Journal of Medicinal Chemistry
ARTICLE
acetate (50 g, 0.58 mol). The reaction mixture was stirred for 60 min at
35 ( 1 °C. The reaction progress was monitored by GC. After
completion of reaction, the reaction mixture subjected for distillation
to afford promoiety 2c as colorless fuming liquid (81.2 g, 84%). Purity by
GC 97.28%. 1H NMR (DMSO, 400 MHz): δ 1.51 (d, 3H, J = 5.30 Hz,
ꢀCHCH3), 2.1 (s, 3H, ꢀCOCH3), 6.4 (q, 1H, J = 5.30 Hz, ꢀOCHBr-
(CH3). IR (Nujol) cmꢀ1 1762 (CdO), 1084 (CꢀO).
(80 mL), and sodium thiosulfate (0.5 g). The pH of reaction mixture was
adjusted to 10.5 by addition of sodium carbonate, and the organic phase
was separated, washed with brine (400 mL), treated with activated
carbon (0.5 g), and filtered. After evaporation of solvent in vacuo, the
desired product 2e was obtained as oil which solidified upon cooling to a
white solid (2.2 g, 69%). Chromatographic purity (HPLC) 99.66%; mp
102 °C; MS (+ESI) m/z = 405.1 (M + H) +. IR (KBr) 1689 (CdO),
1652 (CdO), 762 (CꢀCl str). 1H NMR (CDCl3, 400 MHz): δ 1.44 (d,
3H, J = 5.4 Hz, ꢀOCH(O)CH3), 1.67 (s, 6H, ArOC(CH3)2), 2.03 (s,
3H, ꢀOCOCH3), 6.92 (q, 1H, J = 5.4 Hz, ꢀOCH(O)CH3), 6.89 (d,
2H, J = 8.8 Hz, Ar-H), 6.7.4 (d, 2H, J = 8.4 Hz, Ar-H), 7.7 (d, 2H, J = 8.4
Hz, Ar-H), 7.75 (d, 2H, J = 8.8 Hz, Ar-H). 13C NMR (CDCl3, 100
MHz): δ 18.1, 19.69, 23.92, 24.47, 78.0, 88.2, 116 (2C), 127.5 (2C),
129.5, 130.16 (2C), 130.93 (2C), 135.3, 137.4, 158.3, 167.8, 170.7,
193.2. Anal. Calcd for C21H21ClO6: C, 62.30; H, 5.23. Found: C, 62.20;
H, 5.12.
2-[4-(4-Chlorobenzoyl)phenoxy]-2-methylpropionic Acid 1-Isopro-
poxy Carbonyloxyethyl Ester (1c). Compound 1a (2 g, 6.27 mmol) was
dissolved in DMAc (10 mL) at 25 °C. The reaction mixture was cooled
to ꢀ5 °C. TMG (0.77 g, 6.649 mmol) was added once, and the mixture
was stirred for 20 min at ꢀ5 ( 2 °C. Then, 1-iodoethylisopropyl
carbonate (1.62 g, 6.28 mmol) was added at ꢀ5 °C. The reaction
mixture was stirred for 45 min at ꢀ5 °C under N2 atmosphere. Reaction
completion was monitored by HPLC. The reaction mixture was
transferred to a mixture of ethyl acetate (25 mL), water (80 mL), and
sodium thiosulfate (0.5 g) under vigorous stirring. The organic phase
was separated, washed with brine (220 mL), decolorized with activated
carbon (0.4 g), and filtered. After evaporation of solvent in vacuo, the
desired product 1c was obtained as an oil which solidified upon cooling
to a pale-yellow crystalline solid (2.4 g, 85%), mp 83.9 °C. Chromato-
graphic purity (HPLC) 99.42%; MS (+ESI) m/z = 449 (M + H)+. IR
2-[4-(4-Chlorobenzoyl)phenoxy]-2-methylpropionic Acid Isopro-
poxycarbonyl Oxymethyl Ester (1f). Compound 1a (2 g, 6.279 mmol)
was dissolved in DMAc (10 mL) at room temperature. TMG (0.763 g,
6.588 mmol) was added at 0 °C, and the reaction mixture was stirred for
20 min under N2 atmosphere at ꢀ2 ( 1 °C. To that, iodomethyliso-
propyl carbonate (1.53 g, 6.27 mmol) was added at 0 °C, and the mixture
was stirred at 0 °C for 30 min. The reaction progress was monitored by
HPLC. The reaction mixture was added under stirring to a mixture of
ethyl acetate (25 mL), water (80 mL), and sodium thiosulfate (0.5 g),
and the mixture was stirred for 10 min at pH 10.5 and 25 °C. The organic
layer was separated, washed with brine solution (120 mL), filtered, and
solvent was evaporated completely in vacuo to get viscous oil product,
which upon cooling afforded 1f as white crystalline solid (2.3 g, 83%).
