Vol. 63, No. 8 (2015)
Chem. Pharm. Bull.
633
d, J=4.8Hz), 6.75–6.81 (4H, m), 6.99–7.01 (2H, d, J=8.0Hz),
General Procedure for the Synthesis of 22e–i30,31) Com-
7.16 (1H, s), 7.21–7.23 (2H, d, J=8.8Hz), 7.21 (1H, s), 7.58–7.61 pounds 22e–i were prepared from 19e–i by means of a proce-
(2H, d, J=8.4Hz), 7.63 (1H, s), 7.70–7.72 (2H, d, J=8.8Hz). dure similar to that used for 15a–d.
ESI-MS m/z: 495 [M+H]+.
2-(4-(4-Chlorobenzoyl)phenoxy)-N-(2-(4-fluorophenyl)-2-
2-(4-(2,2-Dichlorocyclopropyl)phenoxy)-N-(2-(4-hydroxy- oxoethyl)-2-methylpropanamide (22e): Yield 82%, mp
1
phenyl)-2-oxoethyl)-2-methylpropanamide (15c): Yield 72%, 125.8–125.9°C. H-NMR (400MHz, CDCl3) δ: 1.66 (6H, s),
1
mp 113.6–115.9°C. H-NMR (400MHz, CDCl3) δ: 1.55 (6H, 4.75–4.78 (2H, d, J=5.2Hz), 7.04–7.06 (2H, d, J=8.8Hz),
s), 1.93–1.97 (2H, m), 2.82–2.88 (1H, m), 4.71–4.72 (2H, d, 7.15–7.20 (2H, m), 7.44–7.48 (2H, m), 7.70–7.77 (4H, m),
J=4.8Hz), 6.89–6.99 (4H, m), 7.15–7.16 (2H, d, J=5.2Hz), 7.99–8.02 (2H, m). ESI-MS m/z: 476 [M+Na]+.
7.72 (1H, s), 7.88–7.90 (2H, d, J=8.8Hz). ESI-MS m/z: 422
2-(4-(4-Chlorobenzoyl)phenoxy)-2-methyl-N-(2-oxo-2-
phenylethyl)propanamide (22f): Yield 89%, mp 141.2–143.3°C.
[M+H]+.
2-(4-(4-Chlorobenzoyl)phenoxy)-N-(2-(4-hydroxyphenyl)-2- 1H-NMR (400MHz, CDCl3) δ: 1.66 (6H, s), 4.79–4.80 (2H,
oxoethyl)-2-methylpropanamide (15d): Yield 65%, mp d, J=4.8Hz), 7.04–7.07 (2H, m), 7.44–7.52 (5H, m), 7.61–7.64
172.4–174.3°C. 1H-NMR (400MHz, CDCl3) δ: 1.67 (6H, s), (1H, m), 7.71–7.77 (4H, m), 7.96–7.98 (2H, m). ESI-MS m/z:
4.70–4.71 (2H, d, J=4.8Hz), 6.64 (1H, s), 6.91–6.93 (2H, d, 436 [M+H]+.
J=8.8Hz), 7.05–7.07 (2H, m), 7.45–7.47 (2H, d, J=8.4Hz), 7.61
2-(4-(4-Chlorobenzoyl)phenoxy)-2-methyl-N-(2-oxo-2-(p-
tolyl)ethyl)propanamide (22g): Yield 83%, mp 124.0–124.3°C.
(1H, s), 7.71–7.83 (6H, m). ESI-MS m/z: 452 [M+H]+.
General Procedure for the Synthesis of 17a, d, 18a, and 1H-NMR (400MHz, CDCl3) δ: 1.65 (6H, s), 2.42 (3H, s),
d32,33) CDI (10.0mmol) was dissolved in N,N-dimethylfor- 4.75–4.76 (2H, d, J=4.4Hz), 7.03–7.05 (2H, d, J=8.0Hz),
mamide (DMF) (20mL) and to this solution a solution of 7.25–7.30 (2H, m), 7.43–7.45 (2H, d, J=8.4Hz), 7.51 (1H,
the carboxylic acids 14a and d (10.0mmol) in DMF (2mL) s), 7.70–7.76 (4H, m), 7.85–7.87 (2H, m). ESI-MS m/z: 472
was added dropwise. Subsequently, the reaction mixture was [M+Na]+.
stirred at room temperature for 1h. Then, H2S was bubbled
2-(4-(4-Chlorobenzoyl)phenoxy)-2-methyl-N-(2-(4-
gently through the reaction mixture for 2h. Sulfuric acid (methylthio)phenyl)-2-oxoethyl)propanamide (22h): Yield 89%,
1
(0.5 M, 40mL) was added and the mixture was extracted with mp 113.9–114.6°C. H-NMR (400MHz, CDCl3) δ: 1.69 (6H, s),
ethyl acetate. The organic layer was dried with magnesium 2.56 (3H, s), 4.77–4.78 (2H, d, J=4.4Hz), 7.07–7.09 (2H, d,
sulfate (MgSO4), filtered, and concentrated to yield 16a, J=8.8Hz), 7.32–7.34 (2H, d, J=8.0Hz), 7.46–7.47 (2H, m),
d, 14a, d, 16a, and d (2.0mmol). They were dissolved in 7.54 (1H, s), 7.74–7.80 (4H, m), 7.89–7.91 (2H, d, J=8.8Hz).
