Journal of Medicinal Chemistry
Article
(4-Chlorophenyl)(3-trifluoromethylphenyl)pyridin-3-yl Methanol
(40). General method C (pyridine) with 3-bromopyridine (0.15 mL,
1.5 mmol), dry diethyl ether (5 mL), n-butyllithium (0.96 mL, 1.4
mmol, 1.6 M solution in hexanes), and 40Bii (280 mg, 0.98 mmol) in
dry tetrahydrofuran (3.5 mL). The crude material was absorbed onto
silica gel and purified by flash column chromatography (eluting with
20% ethyl acetate in hexanes) to give 40 as a pale-yellow gum (58 mg,
3-[(4-Chlorophenyl)(hydroxy)pyridin-3-ylmethyl]benzamide (46).
41 (2.3 g, 7.17 mmol) was hydrolyzed by KOH (1.93 g, 34.4 mmol) in
t-BuOH (20 mL) on heating under reflux for 45 min. The mixture was
cooled, concentrated to half volume under reduced pressure, and then
partitioned between ethyl acetate (100 mL) and dilute HCl (100 mL
to pH7). The organic phase was washed with water (100 mL), brine
(100 mL), separated, dried (MgSO4), filtered, and concentrated under
reduced pressure. Purification by column chromatography (eluent
100% DCM, 50% DCM in EtOAc, 5% 7 M NH3 in MeOH in EtOAc),
followed by trituration with 10% DCM in Et2O, filtration, and washing
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16%). H NMR (300 MHz, CDCl3) δ 8.40−8.52 (m, 2H), 7.65 (s,
1H), 7.55−7.63 (m, 2H), 7.37−7.49 (m, 2H), 7.23−7.35 (m, 4H),
7.15−7.21 (m, 2H), 3.68 (s, 1H). GC/MS (m/z = 363 [M]). HPLC
(water/ACN + 0.1% TFA gradient) 97.7% at 220 nm.
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with Et2O gave 46 as a white powder (1.84 g, 76%). H NMR (300
MHz, CDCl3) δ 8.24 (dd, J = 0.1, 1.8 Hz, 1H), 8.18 (dd, J = 1.2, 4.7
Hz, 1H), 7.88 (br s, 1H), 7.55−7.61 (m, 1H), 7.45−7.54 (m, 1H),
7.03−7.29 (m, 6H), 6.92 (br s, 1H), 6.45 (br s, 1H). ESI [M + H] =
339.4. HPLC (water/ACN + 0.1% TFA gradient) 99.5% at 220 nm.
3-[(4-Chloro-2-fluorophenyl)(hydroxy)pyridin-3-ylmethyl]-
benzamide (47). Method as for 46 with 83 (337 mg, 1 mmol), t-
BuOH (13.2 mL), and KOH (0.4 g, 7 mmol). Heated under reflux for 2 h.
3-[(4-Chlorophenyl)(hydroxy)pyridin-3-yl methyl]benzonitrile
(41). General method D with 37 (123 mg, 0.33 mmol), potassium
ferricyanide (280 mg, 0.66 mmol), palladium(II)acetate (17 mg, 76 μmol),
sodium carbonate (70 mg, 0.66 mmol), and N,N-dimethylacetamide
(3 mL). The crude material was absorbed onto silica and purified by
flash chromatography (eluting with 30% ethyl acetate in hexanes) to
give 41 as a white powder (70 mg, 67%). 1H NMR (300 MHz, CDCl3)
δ 8.37−8.51 (m, 2H), 7.56−7.67 (m, 3H), 7.41−7.55 (m, 2H), 7.27−
7.37 (m, 3H), 7.12−7.21 (m, 2H), 4.03 (br s, 1H). GC/MS (m/z = 320
[M]). HPLC (method 1) 98.8% at 220 nm.
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Usual work up gave 47 as a white powder (60.3 mg, %). H NMR (400
MHz, DMSO-d6) δ 8.50 (br s, 2H), 7.89−8.07 (m, 1H), 7.74−7.87 (m,
2H), 7.62 (d, J = 7.43 Hz, 1H), 7.20−7.53 (m, 6H), 6.88−7.01 (m, 1H), 3.33
(br s, 1H). ESI [M + H] = 357.3. HPLC (method 1) 95.64% at 220 nm.
