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Y. Wang et al. / European Journal of Medicinal Chemistry 44 (2009) 1638–1643
–CH2–CH2–), 3.09–3.11 (m, 1H, –CH–CH–), 3.74 (s, 6H, –OCH3), 4.66
(d, J ¼ 2.3 Hz, 1H, –CHN–), 6.80 (dd, J ¼ 8.4, 17.9 Hz, 4H, Ar-H), 7.21–
7.27 (m, 4H, Ar-H), 7.32–7.36 (m, 4H, Ar-H), 7.79 (s, 1H, –NH–CO–);
MS: 445.2 ([M þ H]þ); Anal. calc. for C27H28N2O4 (444.21): C 72.95,
H 6.35, N 6.30; found: C 72.70, H 6.60, N 5.92.
(s, 3H, –OCH3), 4.69 (d, J ¼ 2.4 Hz, 1H, –CHN–), 6.83–7.07 (m, 4H, Ar-
H), 7.20–7.27 (m, 5H, Ar-H), 7.30–7.34 (m, 5H, Ar-H), 7.39–7.46 (m, 4H,
Ar-H); MS: 500.3 ([M þ Na]ꢂþ); Anal. calc. for: C32H31NO3 (477.23): C
80.23, H 6.69, N 2.81; found: C 80.47, H 6.54, N 2.93.
4.1.12. Trans-1-(4-Fluorophenyl)-3-(3-hydroxy-3,3-
4.1.6. Trans-N-(4-Methylphenyl)-3-(3-[2-oxo-4-(4-methoxyphenyl)-
1-phenyl-azetidinyl])propanamide (2b)
diphenylpropyl)-4-(4-methoxyphenyl)-2-azetidinone (3c)
Yield: 36.4%. White crystals, m.p.157–159 ꢁC. IR (KBr): 3436,1720,
1510, 1389, 1249, 827, 704; 1H NMR (CDCl3): 1.85–1.94 (m, 2H,
–CH2CH2–), 2.56–2.62 (m, 2H, –CH2CH2–), 3.07–3.13 (m,1H, –CHCH–
), 3.81 (s, 3H, –OCH3), 4.50 (d, J ¼ 2.1 Hz, 1H, –CHN–), 6.88–6.91 (m,
4H, Ar-H), 7.19–7.28 (m, 5H, Ar-H), 7.30–7.33 (m, 5H, Ar-H), 7.39–7.43
(m, 4H, Ar-H); MS: 504.1 ([M þ Na]ꢂþ); Anal. calc. for: C32H28FNO3
(481.21): C 77.61, H 5.63, N 2.74; found: C 77.32, H 5.86, N 2.91.
Yield: 46.9%. White crystals, m.p. 102–103 ꢁC. IR (KBr): 3328,
2916, 2848, 2635, 1624, 1467, 1378, 1308, 1243, 1088; 1H NMR
(CDCl3): 2.31 (s, 3H, –CH3), 2.39–2.46 (m, 2H, –CH2–CH2–), 2.60–
2.65 (m, 2H, –CH2–CH2–), 3.07–3.13 (m, 1H, –CH–CH–), 3.78 (3H, s,
–OCH3), 4.69 (d, J ¼ 2.1 Hz, 1H, –CHN–), 7.01–7.05 (m, 4H, Ar-H),
7.09–7.17 (m, 5H, Ar-H), 7.28–7.45 (m, 4H, Ar-H), 7.83 (1H, s, –NH–
CO–); MS: 453.1 ([M þ K]þ); Anal. calc. for: C26H26N2O3 (414.13): C
75.34, H 6.32, N 6.76; found: C 74.89, H 6.48, N 6.74.
4.1.13. Trans-1-(6-Methylphenyl)-3-(3,3-bis(4-fluorophenyl)-3-
hydroxypropyl)-4-(benzo[d][1,3]dioxol-5-yl)-2-azetidinone (3d)
Yield: 21.4%. White crystals, m.p. 89–91 ꢁC. IR (KBr): 3449, 1732,
1446, 1245, 1037, 833, 752; 1H NMR (CDCl3): 1.87–1.92 (m, 2H,
–CH2CH2–), 2.37 (s, 3H, –CH3), 2.59–2.68 (m, 2H, –CH2CH2–), 2.72 (s,
1H, -OH), 3.15–3.16 (m,1H, –CHCH–), 4.65 (d, J ¼ 2.1 Hz,1H, –CHN–),
5.93 (s, 2H, –OCH2O–), 6.74–6.76 (m, 3H, Ar-H), 6.97–7.03 (m, 4H,
Ar-H), 7.07–7.15 (m, 4H, Ar-H), 7.35–7.40 (m, 4H, Ar-H); MS: 550.2
([M þ Na]ꢂþ); Anal.calc. for: C32H27F2NO4 (527.19): C 72.64, H 5.47, N
2.71; found: C 72.85, H 5.16, N 2.66.
