Journal of Medicinal Chemistry
Article
1H), 9.44−9.52 (m, 1H), 8.60−8.67 (m, 1H), 8.53−8.59 (m, 1H),
8.25−8.35 (m, 1H), 7.84−7.92 (m, 1H). 13C NMR (126 MHz,
DMSO) 162.18, 159.58, 159.15, 156.77, 151.34, 135.64, 134.74,
132.29, 131.47, 129.14, 127.41, 113.77. HRMS (ES+) m/z 308.9935
(308.9946 Calcd for C12H6Cl2N4O2 M + H).
precipitate was collected by filtration and dried under vacuum to
give the title compound (0.4 g, 76% yield) as a white solid. MS (ES+)
m/z (M + 1) 240; 1H NMR (500 MHz, DMSO) 8.45 (s, 1H), 8.20 (d,
J = 2.05 Hz, 1H), 7.94 (dd, J = 8.43, 1.97 Hz, 1H), 7.76 (d, J = 8.35
Hz, 1H), 7.02 (br s, 2H), 6.94 (s, 1H). 13C NMR (63 MHz, DMSO)
164.48, 158.75, 158.23, 137.90, 132.61, 131.72, 131.07, 128.16, 126.38,
100.25. HRMS (ES+) m/z 240.0087 (240.0095 Calcd for C10H7Cl2N3
M + H).
4-(3,4-Dichlorophenyl)-6-(1,2,4-oxadiazol-3-yl)pyrimidine (36). A
mixture of 6-(3,4-dichlorophenyl)-N′-hydroxypyrimidine-4-carboximi-
damide (0.12 g, 0.42 mmol), trimethyl orthoformate (3 mL), and
concentrated HCl (3 drops) was stirred at 100 °C for 1 h. After this
time, the reaction mixture was cooled to room temperature and the
resulting precipitate was collected by filtration and washed with
heptane (5 mL) before being dried under vacuum to give the title
compound (0.09 g, 74% yield) as a pale pink solid. MS (ES+) m/z (M
General Method D. N-[6-(3,4-Dichlorophenyl)pyrimidin-4-yl]-
benzenesulfonamide (38). Sodium hydride (0.3 g, 8.0 mmol) was
added portionwise to a stirred solution of 37 (0.61 g, 3.0 mmol) in
dioxane (10 mL), and the mixture was stirred at room temperature
under a nitrogen atmosphere for 1 h. After this time, benzenesulfonyl
chloride (0.49 g, 3.0 mmol) was added dropwise and stirring was
continued for 5 h. After this time, the mixture was partitioned between
ethyl acetate (20 mL) and water (5 mL). The organic layer was
separated, dried (MgSO4), filtered, and concentrated. The resulting
residue was triturated with diethyl ether, and the solid precipitate was
collected by filtration, washed with ether, and dried under vacuum to
give the title compound (0.17 g, 18% yield) as a white solid. MS (ES+)
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+ 1) 293; H NMR (500 MHz, CDCl3) 9.44−9.51 (m, 1H), 8.94−
9.00 (m, 1H), 8.46−8.52 (m, 1H), 8.36 (m, 1H), 8.02−8.10 (m, 1H),
7.62−7.68 (m, 1H). 13C NMR (126 MHz, DMSO) 168.54, 166.03,
162.45, 159.44, 153.97, 135.96, 134.58, 132.26, 131.45, 129.22, 127.53,
115.80. HRMS (ES+) m/z 293.0011 (292.9997 Calcd for
C12H6Cl2N4O M + H).
4-(3,4-Dichlorophenyl)-6-(1H-1,2,3,4-tetrazol-5-yl)pyrimidine
(31). To a stirred solution of 30 (1.0 g, 4.0 mmol) in toluene (50 mL)
were added azido(trimethyl)silane (1.1 mL, 8.0 mmol) and dibutyl-
(oxo)stannane (0.1 g, 0.4 mmol) sequentially. The mixture was heated
to 115 °C and stirred at this temperature for 24 h under a nitrogen
atmosphere. After this time, the mixture was cooled to room
temperature and the mixture was concentrated. The resulting residue
was partitioned between ethyl acetate (200 mL) and saturated sodium
bicarbonate (200 mL). The aqueous layer was removed and acidifed to
pH 2 with HCl (6 M solution), and the resulting precipitate was
collected by filtration and washed with water (10 mL) before being
dried in a vacuum over overnight. The crude solid was then purified by
prep HPLC to give the title compound (0.33 g, 28% yield) as a white
solid. MS (ES+) m/z (M + 1) 293/295; 1H NMR (500 MHz, DMSO)
9.47 (s, 1H), 8.80 (s, 1H), 8.55 (d, J = 1.95 Hz, 1H), 8.30 (dd, J =
1.99, 8.47 Hz, 1H), 7.83 (d, J = 8.46 Hz, 1H). 13C NMR (126 MHz,
DMSO) 162.40, 159.29, 154.35, 152.27, 135.87, 134.62, 132.27,
131.43, 129.17, 127.47, 114.78. HRMS (ES+) m/z 293.0093 (293.0109
Calcd for C11H6Cl2N6 M + H).
