106
Vol. 50, No. 1
Takeda Analytical Research Laboratories, Ltd. and results obtained were (4H, m), 7.95—8.1 (2H, m). Anal. Calcd for C22H19N5O2: C, 68.56; H, 4.97;
within Ϯ0.4% of the theoretical values. Column chromatography was per- N, 18.17. Found: C, 68.53; H, 4.96; N, 18.11. 47; 1H-NMR (dimethyl sulfox-
formed using SiO2 (Merck Kieselgel 60, 70—230 mesh).
General Procedure for Method A. 5-[2-[4-[2-(5-Methyl-2-phenyl-4-ox- 2.87 (2H, t, Jϭ7.5 Hz), 5.01 (2H, s), 6.99 (2H, d, Jϭ8.5 Hz), 7.16 (2H, d,
azolyl)ethoxy]phenyl]ethyl]-1H-tetrazole (31) A mixture of 3-[4-[2-(5- Jϭ8.5 Hz), 7.55—7.7 (2H, m), 7.9—8.15 (4H, m), 8.54 (1H, s). Anal. Calcd
ide (DMSO)-d6) d: 1.9—2.1 (2H, m), 2.49 (3H, s), 2.59 (2H, t, Jϭ7.5 Hz),
methyl-2-phenyl-4-oxazolyl)ethoxy]phenyl]propionitrile (14a, 700 mg, 2.1
for C25H23N5O2: C, 70.57; H, 5.44; N, 16.46. Found: C, 70.38; H, 5.41; N,
mmol), sodium azide (411 mg, 6.3 mmol), ammonium chloride (337 mg, 6.3 16.59. 48; 1H-NMR (CDCl3) d: 1.95—2.15 (2H, m), 2.45 (3H, s), 2.58 (2H,
mmol), and DMF (15 ml) was stirred at 120 °C for 24 h, poured into water t, Jϭ7 Hz), 2.86 (2H, t, Jϭ8 Hz), 4.93 (2H, s), 6.53 (1H, dd, Jϭ3, 1.5 Hz),
and extracted with AcOEt. The extract was washed with water, dried 6.74 (2H, d, Jϭ8.5 Hz), 6.93 (2H, d, Jϭ8.5 Hz), 7.00 (1H, d, Jϭ3 Hz), 7.48
(MgSO4), and concentrated in vacuo to give the title compound (31, 380 mg,
(1H, d, Jϭ1.5 Hz). Anal. Calcd for C19H19N5O3·1/4H2O: C, 61.70; H, 5.31;
1
48%). H-NMR (CDCl3) d: 2.39 (3H, s), 2.8—3.2 (6H, m), 4.15 (2H, t, Jϭ N, 18.93. Found: C, 61.86; H, 5.22; N, 19.07. 49; 1H-NMR (CDCl3) d:
6.5 Hz), 6.65 (2H, d, Jϭ8.5 Hz), 6.85 (2H, d, Jϭ8.5 Hz), 7.35—7.5 (3H, m),
7.9—8.0 (2H, m). Anal. Calcd for C20H19N5O2: C, 66.47; H, 5.30; N, 19.38.
Found: C, 66.52; H, 5.40; N, 18.98. Compounds 29, 30, 32—41, 43, 45—
2.0—2.2 (2H, m), 2.50 (3H, s), 2.59 (2H, t, Jϭ7 Hz), 2.90 (2H, t, Jϭ7.5 Hz),
4.97 (2H, s), 6.74 (2H, d, Jϭ8.5 Hz), 6.93 (2H, d, Jϭ8.5 Hz), 7.25—7.7 (5H,
m). Anal. Calcd for C23H21N5O3·1/4H2O: C, 65.78; H, 5.16; N, 16.68.
