Journal of Medicinal Chemistry
Article
compound 9 via reaction with 1-(pyridin-2-yl)thiourea in a manner
similar to that described for compound 3a. H NMR (DMSO-d6) δ
was added dropwise to a suspension of sodium hydride (10.21 g, 255
mmol, 60% in mineral oil) in DMF (150 mL), and the resulting
mixture was stirred at 100 °C for 30 min. To this mixture was added
11 (35 g, 200 mmol) in dry DMF (40 mL), and the resulting mixture
was stirred at 150 °C for 6 h. The mixture was poured onto an ice−
water mixture, and the aqueous phase was extracted with diethyl
ether. The combined organic phase was washed with 2 N sodium
hydroxide, dried over MgSO4, filtered, and concentrated in vacuo.
The residue was purified by column chromatography with petroleum
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2.17 (3H, s), 2.28 (3H, s), 6.65 (1H, d, J = 8.4 Hz), 6.80 (1H, d, J =
8.2 Hz), 6.92−6.94 (1H, m), 7.02−7.04 (1H, m), 7.11−7.25 (4H, m),
7.48 (1H, s), 7.70−7.73 (1H, m), 8.20 (1H, dd, J = 7.8, 1.8 Hz),
8.30−8.31 (1H, m), 11.37 (1H, s). LC-MS (M + H) 374.
3.1.6. 4-(2-(2,4-Dimethylphenoxy)phenyl)-N-(pyrimidin-2-yl)-
thiazol-2-amine (3d). Compound 3d was obtained (63%) from
compound 9 via reaction with 1-(pyrimidin-2-yl)thiourea in a manner
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similar to that described for compound 3a. H NMR (DMSO-d6) δ
ether as the eluent to afford 12 (12.5 g, 23%) as a colorless oil. H
2.16 (3H, s), 2.28 (3H, s), 6.65 (1H, dd, J = 8.0, 0.9 Hz), 6.80 (1H, d,
J = 8.2 Hz), 7.04 (2H, q, J = 4.9 Hz), 7.14−7.25 (3H, m), 7.57 (1H,
s), 8.22 (1H, dd, J = 7.7, 1.8 Hz), 8.65 (2H, d, J = 8.8 Hz), 11.79 (1H,
s). LC-MS (M + H) 375.
NMR (CDCl3) δ 2.19 (3H, s), 2.31 (3H, s), 6.68 (1H, dd, J = 8.2, 1.4
Hz), 6.75 (1H, d, J = 8.2 Hz), 6.91 (1H, td, J = 7.7, 1.3 Hz), 6.95−
6.97 (1H, m), 7.05−7.07 (1H, m), 7.15−7.17 (1H, m), 7.60 (1H, dd,
J = 8.0, 1.6 Hz).
3.1.7. Dimethyl (4-(2-(2,4-dimethylphenoxy)phenyl)thiazol-2-yl)-
carbonimidodithioate (10). To a solution of 3a (434 mg, 1.37
mmol) and CS2 in DMF (2 mL) was added 10 N NaOH aq (0.29 mL,
2.9 mmol), and the mixture was stirred at room temperature for 30
min. MeI (616 μL, 9.86 mmol) was added to the mixture at 0 °C and
stirred at the same temperature for 4 h. Water was added, and the
mixture was extracted with EtOAc. The extract was washed with
brine, dried over Na2SO4, and concentrated under reduced pressure.
The residue was purified by silica gel column chromatography
(hexane−EtOAc = 50:1 to 10:1) to give 10 (274 mg, 68%) as a
3.1.13. (2-(2,4-Dimethylphenoxy)phenyl)boronic Acid (13). n-
BuLi (24 mL, 58.7 mmol) was added in one portion to a solution of
12 (10 g, 36.7 mmol) in THF (100 mL) at −78 °C, and the mixture
was stirred at −78 °C for 20 min. Triisopropyl borate (25.6 mL, 110
mmol) was added at −78 °C and stirred for 20 min, then warmed to
room temperature, and stirred overnight. After cooling to 0 °C, 2 N
HCl aq. (20 mL) was added and diluted with water (200 mL),
extracted with EtOAc, dried over Na2SO4, purified by column
chromatography (EtOAc−petroleum ether = 1:20) to afford 13 (8.0
g, yield 90%) as a colorless oil. 1H NMR (DMSO-d6) δ 2.12 (s, 3H),
2.27 (s, 3H), 6.48 (d, 1H, J = 7.8 Hz), 6.80 (d, 1H, J = 7.8 Hz), 6.81−
7.05 (m, 2H), 7.11 (s, 1H), 7.25−7.31 (m, 1H), 7.58 (dd, 1H, J = 1.5
Hz, 7.5 Hz).