Chromatographicpurity(HPLC) 99.60%; mp76.5 °C; MS (+ESI) m/z =
1
(KBr) cmꢀ1 1756 (CdO), 1654 (CdO), 1259.1 (CꢀOꢀC str). H
NMR (CDCl3, 400 MHz): δ 1.15 (d, 6H, J = 6.2 Hz, ꢀCH(CH3)2),
1.41 (d, 3H, J = 5.4 Hz, ꢀOCH(O)CH3), 1.6 (s, 6H, ꢀOC(CH3)2CO),
4.74 (sept, 1H, J = 6.2 Hz, ꢀOCH(CH3)2], 6.73 (q, 1H, J = 5.4 Hz,
ꢀOCH(O)CH3), 6.81 (d, 2H, J = 8.8 Hz, Ar-H), 7.37 (d, 2H, J = 8.4 Hz,
Ar-H), 7.63 (d, 2H, J = 8.4 Hz, Ar-H), 7.65 (d, 2H, J = 8.8 Hz, Ar-H). 13
C
NMR (CDCl3, 100 MHz): δ 18.23, 20.54(2C), 23.84, 24.53, 71.93, 78.0,
90.98, 116.51(2C), 129.4 (2C), 130.81, 130.94 (2C), 131.08 (2C),
135.34, 137.35, 151.44, 158.29, 170.71, 193.15. Anal. Calcd for
C23H25ClO7: C, 61.54; H, 5.61. Found: C, 61.45; H, 5.58.
+
1
435.1 (M + H) . IR (KBr) 1745 (CdO), 1654 (CdO). H NMR
(CDCl3, 400 MHz) δ 1.24 (d, 6H, J = 6.2 Hz, ꢀOCH(CH3)2), 1.69 (s,
6H, ꢀArOC(CH3)2), 4.8 (sept, 1H, J = 6.2 Hz, ꢀOCH(CH3)2), 5.83 (s,
2H, ꢀOCH2O), 6.87ꢀ7.74 (m, 8H, Ar-H). 13C NMR (CDCl3): δ 21.7
(2C), 25.37 (2C), 74.47, 79.25, 82.55, 117.7 (2C), 128.71 (2C), 130.8,
131.33 (2C), 132.17 (2C), 126.47, 138.57, 153.19, 159.38, 172.58,
194.29. Anal. Calcd for C22H23ClO7: C, 60.76; H, 5.33. Found: C, 60.55;
H, 5.25.
2-[4-(4-Chlorobenzoyl)phenoxy]-2-methylpropanoic Acid Pivolox-
ymethyl Ester (1d). Compound 1a (2.0 g, 6.279 mmol) was dissolved in
DMAc (10 mL) at 25 °C. The reaction mixture was cooled to ꢀ5 °C
under N2 atmosphere. TMG (0.78 g, 6.64 mmol) was added, and the
mixture was stirred at for 20 min at ꢀ5 °C. Then, promoiety b (1.62 g,
6.694 mmol) was added once at ꢀ5 °C. The reaction mixture was stirred
vigorously at ꢀ5 °C for 15 min. Reaction progress was monitored by
HPLC. The reaction mixture was transferred to a mixture of ethyl acetate
(30 mL), water (80 mL), and sodium thiosulfate (0.6 g) under vigorous
stirring at 25 °C. The organic phase was separated, washed with brine
(220 mL), decolorized with activated carbon (0.4 g), and filtered. The
solvent was evaporated completely under vacuum to get solid residue.
