M. Ohno et al. / Bioorg. Med. Chem. 14 (2006) 2005–2021
2013
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hexane); H NMR (300 MHz, CDCl3) d 2.60 (2H, m),
dles, mp 142–143 °C (recrystallized from ethyl acetate/
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3.27 (2H, t, J = 4 Hz), 3.37 (2H, m), 4.24 (2H, t,
J = 4 Hz), 4.61 (2H, s), 5.23 (1H, s), 6.10 (1H, dd,
J = 1, 8 Hz), 6.31 (1H, dd, J = 1, 8 Hz), 6.66 (1H, t,
J = 8 Hz), 7.22–7.37 (6H, m), 7.42–7.46 (4H, m); IR
(KBr) 1743 cmÀ1 (COOH); Mass (EI, m/e) 435 (M+);
Elemental analysis Calcd. for C25H25NO4S: C, 68.94;
H, 5.79; N, 3.22; S, 7.36. Found: C, 68.85; H, 5.77; N,
3.24; S, 7.25.
n-hexane); H NMR (300 MHz, CDCl3) d 2.02 (3H, s),
2.50 (2H, t, J = 7.6 Hz), 3.21 (2H, t, J = 7.6 Hz), 3.26
(2H, t, J = 7.6 Hz), 4.25 (2H, t, J = 4.4 Hz), 4.62 (2H,
s), 6.06 (1H, dd, J = 8.2, 1.1 Hz), 6.31 (1H, dd, J = 8.2,
1.1 Hz), 6.69 (1H, t, J = 8.2 Hz), 6.95–7.03 (4H, m),
7.33–7.40 (4H, m); IR (KBr) 1744 cmÀ1 (COOH); Mass
(EI, m/e) 485 (M+); Elemental analysis Calcd. for
C26H25F2NO4S: C, 64.32; H, 5.19; N, 2.88; S, 6.60.
Found: C, 64.22; H, 5.13; N, 2.99; S, 6.61.
4.11. (4-(2-(1-Methyl-1-phenylethylthio)ethyl)-3,4-dihy-
dro-2H-1,4-benzoxazin-8-yloxy)acetic acid (10d)
4.15. (4-(2-(1,1-bis-(3-Thienyl)ethylthio)ethyl)-3,4-dihy-
dro-2H-1,4-benzoxazin-8-yloxy)acetic acid (10h)
By the procedure used in 9a, compound 10d (271 mg,
78%) was prepared from 358 mg of 40d. Colorless nee-
dles, mp 114 °C (recrystallized from ethyl acetate/n-hex-
By the procedure used in 9a, compound 10h (161 mg,
91%) was prepared from 183 mg of 40h. Colorless gran-
ular, mp 149 °C (recrystallized from ethyl acetate/n-hex-
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ane); H NMR (300 MHz, CDCl3) d 1.72 (6H, s), 2.42
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(2H, m), 3.10 (2H, m), 3.19 (2H, t, J = 4.5 Hz), 4.22
(2H, t, J = 4.5 Hz), 4.60 (2H, s), 5.98 (1H, dd, J = 1,
8 Hz), 6.29 (1H, dd, J = 1, 8 Hz), 6.66 (1H, t,
J = 8 Hz), 7.24 (1H, m), 7.35 (2H, m), 7.56 (2H, m);
IR (KBr) 1744 cmÀ1 (COOH); Mass (EI, m/e) 387
(M+); Elemental analysis Calcd. for C21H25NO4S: C,
65.09; H, 6.50; N, 3.61; S, 8.27. Found: C, 64.72; H,
6.51; N, 3.57; S, 8.03.
ane); H NMR (300 MHz, CDCl3) d 2.05 (3H, s), 2.54
(2H, t, J = 7.4 Hz), 3.17 (2H, t, J = 7.4 Hz), 3.25 (2H,
t, J = 4.4 Hz), 4.25 (2H, t, J = 4.4 Hz), 4.62 (2H, s),
6.11 (1H, dd, J = 8.2, 1.1 Hz), 6.31 (1H, dd, J = 8.2,
1.1 Hz), 6.72 (1H, t, J = 8.2 Hz), 7.12 (2H, dd, J = 3.0,
1.4 Hz), 7.14 (2H, dd, J = 5.2, 1.4 Hz), 7.29 (2H, dd,
J = 5.2, 3.0 Hz); IR (KBr) 1744 cmÀ1 (COOH); Mass
(EI, m/e) 461 (M+); Elemental analysis Calcd. for
C22H23NO4S3: C, 57.24; H, 5.02; N, 3.03; S, 20.84.
Found: C, 56.84; H, 5.04; N, 3.03; S, 20.45.
4.12. (4-(2-(Benzylthio)ethyl)-3,4-dihydro-2H-1,4-benz-
oxazin-8-yloxy)acetic acid (10e)
4.16. (4-(2-(1,1-Diphenylethoxy)ethyl)-3,4-dihydro-2H-
1,4-benzoxazin-8-yloxy)acetic acid (10i)
By the procedure used in 40a, compound 39 (242 mg)
was coupled with phenylmethanethiol and the methyl es-
ter of the obtained sulfide was hydrolyzed by the proce-
dure used in 9a, to obtain compound 10e (199 mg, 61%).
