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R. Kumar et al. / European Journal of Medicinal Chemistry 42 (2007) 503e510
6.4. (S )-2-Acetylamino-3-[4-(anthracen-9-yl-
6.7. (S )-2-Acetylamino-3-{4-[(2-trifluoromethyl-phenyl
methoxy)phenyl]propionic acid ethyl ester (3b)
carbamoyl)methoxy]-phenyl}propionic acid (4c)
Compound 3b was synthesized according to the procedure
as mentioned in Section 6.2 from (S )-2-acetylamino-3-(4-
hydroxyphenyl)propionic acid ethyl ester (2) (1 mmol) and
9-chloromethylanthracene (1 mmol). IR (cmꢀ1) 3341, 2925,
1735, 1655, 1515, 1216. 1H NMR (CDCl3) d 1.71 (t,
J ¼ 6 Hz, 3H), 1.99 (s, 3H), 2.05 (s, 2H), 3.01e3.11 (dd,
J ¼ 6 Hz 6 Hz, 2H), 4.13 (q, J ¼ 6.6 Hz, 2H), 4.85 (m, 1H),
6.07 (m, 1H), 6.75 (d, J ¼ 7.8 Hz, 2H), 6.95 (d, J ¼ 7.8 Hz,
2H), 7.02 (m, 1H), 7.34 (d, J ¼ 7.8 Hz, 1H), 7.43 (m, 2H),
8.02 (m, 2H), 7.90 (s, 1H), 8.11 (d, J ¼ 7.8 Hz, 1H), 8.43
(m, 1H). MS (MALDI): 442 (m/z Mþ). Anal. Calcd for
(C28H27NO4) C, 76.17; H, 6.16; N, 3.17. Found: C, 76.01;
H, 5.89; N, 3.09.
Compound 4c was synthesized according to the procedure as
mentioned in Section 6.3 from (S )-2-acetylamino-3-{4-[(2-tri-
fluoromethylphenylcarbamoyl) methoxy]phenyl}propionic
acid ethyl ester (3c). IR (cmꢀ1) 3414, 2925, 1659, 1514,
1
1233. H NMR (CD3OD) d 1.92 (s, 3H), 2.90e2.97 (m, 2H),
4.48 (m, 1H), 4.74 (s, 2H), 6.72 (d, J ¼ 7.8 Hz, 2H), 6.97 (d,
J ¼ 7.8 Hz, 2H), 7.28 (d, J ¼ 7.2 Hz, 1H), 7.56e7.66 (m, 3H),
8.21 (d, J ¼ 8.4 Hz, 1H), 8.74 (s, 1H). MS (MALDI): 425
(m/z Mþ1). Anal. Calcd for (C20H19F3N2O5) C, 56.60; H,
4.51; N, 6.60. Found: C, 56.36; H, 4.37; N, 6.28.
6.8. (S )-2-Acetylamino-3-(4-{2-[4-(4-chlorobenzoyl)
phenoxy]ethoxy}phenyl)-propionic acid ethyl ester (3d)
6.5. (S )-2-Acetylamino-3-[4-(anthracen-9-yl-
methoxy)phenyl]propionic acid (4b)
Step
A:
[4-(2-bromoethoxy)phenyl]-(4-chlorophenyl)
methanone was synthesized by refluxing (4-chlorophenyl)-
(4-hydroxyphenyl)methanone (2 g, 0.0086 mol) with 1,2-di-
bromoethane (1.6 g, 0.0086 mol) in acetone in presence of
K2CO3 (0.58 g, 0.009 mol). The reaction mixture was concen-
trated and extracted with ethyl acetate. The organic layer was
treated with water, brine and dried over sodium sulphate. The
column chromatography afforded the pure title compound in
Compound 4b was synthesized according to the procedure
as mentioned in Section 6.3 from (S )-2-acetylamino-3-[4-
(anthracen-9-yl-methoxy)phenyl]propionic acid ethyl ester.
IR (cmꢀ1) 3412, 2921, 1695, 1638, 1512, 1211. 1H NMR
(CD3OD) d 2.03 (s, 3H), 2.93e3.10 (m, 2H), 3.56 (s, 2H),
4.30 (m, 1H), 6.11 (m, 1H), 6.77 (d, J ¼ 7.8 Hz, 2H), 6.96
(d, J ¼ 7.8 Hz, 2H), 7.04 (m, 1H), 7.35 (d, J ¼ 7.8 Hz, 1H),
7.45 (m, 2H), 8.02 (m, 2H), 7.90 (s, 1H), 8.10 (d,
J ¼ 7.8 Hz, 1H), 8.42 (m, 1H). MS (MALDI): 413, 435 (m/z
Mþ1, Mþ23). Anal. Calcd for (C26H23NO4) C, 75.53; H,
5.61; N, 3.39. Found: C, 75.50; H, 5.37; N, 3.17.