Water (50 mL) was added, stirred for 20 min at 10 °C, filtered, washed
with water (50 mL), and dried under vacuo at 45 °C for 4 h to afford 1d
as white crystalline solid (2.3 g, 85%), mp 80.3 °C. Chromatographic
purity (HPLC) 99.65%; MS (+ESI) m/z = 433 (M + H)+. UV max
(ethanol) 284.4 nm (36 mMꢀ1 cmꢀ1). IR (KBr) cmꢀ1 1747 (CdO),
1648 (CdO). 1H NMR (CDCl3, 400 MHz): δ 1.17 (s, 9H, ꢀC(CH3)3),
1.67 (s, 6H, ꢀC(CH3)2), 5.84 (s, 2H, ꢀOCH2O), 6.86 ꢀ7.74 (m, 8H,
Ar-H). 13C NMR (CDCl3, 100 MHz) δ 25.39 (2C), 26.87 (3C), 38.98,
79.22, 80.17, 117.71 (2C), 128.7 (2C), 130.80, 131.32 (2C), 132.1 (2C),
136.43, 138.58, 159.40, 172.65, 176.87, 194.29. Anal. Calcd for
C23H25ClO6: C, 63.81; H, 5.82. Found: C, 63.75; H, 5.72.
2-[4-(4-Chlorobenzoyl)phenoxy]-2-methylpropanoic Acid 2-Mor-
pholin-4-yl Ethyl Ester (1g). 4-(2-Chloroethyl)morpholine hydrochlor-
ide (1.787 g, 9.6 mmol), potassium carbonate (1.511 g, 1.09 mmol), and
compound 1a (3 g, 9.4 mmol) were added in DMF (18 mL), and the
reaction mixture was stirred at 60 °C for 5 h under N2 atmosphere.
Reaction progress was monitored by HPLC. The reaction mixture was
transferred to a mixture of ethyl acetate (45 mL) and water (120 mL) under
vigorous stirring and stirred for 10 min at pH 10.5 and 25 °C. The organic
phase was separated, washed with brine solution (180 mL), decolorized
with activated carbon (0.25 g), filtered, and the solvent was removed in
vacuo. Water (50 mL) was added and the slurry stirred for 30 min at 25 °C,
filtered, and washed with water (50 mL), and dried under vacuum at 45 °C
to afford 1g as white crystalline powder (2.5 g, 70%). Chromatographic
purity (HPLC) 99.58%; mp 89.5 °C; MS (+ESI) m/z = 432.1 (M + H) +;
UV max (ethanol) 286.6 nm (21 mMꢀ1 cmꢀ1). IR (KBr) 1732 (CdO),
1648 (CdO), 760 (CꢀCl str). 1H NMR (CDCl3, 400 MHz): δ 1.68 (s,
6H, ꢀC(CH3)2), 2.42 (t, 4H, J = 4.32 Hz, ꢀN(CH2)2), 2.58 (t, 2H, J =
5.72 Hz, ꢀOCH2CH2N), 3.62 (t, 4H, J = 4.32 Hz, ꢀO(CH2)2), 4.31 (t,
2H, J = 5.72 Hz, ꢀOCH2CH2N), 6.88ꢀ7.74 (m, 8H, Ar-H). 13C NMR
(CDCl3): δ 25.65 (2C), 53.84 (2C), 57.06, 62.74, 67.09 (2C), 79.53,
117.55 (2C), 128.75 (2C), 130.6, 131.34 (2C), 132.17 (2C), 136.52, 138.6,
159.78, 173.76, 194.34. Anal. Calcd for C23H26ClNO5: C, 63.96; H, 6.07; N,
3.24. Found: C, 63.78; H, 5.99; N, 3.21.
2-[4-(4-Chlorobenzoyl)phenoxy]-2-methylpropionic acid 1-acetox-
yethyl ester (1e). Compound 1a (2 g, 6.279 mmol) was dissolved in
DMAc (10 mL) at room temperature. Potassium carbonate (0.46 g, 3.32
mmol) was added, and the mixture was stirred for 90 min at 32 °C under
N2 atmosphere and cooled to ꢀ5 °C. Then, 1-acetoxyethyl bromide
(1.3 g, 7.789 mmol) was added at ꢀ5 °C. The reaction temperature was
increased to 30 °C in 30 min and stirred for 30 min. Reaction completion
was monitored by HPLC. After completion of reaction, the reaction
mixture was transferred to a mixture of ethyl acetate (30 mL), water
2-[4-(4-Chlorobenzoyl)phenoxy]-2-methylpropanoic Acid, 5-Methyl-
2-oxo-[1,3]dioxol-4-yl-methyl Ester (1h). Compound 1a (3 g, 9.4
mmol) was dissolved in DMAc (12 mL) at 30 °C. Sodium carbonate
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dx.doi.org/10.1021/jm200704f |J. Med. Chem. 2011, 54, 5915–5926