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m/z (M + 1) 380; H NMR (500 MHz, DMSO) 12.26 (br s, 1H),
8.75 (br s, 1H), 8.19 (d, J = 1.73 Hz, 1H), 8.00 (d, J = 7.57 Hz, 2H),
7.94 (dd, J = 8.51, 1.89 Hz, 1H), 7.82 (d, J = 8.51 Hz, 1H), 7.63−7.71
(m, 1H), 7.57−7.63 (m, 2H), 7.49 (br s, 1H). 13C NMR (63 MHz,
DMSO) 166.32, 158.32, 157.03, 146.16, 138.77, 131.98, 131.58,
130.97, 129.81, 127.91, 126.48, 126.16, 106.33. HRMS (ES+) m/z
380.0009 (380.0027 Calcd for C16H11Cl2N3O2S M + H).
N-[6-(3,4-Dichlorophenyl)pyrimidin-4-yl]methanesulfonamide
(39). This material was synthesized according to general procedure D
1
as described above. MS (ES+) m/z (M + 1) 318/320; H NMR (250
MHz, DMSO) 11.6 (br s, 1H), 8.89 (s, 1H), 8.25 (d, J = 1.63 Hz, 1H),
7.99 (dd, J = 1.85, 8.42 Hz, 1H), 7.82 (d, J = 8.43 Hz, 1H), 7.41 (s,
1H), 3.40 (s, 3H). 13C NMR (63 MHz, DMSO) 160.64, 159.01,
136.66, 133.79, 132.03, 131.40, 128.63, 126.94, 103.88, 41.81. HRMS
(ES+) m/z 317.9863 (317.9871 Calcd for C11H9Cl2N3O2S M + H).
N-[6-(3,4-Dichlorophenyl)pyrimidin-4-yl]acetamide (40). This
material was synthesized according to general procedure D as
1
described above. MS (ES+) m/z (M + 1) 282/284; H NMR (500
MHz, DMSO) 11.08 (s, 1H), 8.96 (d, J = 1.10 Hz, 1H), 8.55 (d, J =
0.95 Hz, 1H), 8.26 (d, J = 2.05 Hz, 1H), 8.01 (dd, J = 8.43, 2.13 Hz,
1H), 7.83 (d, J = 8.51 Hz, 1H), 2.18 (s, 3H). 13C NMR (63 MHz,
DMSO) 170.98, 161.40, 159.06, 158.55, 137.08, 133.67, 132.04,
131.42, 128.53, 126.88, 104.96, 24.27. HRMS (ES+) m/z 282.0213
(282.0201 Calcd for C12H9Cl2N3O M + H).
4-(3,4-Dichlorophenyl)-6-(1-methyl-1H-1,2,3,4-tetrazol-5-yl)-
pyrimidine (32) and 4-(3,4-Dichlorophenyl)-6-(2-methyl-2H-1,2,3,4-
tetrazol-5-yl)pyrimidine (33). Sodium hydride (60%, 0.03 g, 0.7
mmol) was added in one portion to a cooled (0 °C), stirred solution
of 31 (0.2 g, 0.7 mmol) in DMF, and the reaction mixture was stirred
under a nitrogen atmosphere for 15 min. After this time, methyl iodide
(0.08 mL, 1.4 mmol) was added in one portion, the mixture was
allowed to warm to room temperature, and stirring was continued for a
further 15 h. After this time, the reaction was quenched by the addition
of water (10 mL) before being extracted with ethyl acetate (3 × 25
mL). The combined organic extracts were dried (MgSO4), filtered,
and concentrated. The resulting residue was then purified by flash
column chromatography (elution: 50% EtOAc, 50% heptane) to give
32 (0.048 g, 22% yield) as a beige powder MS (ES+) m/z (M + 1)
N-[6-(3,4-Dichlorophenyl)pyrimidin-4-yl]benzamide (41). This
material was synthesized according to general procedure D as
1
described above. MS (ES+) m/z (M + 1) 343/345; H NMR (500
MHz, DMSO) 11.41 (s, 1H), 9.20−8.89 (m, 1H), 8.82−8.63 (m, 1H),
8.29 (d, J = 2.00 Hz, 1H), 8.14−7.89 (m, 3H), 7.82 (d, J = 8.43 Hz,
1H), 7.64 (t, J = 7.38 Hz, 1H), 7.54 (t, J = 7.68 Hz, 2H). 13C NMR
(63 MHz, DMSO) 167.32, 161.48, 159.64, 158.51, 137.08, 133.73,
133.28, 132.65, 132.07, 131.42, 128.61, 128.52, 128.35, 126.98, 106.15.
HRMS (ES+) m/z 344.0347 (344.0357 Calcd for C17H11Cl2N3O M +
H).
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307/309; H NMR (250 MHz, DMSO) 9.53 (d, J = 1.34 Hz, 1H),
8.87 (d, J = 1.36 Hz, 1H), 8.60 (d, J = 2.10 Hz, 1H), 8.34 (dd, J = 2.16,
8.50 Hz, 1H), 7.87 (d, J = 8.49 Hz, 1H), 4.48 (s, 3H); 13C NMR (63
MHz, DMSO) 162.32, 158.93, 152.86, 150.98, 135.83, 134.69, 132.32,
131.50, 129.24, 127.53, 116.16, 36.98; HRMS (ES+) m/z 307.0261
(307.0266 Calcd for C12H8Cl2N6 M + H) and 33 (0.048 g, 22% yield)
as a beige solid MS (ES+) m/z (M + 1) 307/309; 1H NMR (250 MHz,
DMSO) 9.45 (d, J = 1.34 Hz, 1H), 8.75 (d, J = 1.35 Hz, 1H), 8.58 (d, J
= 2.10 Hz, 1H), 8.33 (dd, J = 2.16, 8.49 Hz, 1H), 7.86 (d, J = 8.48 Hz,
1H), 4.53 (s, 3H). 13C NMR (63 MHz, DMSO) 162.61, 162.07,
159.47, 156.87, 154.51, 136.15, 134.42, 132.24, 131.43, 129.19, 127.49,
114.72; HRMS (ES+) m/z 307.0251 (307.0266 Calcd for C12H8Cl2N6
M + H).
6-(3,4-Dichlorophenyl)pyrimidin-4-amine (37). 29 (0.58 g, 2.6
mmol) was suspended in saturated aqueous ammonia solution (5 mL)
in a pressure tube. The tube was sealed and heated to 100 °C for 18 h.
After this time, the tube was cooled to room temperature and the
mixture was poured onto water (15 mL). The resulting solid
General Method E. 4-(3,4-Dichlorophenyl)-6-(1H-imidazol-1-yl)-
pyrimidine (42). Imidazole (0.16 g, 2.3 mmol) was added in one
portion to a solution of 29 (0.15 g, 0.58 mmol) in ethanol (2 mL) in a
microwave pressure vessel. The vessel was sealed and heated to 140 °C
for 1 h in a microwave. After this time, the reaction was cooled to
room temperature, the reaction mixture was concentrated, and the
resulting residue was triturated with 1:1 acetonitrile/water (5 mL).
The solid precipitate was collected by filtration and dried under
vacuum to give the title compound (0.04 g, 25% yield) as a white
1
powder. MS (ES+) m/z (M + 1) 291; H NMR (500 MHz, CDCl3)
9.03−9.07 (m, 1H), 8.48 (s, 1H), 8.17−8.21 (m, 1H), 7.87−7.92 (m,
1H), 7.67−7.71 (m, 1H), 7.53−7.59 (m, 2H), 7.21 (s, 1H). HRMS
(ES+) m/z 291.0195 (291.0204 Calcd for C13H8Cl2N4 M + H).
4-(3,4-Dichlorophenyl)-6-(1H-pyrazol-1-yl)pyrimidine (43). This
material was synthesized according to general procedure E as
1
described above. MS (ES+) m/z (M + 1) 291; H NMR (500 MHz,
U
J. Med. Chem. XXXX, XXX, XXX−XXX