Colorless needles, mp 127–131 °C (recrystallized from
By the procedure used in 9a, compound 10i (193 mg,
65%) was prepared from 308 mg of 45a. Colorless
granular, mp 108 °C (recrystallized from ethyl acetate/
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ethyl acetate/n-hexane); H NMR (300 MHz, CDCl3) d
n-hexane); H NMR (300 MHz, CDCl3) d 1.83 (3H, s),
2.61 (2H, t, J = 7.6 Hz), 3.30–3.38 (4H, m), 3.76 (2H,
s), 4.27 (2H, t, J = 4.4 Hz), 4.63 (2H, s), 6.25 (1H, dd,
J = 8.2, 1.1 Hz), 6.32 (1H, dd, J = 8.2, 1.1 Hz), 6.72
(1H, t, J = 8.2 Hz), 7.25–7.35 (5H, m); IR (KBr)
1742 cmÀ1 (COOH); Mass (EI, m/e) 359 (M+); Elemen-
tal analysis Calcd. for C19H21NO4S: C, 63.49; H, 5.89;
N, 3.90; S, 8.92. Found: C, 63.20; H, 5.90; N, 3.97; S,
8.78.
3.40–3.51 (6H, m), 4.27 (2H, t, J = 4.4 Hz), 4.63 (2H, s),
6.30 (1H, dd, J = 8.2, 1.1 Hz), 6.33 (1H, dd, J = 8.2,
1.1 Hz), 6.69 (1H, t, J = 8.2 Hz), 7.17–7.33 (10H, m);
IR (KBr) 1746 cmÀ1 (COOH); Mass (EI, m/e) 433
(M+); Elemental analysis Calcd. for C26H27NO5: C,
72.04; H, 6.28; N, 3.23. Found: C, 72.22; H, 5.98; N, 3.40.
4.17. (4-(4,4-Diphenylpentyl)-8-hydroxy-3-oxo-3,4-dihy-
dro-2H-1,4-benzoxazin-8-yloxy)acetic acid (10j)
4.13. (4-(2-(2,2-Diphenylpropylthio)ethyl)-3,4-dihydro-
2H-1,4-benzoxazin-8-yloxy)acetic acid (10f)
By the procedure used in 9a, compound 10j (249 mg,
79%) was prepared from 308 mg of 45b. Colorless gran-
ular, mp 133 °C (recrystallized from ethyl acetate/n-hex-
ane); 1H NMR (300 MHz, CDCl3) d 1.36–1.48 (2H, m),
1.63 (3H, s), 2.08–2.17 (2H, m), 3.16 (2H, t, J = 8.4 Hz),
3.21 (2H, t, J = 4.4 Hz), 4.25 (2H, t, J = 4.4 Hz), 4.62
(2H, s), 6.26 (1H, d, J = 8.5 Hz), 6.30 (1H, d,
J = 8.0 Hz), 6.71 (1H, t, J = 8.2 Hz), 7.16–7.22 (6H,
m), 7.23–7.31 (4H, m); IR (KBr) 1744 cmÀ1 (COOH);
Mass (EI, m/e) 431 (M+); Elemental analysis Calcd.
for C27H29NO4: C, 75.15; H, 6.77; N, 3.25. Found: C,
75.36; H, 6.81; N, 3.21.
By the procedure used in 9a, compound 10f (85 mg, 74%)
was prepared from 119 mg of 40f. Colorless needles, mp
138–139 °C (recrystallized from ethyl acetate/n-hexane);
1H NMR (300 MHz, CDCl3) d 1.78 (3H, s), 2.35 (2H,
t, J = 7.1 Hz), 3.24–3.33 (6H, m), 4.23 (2H, t,
J = 4.4 Hz), 4.62 (2H, s), 6.28–6.33 (2H, m), 6.76 (1H,
t, J = 8.2 Hz), 7.17–7.31 (10H, m); IR (KBr) 1746 cmÀ1
(COOH); Mass (EI, m/e) 463 (M+); Elemental analysis
Calcd. for C27H29NO4S: C, 69.95; H, 6.31; N, 3.02; S,
6.92. Found: C, 69.80; H, 6.22; N, 3.07; S, 6.78.
4.14. (4-(2-(1,1-bis-(4-Fluorophenyl)ethylthio)ethyl)-3,4-
dihydro-2H-1,4-benzoxazin-8-yloxy)acetic acid (10g)
4.18. (4-(2-(1,1-Diphenylethylsulfinyl)ethyl)-3,4-dihydro-
2H-1,4-benzoxazin-8-yloxy)acetic acid (10k)
By the procedure used in 9a, compound 10g (166 mg,
67%) was prepared from 254 mg of 40g. Colorless nee-
To a solution of (4-(2-(1,1-diphenylethylthio)ethyl)-3,4-
dihydro-2H-1,4-benzoxazin-8-yloxy)acetic acid 10a