3.1.14. tert-Butyl (5-(2-(2,4-Dimethylphenoxy)phenyl)thiazol-2-
yl)carbamate (14a). A mixture of compound 13 (317 mg, 1.31
mmol), tert-butyl (5-bromothiazol-2-yl)carbamate (300 mg, 1.08
mmol), Pd(PPh3)4 (62 mg, 0.054 mmol), and 2 M sodium carbonate
aqueous solution (2.15 mL, 4.30 mmol) in dioxane (7 mL) was
heated at 90 °C and stirred overnight. After the reaction mixture was
cooled to room temperature, water and EtOAc were added to the
mixture. The organic layer was washed brine, dried over sodium
sulfate, and concentrated under reduced pressure. The residue was
purified by silica gel column chromatography (hexane−EtOAc =
90:10 to 70:30) to give 14a (113 mg, yield 26%) as a white solid. 1H
NMR (CDCl3) δ 1.52 (9H, s), 2.18 (3H, s), 2.33 (3H, s), 6.64 (1H,
d, J = 8.1 Hz), 6.83 (1H, d, J = 8.1 Hz), 6.97−7.15 (4H, m), 7.60
(1H, dd, J = 7.6, 1.7 Hz), 7.90 (1H, s).
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colorless solid. H NMR (CDCl3) δ 2.21 (3H, s), 2.33 (3H, s), 2.63
(6H, brs), 6.65−6.69 (1H, m), 6.82 (1H, d, J = 8.1 Hz), 6.97 (1H, d, J
= 8.2 Hz), 7.07−7.17 (3H, m), 7.81 (1H, s), 8.31−8.34 (1H, m).
3.1.8. 2-(4-(2-(2,4-Dimethylphenoxy)phenyl)thiazol-2-yl)-1,3-di-
methylguanidine (3e). To a solution of 10 (30 mg, 0.075 mmol)
in DMF (2 mL) was added a solution of 2 N methylamine in THF
(0.374 mL, 0.749 mmol), and the mixture was stirred at 140 °C for 10
h. After being cooled to room temperature, water was added, and the
mixture was extracted with EtOAc. The extract was washed with
brine, dried over MgSO4, and concentrated under reduced pressure.
The residue was purified by amino silica gel column chromatography
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(hexane−EtOAc = 9:1 to 1:1) to give 3e (13 mg, 47%). H NMR
(CDCl3) δ 2.21 (3H, s), 2.31 (3H, s), 2.93 (6H, d, J = 3.8 Hz), 6.69
(1H, dd, J = 7.8, 1.6 Hz), 6.80 (1H, d, J = 8.2 Hz), 6.94−6.96 (1H,
m), 7.05−7.15 (3H, m), 7.30 (1H, s), 8.01 (1H, dd, J = 7.4, 2.1 Hz).
LC-MS (M + H) 367.
3.1.9. N-(4-(2-(2,4-Dimethylphenoxy)phenyl)thiazol-2-yl)-
imidazolidin-2-imine (3f). To a solution of 10 (30 mg, 0.075
mmol) in dioxane (2 mL) was added ethylenediamine (45 mg, 0.749
mmol). The mixture was stirred at 100 °C for 2 h. After being cooled
to room temperature, the reaction was concentrated under reduced
pressure. The residue was purified by silica gel column chromatog-
raphy (hexane−EtOAc = 9:1 to 1:1) to give 3f (16 mg, 59%) as a
white solid. 1H NMR (CDCl3) δ 2.22 (3H, s), 2.31 (3H, s), 3.69 (4H,
brs), 6.71 (1H, dd, J = 7.8, 1.4 Hz), 6.79 (1H, d, J = 8.2 Hz), 6.95−
6.97 (1H, m), 7.05−7.17 (3H, m), 7.30 (1H, s), 8.04 (1H, dd, J = 7.5,
2.1 Hz). LC-MS (M + H) 365.
3.1.15. Dimethyl(5-(2-(2,4-dimethylphenoxy)phenyl)thiazol-2-yl)
carbonimidodithioate (16a). To a solution of 14a in CH2Cl2 (0.9
mL) was added TFA (0.9 mL) at 0 °C. The reaction was warmed to
room temperature and then stirred for 2 h. The reaction was poured
into sat NaHCO3 aq. and extracted with EtOAc. The extract was
washed with brine, dried over Na2SO4, and concentrated under
reduced pressure to give 15a (74 mg, 93%) as a slightly reddish solid.