3-[(4-(Trifluoromethyl)phenyl(hydroxy)pyridin-3-ylmethyl]-
benzamide (48). Method as for 46 with 85 (876 mg, 2.47 mmol),
t-BuOH (45 mL), and KOH (1.2 g, 21 mmol). Heated under reflux for
4-((4-Chlorophenyl)(hydroxy)pyridin-3-ylmethyl)benzonitrile
(42). General method D with 14 (232 mg, 0.61 mmol), potassium
ferricyanide (535 mg, 1.3 mmol), palladium(II)acetate (18 mg,
80 μmol), sodium carbonate (66 mg, 0.63 mmol), and N,N-
dimethylacetamide (5 mL). The crude material was absorbed onto
silica and purified by flash chromatography (eluting with 30% ethyl
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2 h. Usual work up gave 48 as a cream powder (278 mg, 51%). H
NMR (400 MHz, chloroform-d) δ 8.14−8.46 (m, 2H), 7.89 (s, 1H),
7.28−7.72 (m, 7H), 7.01−7.25 (m, 2H), 6.47 (br s, 2H). ESI [M + H] =
373.2. HPLC (method 1) 97.28% at 220 nm.
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acetate in hexanes) to give 42 as a cream powder (31 mg, 16%). H
NMR (300 MHz, CDCl3) δ 8.41 (s, 2H), 7.53−7.71 (m, 4H), 7.40−
7.49 (m, 2H), 7.22−7.36 (m, 3H), 7.09−7.20 (m, 1H), 4.21 (br s,
1H). GC/MS (m/z = 320 [M]). HPLC (water/ACN + 0.1% TFA
gradient) 99.5% at 220 nm.
4-[4-(Trifluoromethyl)phenyl(hydroxy)pyridin-3-ylmethyl]-
benzamide (49). 43 was hydrolyzed as described for the preparation
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of 46 to give 49 as a white powder (15 mg, 28%). H NMR (300
MHz, CDCl3) δ 8.51 (br s, 2H), 7.82 (d, J = 8.4 Hz, 2H), 7.53−7.70
(m, 3H), 7.34−7.50 (m, 4H), 7.23−7.32 (m, 1H), 6.90 (br s, 1H),
6.17 (br s, 1H), 6.01−6.12 (m, 1H). ESI [M + H] = 373.3. HPLC
(method 1) 95.1% at 220 nm.
N-(4-((4-Chlorophenyl)(hydroxy)(pyridin-3-yl)methyl)phenyl)-
methanesulfonamide (50). Prepared according to Yin and
Buchwald27 from 14 to give 50 as an off-white solid (15.4 mg, 6%).
1H NMR (300 MHz, chloroform-d) δ 8.45−8.58 (m, 2H), 7.60−7.67
4-((4-Trifluoromethylphenyl)(hydroxy)pyridin-3-ylmethyl)-
benzonitrile (43). General method D with 38 (1.5 g, 3.66 mmol),
potassium ferricyanide (3.27 g, 7.74 mmol), palladium(II)acetate
(495 mg, 0.72 mmol), sodium carbonate (435 mg, 4.05 mmol), and
N,N-dimethylacetamide (15 mL). The crude material was absorbed
onto silica and purified by flash chromatography (eluting with
dichloromethane increasing to 50% ethyl acetate in dichloromethane)
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to give 43 as an off-white glass (930 mg, 72%). H NMR (300 MHz,
(m, 1H), 7.29−7.36 (m, 2H), 7.14−7.25 (m, 6H), 6.52 (s, 1H), 3.05
(s, 3H), 2.93 (s, 1H). [M + 1] 389. HPLC (water/ACN + 0.1% TFA
gradient) >99% at 220 nm.
chloroform-d) δ 8.42−8.55 (m, 2H), 7.56−7.67 (m, 5H), 7.38−7.46
(m, 4H), 7.24−7.32 (m, 1H), 3.63 (s, 1H). GCMS m/z 354. HPLC
(water/ACN + 0.1% TFA gradient) 97.2% at 220 nm.