THF (10mL), anhydrous K2CO3 (4.0mmol) and 2-bromo-4′- ESI-MS m/z: 504 [M+Na]+.
hydroxyacetophenone 11 (2.0mmol) were added, and the
2-(4-(4-Chlorobenzoyl)phenoxy)-N-(2-(3-hydroxyphenyl)-2-
mixture was stirred for 4h at room temperature. Dilute HCl oxoethyl)-2-methylpropanamide (22i): Yield 69%, mp
was added, and the mixture was extracted with ethyl acetate, 168.1–172.3°C. 1H-NMR (400MHz, CDCl3) δ: 1.53 (6H,
washed with brine, dried over MgSO4, filtered, and concen- s), 3.26 (2H, s), 7.00–7.01 (4H, m), 7.24 (1H, s), 7.51 (1H,
trated, and the residue was purified by chromatography to af- s), 7.59–7.62 (4H, m), 7.70–7.73 (4H, m). ESI-MS m/z: 474
ford target compounds 17a, d, 18a, and d.
2-(4-Hydroxyphenyl)-2-oxoethyl-5-(2,5-dimethylphenoxy)-
[M+Na]+.
General Procedure for the Synthesis of 2634–36) DMAP
2,2-dimethylpentanoate (17a): Yield 83%, mp 105.6–108.3°C. (2.0mmol) and EDCI·HCl (40.0mmol) were added to a solu-
1H-NMR (400MHz, CDCl3) δ: 1.32 (6H, s), 1.81–1.85 (4H, m), tion of 1-(tert-butoxycarbonyl) piperazine 23 (20.0mmol) and
2.18 (3H, s), 2.30 (3H, s), 3.94–3.97 (2H, m), 5.23 (2H, s), 5.62 carboxylic acid 14d (20.0mmol) in CH2Cl2 (125mL). The
(1H, s), 6.63–6.66 (2H, m), 6.85–6.87 (2H, m), 6.98–7.00 (1H, reaction mixture was stirred at room temperature for 12h and
d, J=7.6Hz), 7.80–7.82 (2H, m). ESI-MS m/z: 385 [M+H]+.
then washed with dilute HCl and water. The organic layer was
2-(4-Hydroxyphenyl)-2-oxoethyl-2-(4-(4-chlorobenzoyl)- dried over MgSO4, filtered, and the filtrate concentrated in
phenoxy)-2-methylpropanoate (17d): Yield 89%, mp vacuo to provide 24. Compound 24 (2.0mmol) was dissolved
112.0–115.2°C. 1H-NMR (400MHz, CDCl3) δ: 1.79 (6H, s), in THF (10mL), TFA (1mL) was added, and the resulting
5.35 (2H, s), 6.21 (1H, s), 6.87–6.88 (2H, m), 7.02–7.26 (2H, mixture shaken at room temperature for 24h. The reaction
m), 7.44–7.46 (2H, d, J=8.8Hz), 7.70–7.81 (6H, m). ESI-MS mixture was concentrated at reduced pressure and basified
m/z: 453 [M+H]+.
with NaOH solution (until pH 10), extracted with CH2Cl2,
S-(2-(4-Hydroxyphenyl)-2-oxoethyl)-5-(2,5-dimethyl- dried over MgSO4, filtered, and evaporated at reduced pres-
phenoxy)-2,2-dimethylpentanethioate (18a): Yield 67%, mp sure, and then the residue was purified by chromatography to
90.3–93.9°C. 1H-NMR (400MHz, CDCl3) δ: 1.32 (6H, s), afford 25. K2CO3 (4.0mmol) and 11 (2.0mmol) were added to
1.84–1.86 (4H, m), 2.18 (3H, s), 2.30 (3H, s), 3.94–3.97 (2H, a solution of 25 (2.0mmol) in THF (10mL), and the reaction
m), 5.24 (2H, s), 5.68 (1H, s), 6.63–6.66 (2H, m), 6.86–6.88 mixture was stirred at room temperature for 12h, filtered, and
(2H, m), 6.99–7.01 (1H, d, J=7.2Hz), 7.80–7.82 (2H, m). ESI- evaporated at reduced pressure. The residue was then purified
MS m/z: 423 [M+Na]+.
S-(2-(4-Hydroxyphenyl)-2-oxoethyl)-2-(4-(4-chlorobenzoyl)-
by chromatography to afford target compound 26.
2-(4-(4-Chlorobenzoyl)phenoxy)-1-(4-(2-(4-hydroxy-
phenoxy)-2-methylpropanethioate (18d): Yield 57%, mp phenyl)-2-oxoethyl)piperazin-1-yl)-2-methylpropan-1-one (26):
1
150.1–153.6°C. 1H-NMR (400MHz, CDCl3) δ: 1.65 (6H, Yield 37%, mp 225.6–228.3°C. H-NMR (400MHz, DMSO-
s), 4.33 (2H, s), 5.57 (1H, s), 6.88–6.90 (2H, d, J=8.8Hz), d6) δ: 1.61 (6H, s), 2.12 (2H, s), 2.39 (2H, s), 3.51–3.68 (6H,
6.99–7.01 (2H, d, J=8.8Hz), 7.45–7.47 (2H, d, J=8.4Hz), t), 6.78–6.80 (2H, d), 6.91–6.94 (2H, d), 7.58–7.61 (2H, d),
7.71–7.74 (2H, m), 7.91–7.93 (2H, d,=8.4Hz). ESI-MS m/z: 491 7.71–7.81 (6H, m), 10.36 (1H, s). ESI-MS m/z: 521 [M+H]+.
[M+Na]+.
Biology Materials HEK293 cells were purchased from