4.1.7. Trans-N-(4-Chlorophenyl)-3-(3-[2-oxo-4-(4-methoxyphenyl)-
1-(4-methylphenyl)-azetidinyl])propanamide (2c)
Yield: 35.8%. Yellow oil. IR (KBr): 3518, 3331, 2901, 2548, 1888,
1755, 1613, 1537, 1392, 1249, 1176, 1089, 1033; 1H NMR (CDCl3): 2.24
(s, 3H, –CH3), 2.26–2.43 (m, 2H, –CH2–CH2–), 2.61–2.67 (m, 2H,
–CH2–CH2–), 3.08–3.15 (m, 1H, –CH–CH–), 3.77 (s, 3H, –OCH3), 4.88
(d, 1H, J ¼ 2.2 Hz, –CHN–), 7.08–7.16 (m, 4H, Ar-H), 7.18–7.29 (m, 4H,
Ar-H), 7.40–7.49 (m, 4H, Ar-H), 9.60 (1H, br, –NH–CO–); MS: 449.3
([M þ H]þ); Anal. calc. for C26H25ClN2O3 (448.16): C 69.18, H 5.94, N
6.30; found: C 69.56, H 5.61, N 6.24.
4.1.14. Trans-1-(4-Bromophenyl)-3-(3,3-bis(4-fluorophenyl)-3-
hydroxypropyl)-4-(4-methoxyphenyl)-2-azetidinone (3e)
Yield: 19.9%. White crystals, m.p. 122–124 ꢁC. IR (KBr): 3429,
1750, 1609, 1489, 1250, 1071, 827; 1H NMR (CDCl3): 1.85–1.87 (m,
2H, –CH2CH2–), 2.47 (s, 1H, –OH), 2.51–2.59 (m, 2H, –CH2CH2–),
3.09–3.10 (m, 1H, –CHCH–), 3.80 (s, 3H, –OCH3), 4.50 (d, J ¼ 2.4 Hz,
1H, –CHN–), 6.88–6.91 (m, 4H, Ar-H), 6.99–7.14 (m, 4H, Ar-H), 7.21–
7.33 (m, 4H, Ar-H), 7.35–7.38 (m, 4H, Ar-H); MS: 601.0 ([M þ Na]ꢂþ);
Anal. calc. for: C31H26BrF2NO3 (577.11): C 67.9, H 4.27, N 2.49; found:
C 64.37, H 4.53, N 2.42.
4.1.8. Trans-N-(4-Methylphenyl)-3-(3-[2-oxo-4-(4-methoxyphenyl)-
1-(4-methylphenyl)-azetidinyl])propanamide (2d)
Yield: 36.6%. Yellow oil. IR (KBr): 3848, 2900, 1742, 1600, 1513,
1442, 1392, 1249, 1065; 1H NMR (CDCl3): 2.29 (s, 6H, –CH3), 2.27–
2.44 (m, 2H, –CH2–CH2–), 2.62–2.67 (m, 2H, –CH2–CH2–), 3.06–3.12
(m, 1H, –CH–CH–), 3.77 (s, 3H, –OCH3), 4.66 (d, J ¼ 2.3 Hz, 1H,
–CHN–), 7.11–7.16 (m, 4H, Ar-H), 7.15–7.27 (m, 4H, Ar-H), 7.35–7.46
(m, 4H, Ar-H), 7.98 (s, 1H, –NH–CO–); MS: 429.3 ([M þ H]þ); Anal.
calc. for C27H28N2O3 (428.21): C 75.93, H 6.27, N 6.49; found: C
75.68, H 6.59, N 6.54.
4.1.15. Trans-1-(4-Methoxyphenyl)3-(3,3-bis(4-fluorophenyl)-
3-hydroxypropyl)-4-(6-bromobenzo[d][1,3]dioxol-5-yl)-2-
azetidinone (3f)
4.1.9. Trans-N-(4-Chlorophenyl)-3-(3-[2-oxo-4-(4-methoxyphenyl)-
1-(4-methoxyphenyl)-azetidinyl])propanamide (2e)
Yield: 21.5%. Yellow crystals, m.p. 104–106 ꢁC. IR (KBr): 3487,
1720, 1510, 1240,1034, 930, 830; 1H NMR (CDCl3): 1.93–1.99 (m, 2H,
–CH2CH2–), 2.47–2.54 (m, 2H, –CH2CH2–), 3.02 (d, J ¼ 2.1 Hz, 1H,
–CHCH–), 3.76 (s, 3H, –OCH3), 5.00 (d, J ¼ 2.1 Hz, 1H, –CHN–), 5.95
(s, 2H, –OCH2O–), 6.80–6.83 (m, 2H, Ar-H), 6.96–7.04 (m, 4H, Ar-H),
7.15–7.18 (m, 4H, Ar-H), 7.35–7.39 (m, 4H, Ar-H); MS: 644.1/646.2
([M þ Na]ꢂþ); Anal. calc. for: C32H26BrF2NO5 (622.45): C 72.64, H
5.47, N 2.71; found: C 61.75, H 4.21, N 2.25.