(4-Trifluoromethylphenyl)(4-dimethylaminophenyl)pyrid-3-yl)
Methanol (51). General method C (pyridine) with 4-bromo benzotri-
fluoride (298 mg, 132 mmol), dry diethyl ether (3 L), n-butyllithium
(1.6 equiv of a 1.6 M solution in hexanes, 0.77 mL, 1.24 mmol), 51Biii
(200 mg, 0.88 mmol), and dry tetrahydrofuran (3 mL). Purification by
flash column chromatography (eluting with 10% ethyl acetate in
dichloromethane, increasing to 40% ethyl acetate) gave 51 as an off-
2-Fluoro-4-{hydroxy(pyridin-3-yl)[4-(trifluoromethyl)phenyl]-
methyl}benzonitrile (44). General method D with aryl bromide 81
(0.25 g, 0.604 mmol), potassium ferricyanide (K4[Fe(CN)6]·3H2O)
(0.53 g, 1.27 mmol), palladium(II)acetate (38 mg), anhydrous sodium
carbonate (0.071 g, 0.66 mmol), and anhydrous N,N-dimethylaceta-
mide (3 mL). The crude material was purified by Flashmaster II
(eluting with hexanes increasing to 40% ethyl acetate over 35 min) to
give a semipurified oil which was taken up in diethyl ether and washed
with water, organic phases combined, dried over magnesium sulfate,
filtered, and concentrated to remove residual N,N-dimethylacetamide,
and then triturated with diethyl ether to give 44 (60 mg, 27%) as a
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white solid (240 mg, 73%). H NMR (300 MHz, chloroform-d) δ
8.45−8.59 (m, 2H), 7.63−7.70 (m, 1H), 7.58 (d, J = 8.4 Hz, 2H), 7.47
(d, J = 8.4 Hz, 2H), 7.20−7.31 (m, 1H), 7.01 (d, J = 6.9 Hz, 2H), 6.65
(d, J = 6.9 Hz, 2H), 3.01 (s, 1H), 2.96 (s, 6H). GCMS m/z 372.
HPLC (method 1) 99% at 220 nm.
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white solid. H NMR (400 MHz, DMSO-d6) δ 8.52−8.55(m, 1H),
4-(Trifluoromethyl)phenyl(4-(propan-2-yl)phenyl)pyridin-3-yl
Methanol (52). General method C (pyridine) with 3-bromopyridine
(0.13 mL, 1.3 mmol), dry diethyl ether (5 mL), n-butyllithium (0.77
mL, 1.23 mmol, 1.6 M solution in hexanes), and 52Bii (300 mg, 1.03
mmol) in dry tetrahydrofuran (5 mL). Purification by flash column
chromatography (eluting with 20% ethyl acetate in hexanes increasing
8.46 (s, 1H), 7.58−7.88 (m, 5H), 7.50 (d, J = 7.8 Hz, 2H), 7.41 (dd,
J = 4.7, 7.8 Hz, 1H), 7.26 (s, 1H). ESI m/z: 372 (M). HPLC (water/
ACN + 0.1% TFA gradient) >99% at 220 nm.
(4-Chlorophenyl)(4-chloro-2-fluorophenyl)pyridin-3-yl Methanol
(45). General method C (pyridine) with 2-fluoro-4-chlorobenzene
(361 mg, 1.73 mmol), n-butyllithium (1.6 M in hexanes, 1.0 mL, 1.6
mmol), dry diethyl ether (3 mL), 13Biii (250 mg, 1.15 mmol), and
dry tetrahydrofuran (3 mL). Purification by flash column chromatog-
raphy (eluting with 10% ethyl acetate in dichloromethane increasing to
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to 40%) gave 52 as an amber glass (200 mg, 53%). H NMR (300
MHz, CDCl3) δ 8.47 (dd, J = 0.7, 2.3 Hz, 1H), 8.42 (dd, J = 1.6, 4.8
Hz, 1H), 7.61−7.66 (m, 1H), 7.57 (d, J = 8.2 Hz, 2H), 7.44 (d, J = 8.2
Hz, 2H), 7.14−7.25 (m, 3H), 7.07−7.13 (m, 2H), 3.72 (s, 1H), 2.91
(spt, J = 6.9 Hz, 1H), 1.24 (d, J = 6.9 Hz, 6H). GC/MS (m/z = 371
[M]). HPLC (method 1) 97% at 220 nm.
(4-Chlorophenyl)-(2,4-difluorophenyl)pyridin-3-yl Methanol (53).
General method C (pyridine) with 53Bi (300 mg, 1.19 mmol), 3-
bromopyridine (281 mg, 1.78 mmol), dry diethyl ether (3 mL), dry
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35% ethyl acetate) gave 45 as a white solid (223 mg, 56%). H NMR
(300 MHz, chloroform-d) δ 8.55 (dd, J = 1.51, 4.90 Hz, 1H), 8.47 (d,
J = 2.26 Hz, 1H), 7.58−7.65 (m, 1H), 7.24−7.41 (m, 3H), 7.03−7.24
(m, 4H), 6.83 (t, J = 8.6 Hz, 1H), 3.60 (d, J = 8.3 Hz, 1H). GCMS
m/z 347. HPLC (water/ACN + 0.1% TFA gradient) 97.2% at 220 nm.
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dx.doi.org/10.1021/jm2015809 | J. Med. Chem. 2012, 55, 4189−4204