1
50, 52—55, and 58—61 were obtained similarly. The yields, recrystalliza- Found: C, 65.75; H, 5.28; N, 16.82. 50; H-NMR (CDCl3) d: 1.5—1.8 (4H,
tion solvents, and melting points were listed in Table 1. 29; 1H-NMR m), 2.46 (3H, s), 2.50 (2H, t, Jϭ7 Hz), 2.94 (2H, t, Jϭ7.5 Hz), 5.02 (2H, s),
(CDCl3) d: 2.39 (3H, s), 2.85—3.0 (4H, m), 3.12 (2H, t, Jϭ7 Hz), 4.15 (2H, 6.65—6.8 (2H, m), 6.89 (1H, t, Jϭ8.5 Hz), 7.35—7.5 (3H, m), 7.9—8.0
t, Jϭ6.5 Hz), 6.65 (2H, d, Jϭ8.5 Hz), 6.85 (2H, d, Jϭ8.5 Hz), 7.35—7.5 (2H, m). Anal. Calcd for C22H22FN5O2: C, 64.85; H, 5.44; N, 17.19. Found:
(3H, m), 7.85—8.0 (2H, m). Anal. Calcd for C21H21N5O2: C, 67.18; H, 5.64; C, 64.67; H, 5.16; N, 17.21. 52; 1H-NMR (CDCl3) d: 1.9—2.15 (2H, m),
N, 18.65. Found: C, 67.11; H, 5.62; N, 18.56. 30; 1H-NMR (CDCl3) d: 2.49 (3H, s), 2.54 (2H, t, Jϭ7 Hz), 2.89 (2H, t, Jϭ7.5 Hz), 5.26 (2H, s), 6.55
1.95—2.13 (2H, m), 2.30 (3H, s), 2.56—2.70 (2H, m), 3.87—3.96 (2H, m),
4.16 (2H, s), 6.60—6.72 (2H, m), 6.96—7.06 (2H, m), 7.34—7.46 (3H, m),
(1H, d, Jϭ8.5 Hz), 7.25 (1H, dd, Jϭ8.5, 2 Hz), 7.35—7.5 (3H, m), 7.79 (1H,
d, Jϭ2 Hz), 7.9—8.0 (2H, m). Anal. Calcd for C20H20N6O2: C, 63.82; H,
5.36; N, 22.33. Found: C, 63.75; H, 5.35; N, 22.56. 53; 1H-NMR (CDCl3) d:
7.80—7.92 (2H, m). Anal. Calcd for C21H21N5O2: C, 67.18; H, 5.64; N,
1
18.65. Found: C, 67.09; H, 5.72; N, 18.43. 32; H-NMR (CDCl3) d: 1.85— 1.5—1.8 (4H, m), 2.47 (2H, t, Jϭ6.5 Hz), 2.49 (3H, s), 2.96 (2H, t,
2.05 (2H, m), 2.40 (3H, s), 2.51 (2H, t, Jϭ7.5 Hz), 2.74 (2H, t, Jϭ7.5 Hz), Jϭ7.5 Hz), 5.26 (2H, s), 6.55 (1H, d, Jϭ8.5 Hz), 7.23 (1H, dd, Jϭ8.5, 2 Hz),
2.98 (2H, t, Jϭ6.5 Hz), 4.20 (2H, t, Jϭ6.5 Hz), 6.69 (2H, d, Jϭ8.5 Hz), 6.90
7.35—7.5 (3H, m), 7.79 (1H, d, Jϭ2 Hz), 7.9—8.0 (2H, m). Anal. Calcd for
(2H, d, Jϭ8.5 Hz), 7.35—7.45 (3H, m), 7.85—8.0 (2H, m). Anal. Calcd for C21H22N6O2: C, 64.60; H, 5.68; N, 21.52. Found: C, 64.42; H, 5.47; N,
C22H23N5O2: C, 67.85; H, 5.95; N, 17.98. Found: C, 67.60; H, 6.03; N,
21.57. 54; 1H-NMR (CDCl3) d: 1.85—2.1 (2H, m), 2.53 (2H, t, Jϭ7 Hz),
17.74. 33; 1H-NMR (CDCl3) d: 1.4—1.6 (4H, m), 2.40 (3H, s), 2.46 (2H, t, 2.56 (3H, s), 2.77 (2H, t, Jϭ7.5 Hz), 5.10 (2H, s), 6.77 (2H, d, Jϭ9 Hz),
Jϭ6.5 Hz), 2.78 (2H, t, Jϭ7.5 Hz), 2.98 (2H, t, Jϭ6.5 Hz), 4.20 (2H, t, 6.90 (2H, d, Jϭ9 Hz), 7.35—7.5 (3H, m), 7.75—7.9 (2H, m). Anal. Calcd
Jϭ6.5 Hz), 6.67 (2H, d, