Journal of Medicinal Chemistry
Article
4-{5-(1H-Imidazol-2-yl)-2-[2-(5-nitro-pyridin-2-ylamino)-ethyla-
mino]-pyrimidin-4-yl}-benzonitrile (35a). A solution of 4-(2-
imidazol-2-ylacetyl)benzenecarbonitrile (30a) (0.32 g, 1.5 mmol)
(prepared from 4-cyano-benzoyl chloride (27) and 2-methylimidazole
(28) according to the procedure described by Macco et al.42−44) and
DMFDMA (15 mL) was stirred at reflux for 12 h. After concentration
of this solution in vacuo, the residual solid was dissolved in DMF (15
mL). To the resulting solution was added Cs2CO3 (0.98 g, 3.0 mmol)
and (2-(5-nitro(2-pyridyl)amino]ethyl)carboxamidinium 4-methyl-
benzenesulfonate (13) (0.59 g, 1.5 mmol), and the mixture stirred
for 8 h at 100 °C. The mixture was cooled, filtered and the filtrate
diluted with ethyl acetate (100 mL), and washed with saturated
aqueous sodium bicarbonate (2 × 10 mL), water (4 × 10 mL), and
brine (10 mL), dried (Na2SO4), filtered, and concentrated in vacuo to
give 513 mg (80%) of the product as a yellow solid (HPLC, 94% at
220 nm; HPLC/MS, m/z 428 [MH+]).
stirring and preheated solution of sodium ethoxide [(0.62 g, 8.66
mmol) (dissolved in abs ethanol (15 mL))], N-[2-(5-cyano-pyridin-2-
ylamino)-ethyl]-guanidine (33) (2.18 g, 9.08 mmol), and abs ethanol
(10 mL) at 75−80 °C. The reaction was then heated to 75−80 °C for
2.5 h. The reaction can be monitored by HPLC or by TLC by using
5% methanol in ethyl acetate as the solvent system. The product has
UV activity in the long wavelength region. On cooling, the reaction
was diluted with ethyl acetate (400 mL) washed with satd aq NaHCO3
(100 mL), distilled water (2 × 100 mL), and brine (100 mL), dried
(Na2SO4), filtered, and concentrated under reduced pressure. Please
note: Dry over Na2SO4 for only 10−20 min. Longer times may cause
the product to precipitate over the drying agent! The crude product ca.
2 g (∼50−70% purity) was dried in vacuo, resulting in a hard tacky
white glass. To the dry glass was added a solution of MeOH/Et2O
(15:85 v/v) (10 mL). The glass was manipulated and stirred to break
up any lumps of material until a fine suspension forms. The suspension
was allowed to stand for 10−15 min and then filtered. The off-white
solid was washed with a solution of MeOH/Et2O (10:90 v/v) (2 × 5
mL) and then with Et2O (2 × 5 mL). This procedure gave material in
a purity range of 90−99% and ca. 50% yield. The compound can be
purified further using a prep HPLC. Impure 36c (1 g) was loaded onto
a large prep HPLC in DMSO (4 mL) containing TFA (100 μL). Using
a C18 reverse phase column, the gradient was started at 90:10 H2O/
CH3CN with a 1 mL/min gradient. After 45 min, the gradient reached
45:50 H2O/CH3CN. The compound typically eluted at about 20−25
min. 6-{2-[4-(2,4-Dichloro-phenyl)-5-(1H-imidazol-2-yl)-pyrimidin-2-
ylamino]-ethylamino}-nicotinonitrile (36c) was obtained in high
purity (99% pure) with yields between 25 and 45% (HPLC, 99% at
Compounds 35b and 36a−d were synthesized by procedures
similar to those used to produce 36a with the exception that the
correct 1-(substituted phenyl)-2-(1H-imidazol-2-yl)-ethanone (30a)
was used to form the pyrimidine products. Identity and purity were
minimally assessed by HPLC and HPLC/MS.
N-[4-(2,4-Dichloro-phenyl)-5-(1H-imidazol-2-yl)-pyrimidin-2-yl]-
N′-(5-nitro-pyridin-2-yl)-ethane-1,2-diamine (36a). A solution of
sodium ethoxide (4.0 g, 58.8 mmol) dissolved in abs ethanol (100 mL)
was added to a stirred mixture of enaminone 31a (18.2 g, 58.8 mmol),
guanidine 13 (15.6 g, 60.0 mmol), and abs ethanol (260 mL). The
reaction was stirred at room temperature for 15 min and then at 75−
80 °C for 2.5 h. On cooling, a yellow precipitate was collected by
filtration. The filtrate was stored for possible further isolation and
purification of 36a. The solid product was washed with abs ethanol (3
× 50 mL), distilled water (3 × 50 mL), and ethyl ether (3 × 50 mL).
The yellow solid was dried overnight in vacuo, giving 14.6 g (53%) of
final product N-[4-(2,4-dichloro-phenyl)-5-(1H-imidazol-2-yl)-pyrimi-
din-2-yl]-N′-(5-nitro-pyridin-2-yl)-ethane-1,2-diamine (36a) (HPLC,
99% at 482 nm; HPLC/MS, m/z 471 [MH+]). 1H NMR (DMSO-d6)
δ 8.84 (s, 1H), 8.62 (s, 1H), 8.21 (br s, 1 H), 8.01 (br s, 1H), 7.65 (s,
1H), 7.47 (s, 1H), 7.35 (d, J = 11 Hz, 2H), 6.90 (s, 2 H), 6.51 (br s,
1H), 4.12−305 (br m, 4H). 13C NMR (DMSO-d6) δ 161.6, 161.3,
158.5, 158.0, 146.9, 141.9, 137.2, 134.4, 133.7, 132.6, 132.2, 131.7,
128.6, 127.2, 114.3, 108.8. HRMS (FAB+): m/z calcd for
C20H17Cl2N8O2 [MH+] 471.0846, found 471.0859.
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482 nm; HPLC/MS, m/z 451 [MH+]). H NMR (DMSO-d6) δ 8.67
(d, J = 20 Hz, 1H), 7.75−7.43 (m, 6H), 6.62 (dd, J = 23, 9 Hz, 1H),
4.12−3.05 (br m, 4H). 13C NMR (DMSO-d6) δ 163.3, 162.7, 162.5,
160.1, 159.3, 159.1, 151.9, 151.4, 140.6, 140.5, 139.0, 135.5, 134.0,
132.0, 131.8, 129.1, 128.9, 128.0, 120.2, 118.7, 118.5, 107.1, 106.9,
94.8. HRMS (FAB+): m/z calcd for C21H17Cl2N8 [MH+] 451.0947,
found 451.0937.
Compounds 37a were synthesized by procedures similar to those
used to produce 1 with the exception that the correct 1-(2,4-dichloro-
phenyl)-2-(4-methyl-1H-imidazol-2-yl)-ethanone (30b) was used to
form the pyrimidine products. Identity and purity were minimally
assessed by HPLC and HPLC/MS.
N2-(2-(4-(2,4-Dichlorophenyl)-5-(4-methyl-1H-imidazol-2-yl)-
pyrimidin-2-ylamino)ethyl)-5-nitropyridine-2,6-diamine (37b).
Compound 37b was synthesized by procedures similar to those used
to produce 1, with the exception that 2-(2-aminoethyl)amino-6-
amino-5-nitropyridine was used to form the pyrimidine (HPLC, 99%
N6-{2-[4-(2,4-Dichloro-phenyl)-5-(1H-imidazol-2-yl)-pyrimidin-2-
ylamino]-ethyl}-3-nitro-pyridine-2,6-diamine (36b). A solution of
sodium ethoxide (0.27 g, 4.00 mmol) dissolved in abs ethanol (8 mL)
was added to a stirred mixture of 1-(2,4-dichloro-phenyl)-3-
dimethylamino-2-(1H-imidazol-2-yl)-propenone (31a) (1.24 g, 4.00
mmol), N-[2-(6-amino-5-nitro-pyridin-2-ylamino)-ethyl]-guanidine 32
(1.13 g, 4.08 mmol), and abs ethanol (7 mL). The reaction was then
heated to 75−80 °C for 2.5 h (Note: use of excess base or heat can cause
side products). On cooling, a yellow precipitate was collected by
filtration. The filtrate was stored for possible further isolation and
purification of 36b. The solid product was washed with abs ethanol (3
× 10 mL), distilled water (3 × 10 mL), and ethyl ether (3 × 10 mL).
The yellow solid was dried overnight in vacuo, giving 1.36 g (70%) of
final product N6-{2-[4-(2,4-dichloro-phenyl)-5-(1H-imidazol-2-yl)-
pyrimidin-2-ylamino]-ethyl}-3-nitro-pyridine-2,6-diamine (36b)
1
at 482 nm; HPLC/MS, m/z 500 [MH+]). H NMR (DMSO-d6) δ
8.67 (d, J = 21 Hz, 1H), 8.53 (br s, 1H), 8.25 (br s, 2H), 7.90 (dd, J =
29, 9 Hz, 1H), 7.62−7.43 (m, 3H), 7.29 (s, 1H), 5.97 (dd, J = 29, 9
Hz, 1H), 3.82−3.22 (br m, 4H), 2.23 (s, 3H). 13C NMR (DMSO-d6)
δ 163.6, 163.0, 160.5, 159.9, 158.9, 155.6, 154.9, 140.2, 135.9, 135.9,
135.5, 134.4, 132.6, 132.4, 130.4, 129.6, 128.4, 117.3, 107.7, 103.1,
41.3, 40.3, 10.9. HRMS (FAB+): m/z calcd for C21H20Cl2N9O2
[MH+] 500.1111, found 500.1106.
Preparation of Polymer-Bound N-BOC-ethylenediamine (40). To
a suspension of Merrifield resin (30 g, 21 mmol) and NMP (200 mL)
was added 4-hydroxy-2-methoxybenzaldehyde (6.4 g, 42 mmol) and
K2CO3 (8.7 g, 63 mmol). The resulting mixture was heated at 120 °C
with shaking for 16 h. The resulting light-brown mixture was filtered,
and the resin was washed with H2O, NMP, and CH2Cl2. The resin was
dried under vacuum at 40 °C for 12 h. To a suspension of the resin-
bound aldehyde (30 g, 21 mmol) and (MeO)3CH (200 mL) was
added N-BOC-ethylenediamine (6.7 mL, 42 mmol). The resulting
mixture was shaken at 23 °C for 12 h, filtered, and washed with
CH2Cl2. The resin-bound imine was used immediately, slightly moist,
with CH2Cl2. To a suspension of the resin-bound imine (30 g, 21
mmol) and MeOH/CH2Cl2/HOAc (200 mL, 2:2:1) was added
borane−pyridine complex (6.8 mL, 67 mmol). The resulting mixture
was shaken at 23 °C for 12 h, filtered, and washed with NMP and
CH2Cl2. The resin was dried under vacuum at 30 °C for 12 h to yield
polymer-bound N-BOC-ethylenediamine.
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(HPLC, 98% at 482 nm; HPLC/MS, m/z 486 [MH+]). H NMR
(DMSO-d6) δ 8.68 (d, J = 22 Hz, 1H), 8.41 (br s, 1H), 8.28 (br s, 1
H), 7.91 (dd, J = 26, 9 Hz, 2H), 7.68−7.42 (m, 5H), 5.95 (dd, J = 26,
1
9 Hz, 2H), 4.12−305 (br m, 4H). H NMR (CDCl3) δ 9.40 (br s,
4H), 9.29 (s, 1H), 8.70 (s, 1H), 8.13 (d, J = 9 Hz, 1H), 7.70 (d, J = 9
Hz, 1H), 7.61 (s, 1H), 7.44 (s, 2 H), 7.34 (d, J = 3 Hz, 1H), 7.28 (dd, J
= 9, 3 Hz, 1H), 6.27 (d, J = 9 Hz, 1H), 4.04−3.83 (br m, 4H). 13C
NMR (pyridine-d5) δ 163.2, 162.1, 160.5, 156.8, 142.7, 136.5, 134.0,
133.8, 129.9, 128.1, 121.9, 119.7, 111.5, 42.1, 41.9. HRMS (FAB+):
m/z calcd for C20H18Cl2N9O2 [MH+] 486.0955, found 486.0937.
6-{2-[4-(2,4-Dichloro-phenyl)-5-(1H-imidazol-2-yl)-pyrimidin-2-
ylamino]-ethylamino}-nicotinonitrile (36c). A solution of 1-(2,4-
dichloro-phenyl)-3-dimethylamino-2-(1H-imidazol-2-yl)-propenone
(31a) (2.67 g, 8.25 mmol) in abs EtOH (10 mL) was added to a
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J. Med. Chem. XXXX, XXX, XXX−XXX