀ1.55 (m, 2H).
3-Fluoro-4-(4-formylphenoxy)benzonitrile (21). Compound 21 was
prepared from 4-hydroxybenzaldehyde and 3, 4-difluoro-benzonitrile
using general procedure A. Yield (72%). 1H NMR (300 MHz, DMSO):
9.92 (s, 1H), 7.98ꢀ7.89 (m, 2H), 7.76 (dd, J = 1.8, 10.3 Hz, 1H),
7.65ꢀ7.56 (m, 1H), 7.34 (d, J = 8.1 Hz, 1H), 7.22ꢀ7.12 (m, 2H).
3-Fluoro-4-(4-formylphenoxy)benzamide (22). Compound 22 was
prepared from 21 using general procedure B. Yield (100%). HPLC =
100% at 3.19 min by HPLC method 2, mass spectrum (m/z): 260 (M + 1).
1H NMR (300 MHz, DMSO): 9.94 (s, 1H), 8.11 (bs, 1H), 7.98ꢀ7.88
(m, 3H), 7.74ꢀ7.78 (m, 1H), 7.58 (bs, 1H), 7.41 (t, J = 8.2 Hz, 1H),
7.22ꢀ7.15 (m, 2H).
min. Specific rotation = [α]23 +36.30 (c 1.00, MeOH). 3-[(2S)-
D
pyrrolidin-2-yl]pyridine: Yield = 30%. Chiral HPLC = 99% at 2.62
min. Specific rotation = [α]23D ꢀ36.20 (c 1.00, MeOH).
3-Chloro-4-[4-[[(2S)-2-(3-pyridyl)pyrrolidin-1-yl]methyl]phenoxy]-
benzamide (18). Compound 18 was prepared from 17 using general
procedure E. Yield (40%). HPLC = 100% at 1.41 min, mass spectrum
(m/z): 408.2 (M + 1) by HPLC-MS method 2. Chiral HPLC = 99% at
3.612 min by chiral HPLC method 4, Specific rotation = [α]20D +30.21
(c 1.00, EtOH). 1H NMR (399.83 MHz, DMSO): 8.55 (d, J = 1.3 Hz,
1H), 8.43 (dd, J = 1.5, 4.6 Hz, 1H), 8.05 (d, J = 2.2 Hz, 1H), 8.00 (s, 1H),
7.81ꢀ7.78 (m, 2H), 7.45ꢀ7.42 (m, 1H), 7.34 (dd, J = 4.8, 7.9 Hz, 1H),
7.26ꢀ7.24 (m, 2H), 6.95ꢀ6.91 (m, 3H), 3.59 (d, J = 13.2 Hz, 1H), 3.45
(t, J = 8.1 Hz, 1H), 3.29 (m, 1H), 3.17 (d, J = 13.2 Hz, 1H), 3.03ꢀ2.98
(m, 1H), 2.27ꢀ2.17 (m, 2H), 1.88ꢀ1.55 (m, 2H).
3-Fluoro-4-[4-[[2-(3-fluorophenyl)pyrrolidin-1-yl]methyl]phenoxy]-
benzamide (24). Compound 24 was prepared from 21 and 2-(3-
fluorophenyl)pyrrolidine using general procedure C. Yield (27%).
HPLC = 98% at 4.161 min by HPLC-MS method 2, mass spectrum
(m/z): 409 (M + 1). 1H NMR (300 MHz, MeOD): 7.77 (dd, J = 2.6,
11.7 Hz, 1H), 7.66 (m, 1H), 7.40ꢀ7.16 (m, 5H), 703ꢀ6.93 (m, 4H),
3.74 (d, J = 12.8 Hz, 1H), 3.42 (t, J = 8.0 Hz, 1H), 3.16 (t, J = 12.8 Hz,
1H), 3.10 (m, 1H), 2.35ꢀ2.16 (m, 2H), 1.97ꢀ1.62 (m, 3H).
3-Fluoro-4-[4-[[(2S)-2-(3-fluorophenyl)pyrrolidin-1-yl]methyl]-
phenoxy]benzamide (25). Compound 25 was prepared from 24 using
general procedure D. Compound 25 was obtained after chiral chroma-
tography utilizing a Chiralpak AD (20 mm ꢂ 250 mm ꢂ 10 μm) eluting
with 0.2% DMEA in ethanol at 8 mL/min monitoring at λ = 254/325
nM. Yield (42%). HPLC = 100% at 4.17 min by HPLC-MS method 2,
mass spectrum (m/z): 409 (M + 1). Chiral HPLC = 98% at 5.772 min by
3-Chloro-4-[4-[[(2S)-2-(3-pyridyl)pyrrolidin-1-yl]methyl]phenoxy]-
benzamide (18). To a solution 3-[(2S)-pyrrolidin-2-yl]pyridine (1.0
equiv, 0.54 mmol), 3-chloro-4-(4-formylphenoxy)benzamide (1 equiv,
0.54 mmol), and 1,2-dichloroethane (0.02M, 27 mL) was added sodium
triacetoxyborohydride (1.5 equiv, 0.82 mmol) and acetic acid (1.5 equiv,
0.82 mmol) were added to the reaction. After stirring at room temperature
overnight, the reaction was quenched with saturated aqueous sodium
bicarbonate (20 mL) and then extracted with ethyl acetate (3 ꢂ
100 mL). The combined organic extracts were dried over magnesium
sulfate, filtered, and then concentrated on a rotary evaporator. The
resulting crude material was purified by flash chromatography on silica
chiral HPLC method 6. Specific rotation = [α]20 ꢀ23.26 (c 1.00,
D
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dx.doi.org/10.1021/jm200789r |J. Med. Chem. 2011, 54, 8000–8012