Yield: 43.7%. Yellow crystals, m.p. 58–59 ꢁC. IR (KBr): 3501, 2923,
1731, 1666, 1613, 1512, 1395, 1298, 1246, 1173, 1089, 1029; 1H NMR
(CDCl3, 300 M): 2.19–2.25 (m, 2H, –CH2–CH2–), 2.61–2.68 (m, 2H,
–CH2–CH2–), 3.05–3.11 (m, 1H, –CH–CH–), 3.70 (s, 6H, –OCH3), 4.65
(d, J ¼ 2.3 Hz, 1H, –CHN–), 6.84–7.05 (m, 4H, Ar-H), 7.09–7.17 (m,
4H, Ar-H), 7.30–7.42 (m, 4H, Ar-H), 8.16 (s, 1H, –NH–CO–); MS:
465.3 ([M þ H]þ); Anal. calc. for: C26H25ClN2O4 (464.15): C 67.17, H
5.42, N 6.03; found: C 66.95, H 5.38, N 5.96.
4.1.16. (3R,4S)-N-(4-Methylphenyl)-(3-[2-oxo-4-
4.1.10. Trans-1-(4-Chlorophenyl)-3-(3-hydroxy-3,3-
(4-methoxyphenyl)-1-(4-methoxyphenyl)-azetidinyl])
propanamide (4a)
diphenylpropyl)-4-(benzo[d][1,3]dioxol-5-yl)-2-azetidinone (3a)
Yield: 33.7%. White crystals. m.p.148–150 ꢁC. IR (KBr): 3461,
1742, 1492, 1447, 1390, 1246, 1040, 702; 1H NMR (CDCl3): 1.85–1.98
(m, 2H, –CH2CH2–), 2.35–2.70 (m, 2H, –CH2CH2–), 3.04–3.18 (m, 1H,
–CHCH–), 4.46 (d, J ¼ 2.1 Hz, 1H, –CHN–), 5.97 (s, 2H, –OCH2O–),
6.75–6.80 (m, 3H, Ar-H), 7.19–7.29 (m, 5H, Ar-H), 7.30–7.35 (m, 5H,
Ar-H), 7.39–7.42 (m, 4H, Ar-H); MS: 534.3 ([M þ Na]ꢂþ); Anal. calc.
for: C31H26ClNO4 (511.16): C 72.51, H 5.39, N 2.96; found: C 72.72, H
5.12, N 2.74.
Yield: 22.7%. Yellow oil. IR (KBr): 3316, 2923, 1728, 1599, 1537,
1511, 1249, 1110, 834; 1H NMR (CDCl3): 2.31 (s, 3H, –CH3), 2.24–2.30
(m, 2H, –CH2–CH2–), 2.59–2.64 (m, 2H, –CH2–CH2–), 3.09–3.14 (m,
1H, –CH–CH–), 3.78 (s, 6H, –OCH3), 4.66 (d, J ¼ 2.0 Hz, 1H, –CHN–),
6.76–6.85 (m, 4H, Ar-H), 7.19–7.27 (m, 4H, Ar-H), 7.28–7.40 (m, 4H,
Ar-H), 7.79 (s, 1H, –NH–CO–); MS: 445.4 ([M þ H]þ); Anal. calc. for
C27H28N2O4 (444.20): C 72.73, H 6.49, N 6.41; found: C 72.95, H
6.35, N 6.30.
4.1.11. Trans-1-(6-Methylphenyl)-3-(3-hydroxy-3,3-
4.1.17. (3R,4S)-N-(4-Methylphenyl)-3-(3-[2-oxo-4-(4-
diphenylpropyl)-4-(4-methoxyphenyl)-2-azetidinone (3b)
Yield: 35.1%. White oil. IR (KBr): 3384, 1727, 1514, 1252, 1029, 749,
701; 1H NMR (CDCl3): 1.92–1.96 (m, 2H, –CH2CH2–), 2.44 (s, 3H,
–CH3), 2.64–2.69(m, 2H, –CH2CH2–), 3.15–3.21 (m,1H, –CHCH–), 3.77
methoxyphenyl)-1-phenyl-azetidinyl])propanamide (4b)
Yield: 19.1%. White crystals, m.p. 115–117 ꢁC. IR (KBr): 3332,
2927, 1737, 1669, 1598, 1513, 1386, 1249, 1178, 1033, 818, 754, 691;
1H NMR (CDCl3): 2.31 (s, 3H, –CH3), 2.22–2.27 (m, 2H, –CH2–CH2–),