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B.P. Bandgar et al. / European Journal of Medicinal Chemistry 57 (2012) 217e224
N2 atmosphere. TMG (0.672 g, 5.8 mmol) was added once and stir-
red for 15 min at ꢁ15 ꢀC. Then, 1-iodomethylisopropyl carbonate
(1.35 g, 5.52 mmol) was added atonce. Thereaction masswas stirred
for 30 min at ꢁ15 to ꢁ10 ꢀC. 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 (0.5 g) under
vigorous stirring. Then, pH of reaction mixture was adjusted to 10.5
with sodium carbonate. The organic phase was separated, washed
with brine (4 ꢃ 30 mL), decolorized with activated carbon (0.5 g),
and filtered. After evaporation of solvent in vacuo solid product was
obtained in the flask. Then, water (75 mL) was added, and stirred to
get homogeneous slurry, filtered, washed with water (50 mL) and
dried in vacuo at 45 ꢀC to afford the desired product 4 as off white
solid (2.2 g, 83%). Chromatographic purity (HPLC) 100%; mp
104.2 ꢀC; MS (ESIþ) m/z ¼ 478.2 [M þ H].þ; IR (KBr) cmꢁ13269, 2990,
The pH of reaction mixture was adjusted to 10.5 with sodium
carbonate and stirred for 10 min at 25 ꢀC. The organic phase was
separated, washed with brine solution (2 ꢃ 30 mL), filtered, and
solvent was evaporated in vacuo at 40 ꢀC to get residual solid in the
flask. Then, water (25 mL) was added, stirred for 10 min at 4 ꢀC,
filtered, washed with water (40 mL), and dried in vacuo at 45 ꢀC to
afford the title compound 7 as white fluffy solid (0.5 g, 76%).
Chromatographic purity (HPLC) 99.95%; mp 141.9 ꢀC; MS (ESIþ)
m/z ¼ 475.1 [M þ H].þ; IR (KBr) cmꢁ1 3257, 1727, 1633. 1H
NMR (DMSO, 400 MHz)
d
1.49 (s, 6H, eOC(CH3)2), 2.35 (t, 4H, J ¼ 4.4
Hz, eN(CH2)2), 2.52 (t, 2H, J ¼ 5.5 Hz, eOCH2CH2N), 2.78 (t, 2H,
J ¼ 7.6 Hz, eNCH2CH2Ar), 3.33 (t, 2H, J ¼ 7.6 Hz, eNCH2CH2Ar), 3.50
(t, 4H, J ¼ 4.4 Hz, eO(CH2)2), 4.23 (t, 2H, J ¼ 5.5 Hz, eOCH2CH2N),
6.75e7.84 (m, 8H, AreH), 8.64 (bs, 1H, eNeH). 13C NMR (CDCl3,
100 MHz)
d 25.09 (2C, ArOCH(CH3)2), 34.15 (eHNCH2CH2Ar), 40.99
2940, 1770, 1632; 1H NMR (CDCl3, 400 MHz)
d
1.28 (d, 6H,
(eHNCH2CH2Ar), 53.22 (2C, eN(CH2)2), 56.31 (eOCH2CH2N), 61.96
(eOCH2CH2N), 66.17 (2C, eO(CH2)2), 78.55 (eOCHCOO), 118.86e
153.4 (12C, Ar), 165.03 (ArCONH), 173.25 (eOCHCOO). Anal. Calcd.
for C25H31ClN2O5: C, 63.22; H, 6.58; N, 5.90. Found: C, 63.15; H, 6.55;
N, 5.88.
J ¼ 6.2 Hz, eOCH(CH3)2), 1.60 (s, 6H, eOC(CH3)2), 2.87 (t, 2H,
J ¼ 6.4 Hz, eNHCH2CH2Ar), 3.69 (t, 2H, J ¼ 6.4 Hz, eNHCH2CH2Ar),
4.9 (sept, 1H, J ¼ 6.2 Hz, eOCH(CH3)2), 5.82 (s, 2H, eOCH2O),
6.1(bs, 1H, eNH), 6.8e7.63 (m, 8H, AreH); 13C NMR (CDCl3,
100 MHz) d 21.26 (2C, eOCH(CH3)2), 24.71 (2C, eOCH(CH3)2), 34.17
(eHNCH2CH2Ar), 40.96 (eHNCH2CH2Ar), 72.76 (eOCH(CH3)2),
78.44 (ArOCH(CH3)2), 82.40 (eOCH2O), 119.14e153.01 (12C, Ar),
152.61 (eOCOO), 165.06 (ArCONH), 172.23 (eOCHCOO). Anal. Calcd.
for C24H28ClNO7: C, 60.31; H, 5.91; N, 2.93. Found: C, 60.25; H, 5.88;
N, 2.91.