1
75% yield (2.19 g). H NMR (CDCl3) d 3.67 (t, J ¼ 6.0 Hz,
2H), 4.38 (t, J ¼ 6.0 Hz, 2H), 6.97 (d, J ¼ 9.0 Hz, 2H), 7.45
(d, J ¼ 8.4 Hz, 2H), 7.73 (d, J ¼ 9 Hz, 2H), 7.80 (d,
J ¼ 8.7 Hz, 2H). MS (MALDI): 339, 341 (m/z Mþ, Mþ2).
Step
B:
[4-(2-bromoethoxy)phenyl]-(4-chlorophenyl)
methanone (1 g, 0.003 mol) and (S )-2-acetylamino-3-(4-
hydroxyphenyl)propionic acid ethyl ester (0.74 g, 0.015 mol)
were refluxed to afford 2-acetylamino-3-(4-{2-[4-(4-chloro-
benzoyl)-phenoxy]ethoxy}phenyl)propionic acid ethyl ester
(3d) according to the procedure mentioned in Section 6.2.
IR (cmꢀ1) 3426, 2935, 1725, 1644, 1523, 1231. 1H NMR
(CDCl3) d 1.24 (t, J ¼ 6.9 Hz, 3H), 1.98 (s, 3H), 2.93e3.09
(m, 2H), 4.15 (q, J ¼ 7.2 Hz, 2H), 4.39 (t, J ¼ 6 Hz, 2H),
4.44 (m, 1H), 4.81 (t, J ¼ 6 Hz, 2H), 6.28 (d, J ¼ 7.8 Hz,
2H), 6.75 (d, J ¼ 8.1 Hz, 2H), 6.93 (d, J ¼ 7.8 Hz, 2H), 7.06
(m, 2H), 7.44 (d, J ¼ 8.4 Hz, 2H), 7.71 (d, J ¼ 5.1 Hz, 1H),
7.79 (d, J ¼ 8.4 Hz, 2H). MS (MALDI): 510, 532 (m/z Mþ,
Mþ22). Anal. Calcd for (C28H28ClNO6) C, 65.94; H, 5.53;
N, 2.75. Found: C, 65.59; H, 5.34; N, 2.57.
6.6. (S )-2-Acetylamino-3-{4-[(2-trifluoromethylphenyl
carbamoyl)methoxy]-phenyl}propionic
acid ethyl ester (3c)
Step A: 2-chloro-N-(2-trifluoromethylphenyl)acetamide was
synthesized by condensing 2-trifluoromethylphenylamine (2 g,
1
0.012 mol) with chloroacetylchloride (1.37 g, 0.012 mol). H
NMR (CDCl3) d 4.22 (s, 2H), 7.28 (t, J ¼ 7.5 Hz, 1H),
7.56e7.66 (m, 2H), 8.22 (d, J ¼ 8.4 Hz, 1H), 8.74 (s, 1H).
13C NMR (CDCl3) d 42.82, 123.96, 125.21, 126.17, 132.94,
164.25. MS (MALDI): 275 (m/z Mþ38).
Step B: compound 3c was synthesized according to the pro-
cedure as mentioned in Section 6.2 from (S )-2-acetylamino-3-
(4-hydroxyphenyl)propionic acid ethyl ester (2) (0.5 g,
0.019 mol) and 2-chloro-N-(2-trifluoromethylphenyl)aceta-
mide (0.54 g, 0.019 mol). 1H NMR (CDCl3) d 1.25 (t,
J ¼ 6.9 Hz, 3H), 1.93 (s, 3H), 2.92 (m, 1H), 3.11 (m, 1H),
4.10 (q, J ¼ 6.9 Hz, 2H), 4.47 (m, 1H), 4.73 (s, 2H), 6.70 (d, J
¼ 7.8 Hz, 2H), 6.98 (d, J ¼ 7.8 Hz, 2H), 7.22 (d, J ¼ 7.2 Hz,
1H), 7.53e7.63 (m, 3H), 8.26 (d, J ¼ 8.4 Hz, 1H), 8.99 (s,
1H). MS (MALDI): 452 (m/z Mþ). Anal. Calcd for
(C22H23F3N2O5) C, 58.40; H, 5.12; N, 6.12. Found: C, 58.23;
H, 5.03; N, 5.98.
6.9. (S )-2-Acetylamino-3-(4-{2-[4-(4-chlorobenzoyl)
phenoxy]ethoxy}phenyl)-propionic acid (4d)
Compound 4d was synthesized according to the procedure
as mentioned in Section 6.3 from 2-acetylamino-3-(4-{2-[4-
(4-chlorobenzoyl)phenoxy]-ethoxy}phenyl)propionic acid
ethyl ester (3d). IR (cmꢀ1) 3428, 2935, 1646, 1521, 1230.
1H NMR (DMSO-d6) d 1.78 (s, 3H), 2.73e2.81 (m, 1H),
2.93e3.09 (m, 2H), 4.32e4.42 (m, 5H), 6.89 (d, J ¼ 8.4 Hz,
2H), 7.16 (m, 3H), 7.61 (d, J ¼ 9 Hz, 2H), 7.70e7.79 (m,