To a solution of 15a in DMF (0.5 mL) was added 10 N NaOH
(0.049 mL, 0.49 mmol) and CS2 (0.046 mL, 0.764 mmol) at room
temperature. The mixture was stirred for 30 min at room temperature.
MeI (0.104 mL, 1.67 mmol) was added to the reaction at 0 °C, and
the mixture was stirred at 0 °C for 4 h. Water was added to the
reaction. The mixture was extracted with EtOAc. The organic layer
was washed brine, dried over sodium sulfate, and concentrated under
reduced pressure. The residue was purified by silica gel column
chromatography (hexane−EtOAc = 95:5 to 3:1) to give 63 mg (yield
3.1.10. N-(4-(2-(2,4-Dimethylphenoxy)phenyl)thiazol-2-yl)-1,3-
diazepan-2-imine (3g). Compound 3g was obtained (35%) from
compound 10 via reaction with 1,4-diaminobutane in a manner
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similar to that described for compound 3f. H NMR (DMSO-d6) δ
1.24 (2H, br s), 1.62 (4H, br s), 2.16 (3H, s), 2.28 (3H, s), 3.13 (4H,
br s), 6.65 (1H, d, J = 8.1 Hz), 6.75 (1H, d, J = 8.2 Hz), 7.01−7.03
(1H, m), 7.12−7.18 (2H, m), 7.19−7.25 (1H, m), 7.26 (1H, s), 8.01
(1H, dd, J = 7.7, 1.6 Hz). LC-MS (M + H) 393.
3.1.11. (E)-N-(4-(2-(2,4-Dimethylphenoxy)phenyl)thiazol-2-yl)-1-
methyltetrahydropyrimidin-2(1H)-imine (3h). Compound 3h was
obtained (29%) from compound 10 via reaction with N-methyl-1,3-
diaminopropane in a manner similar to that described for compound
3f. 1H NMR (DMSO-d6) δ 1.88−1.93 (2H, m), 2.15 (3H, s), 2.27
(3H, s), 2.99 (3H, s), 3.27−3.39 (4H, m), 6.64 (1H, dd, J = 8.1, 1.2
Hz), 6.73 (1H, d, J = 8.2 Hz), 7.00 (1H, d, J = 4.1 Hz), 7.11−7.16
(3H, m), 7.20 (1H, dt, J = 10.8, 3.9 Hz), 7.98 (1H, dd, J = 7.7, 1.9
Hz), 9.64 (1H, s). LC-MS (M + H) 393.
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68%) of compound 16a as a yellow oil. H NMR (CDCl3) δ 2.22
(3H, s), 2.32 (3H, s), 2.61 (6H, s), 6.71 (1H, d, J = 8.2 Hz), 6.78
(1H, d, J = 8.1 Hz), 6.93−7.19 (4H, m), 7.07 (4H, tt, J = 27.3, 9.9
Hz), 7.68 (1H, dd, J = 7.7, 1.6 Hz), 8.05 (1H, s).
3.1.16. N-(5-(2-(2,4-Dimethylphenoxy)phenyl)thiazol-2-yl)-
tetrahydropyrimidin-2(1H)-imine (4a). To a solution of 16a (54
mg, 0.135 mmol) in DMF (0.5 mL) was added 1,3-propanediamine
(12 mg, 0.162 mmol), and the mixture was stirred for 7 h at 85 °C.
After being cooled to room temperature, water was added to the
reaction. The obtained insoluble material was collected by filtration.
The obtained material was dissolved in CHCl3, dried over Na2SO4,
and concentrated under reduced pressure. The residue was purified by
silica gel column chromatography (EtOAc−hexane = 45:55 to 65:35)
3.1.12. 1-(2-Bromophenoxy)-2,4-dimethylbenzene (12). A sol-
ution 2,4-dimethylphenol (24 g, 196 mmol) in dry DMF (100 mL)
10491
J. Med. Chem. 2021, 64, 10482−10496