4.8. 2-[4-[2-[(4-Chlorobenzoyl)amino]ethyl]phenoxy}-2-methyl-
propanoic acid 5-methyl-2-oxo-[1,3]dioxol-4-yl methyl ester (7)
A solution of 1a (2.0 g, 5.52 mmol) in DMAc (10 mL) was treated
with micronized sodium carbonate (0.44 g, 4.1 mmol) and 5-methyl-
2-oxo-1, 3-dioxolene-4-yl-4-methylene chloride (0.9 g, 6.06 mmol)
for 70 h at 32 ꢀC under N2 atmosphere. Reaction progress was
monitored by HPLC. The reaction mixture was transferred to
amixtureofethylacetate(50 mL)andwater(100 mL)undervigorous
stirring. The pH of reaction mixture was adjusted to 11.0 with sodium
carbonate, and stirred for 10 min at 25 ꢀC. The organic phase was
separated, washed with brine solution (2 ꢃ 100 mL), filtered, and
solvent was evaporated completely under vacuum at 35e40 ꢀC to
give solid residue. Then, water (50 mL) was added, stirred for 10 min,
filtered, washed with water (50 mL), and dried in vacuo at 45 ꢀC to
afford the title compound 7 as white solid (1.9 g, 73þ%). Chromato-
graphic purity (HPLC) 98.87%; mp 129.8 ꢀC; MS (ESI ) m/z ¼ 474.1
[M þ H].þ; IR (KBr) cmꢁ1: 3282, 1823, 1743, 1634; 1H NMR (DMSO,
4.6. 2-[4-[2-[(4-Chlorobenzoyl)amino]ethyl]phenoxy}-2-
methylpropanoic acid 2-acetoxyethyl ester (5)
A solution of 1a (3 g, 8.29 mmol) in DMAc (15 mL) was treated
with sodium carbonate (0.59 g, 5.55 mmol) and 2-acetoxyethyl
bromide (1.73 g, 10.36 mmol) at room temperature. The reac-
tion mixture was heated to 55 ꢀC, and stirred for 8 h under N2
atmosphere. Reaction progress was monitored by HPLC. The
reaction mixture was added under stirring into the mixture of
ethyl acetate (41 mL), water (120 mL) and sodium thiosulfate
(0.5 g) under vigorous stirring. The organic phase was separated,
washed with brine solution (3 ꢃ 38 mL), filtered, and solvent was
evaporated in vacuo at 35e40 ꢀC to get solid residue. Then, water
(50 mL) was added, stirred at 5 ꢀC for 30 min, filtered, washed
with water (50 mL), and dried in vacuo to afford the title
compound 5 as white fluffy solid (3.2 g, 87%). Chromatographic
purity (HPLC) 98.13%; mp 108.9 ꢀC; MS (ESIþ) m/z ¼ 448.2
[M þ H].þ; IR (KBr) cmꢁ1 3256, 1737, 1634. 1H NMR (DMSO,
400 MHz)
J ¼ 7.7 Hz, eNHCH2CH2Ar), 3.45 (t, 2H, J ¼ 7.7 Hz, eNHCH2CH2Ar),
5.07 (s, 2H, eOCH2), 6.69e7.84 (m, 8H, AreH), 8.65 (bs,1H, eNH); 13
NMR (DMSO, 100 MHz) 8.80 (eCCH3), 24.96 (2C, eOCH(CH3)2),
d
1.55 (s, 6H,eOC(CH3)2), 2.13 (s, 3H,eC¼CCH3), 2.77(t,2H,
C
d
34.21 (eHNCH2CH2Ar), 40.96 (eHNCH2CH2Ar), 54.47 (eOCH2C),
78.67 (eOCHCOO), 118.73e153.19 (12C, Ar þ 2C, ethylene), 151.71
(eOCOO), 165.04 (ArCONH), 172.89 (eOCHCOO). Anal. Calcd. for
400 MHz)
d 1.49 (s, 6H, eOC(CH3)2), 1.94 (s, 3H, eOCOCH3), 2.79
(t, 2H, J ¼ 7.44 Hz, eNHCH2CH2Ar), 3.46 (t, 2H, J ¼ 7.44 Hz, e
C24H24ClNO7: C, 60.83; H, 5.10; N, 2.96. Found: C, 60.77; H, 5.07; N,
NHCH2CH2Ar), 4.34 (m, 4H, eOCH2CH2O), 6.73e7.84 (m, 8H, Are
2.94.
H), 8.6 (bs, 1H, eNeH); 13C NMR (CDCl3, 100 MHz)
d 20.8 (e
OCOCH3), 25.49 (2C, eOCH(CH3)2), 34.85 (eHNCH2CH2Ar),
41.43 (eHNCH2CH2Ar), 62.08 (eOCH2CH2O), 62.87 (e
OCH2CH2O), 79.2 (ArOCH(CH3)2), 119.38e154.16 (12C, Ar),
166.59 (ArCONH), 170.87 (eOCOCH3), 174.19 (eOCHCOO). Anal.
Calcd. for C23H26ClNO6: C, 61.67; H, 5.85; N, 3.13. Found: C, 61.58;
H, 5.82; N, 3.11.
4.9. HPLC analysis
Testing procedure for in-process analysis, aqueous solubility,
chromatographic purity, partition coefficient analysis, and limit of
detection (LOD). A reverse phase HPLC method was used. Instru-
ments used: HPLC, Waters Alliance, pump model 2695, UV detector
model 2487. Mobile phase A was prepared by mixing glacial acetic
4.7. 2-[4-[2-[(4-Chlorobenzoyl)amino]ethyl]phenoxy}-2-
methylpropanoic acid 2-morpholin-4-yl-ethyl ester (6)
acid (2.0 mL in Milli Q water 1000 mL), filtered through 0.45 mm
filter, and degassed by sonication (pH of this solution is around 3.0).
Mobile phase B, involved filtered and degassed methanol (HPLC
grade). Chromatographic parameters were as follows: column,
A
solution of 4-(2-chloroethyl) morpholine hydrochloride
(0.27 g, 1.451 mmol) in DMAc (2.5 mL) was treated with potassium
carbonate (0.3245 g, 2.279 mmol) and 1a (0.5 g, 0.1381 mmol) for
6 h at 65 ꢀC under N2 atmosphere. Reaction progress was moni-
tored by HPLC. The reaction mixture was transferred to a mixture of
ethyl acetate (12 mL) and water (40 mL) under vigorous stirring.
YMC-Pack C-8, 100 mm length, 4.6 mm internal diameter, 3
particle size; flow rate, 0.8 mL/min; wavelength, 254 nm; injection
volume, 20 L; run time, 30 min. The gradient elution program is
given below
mm
m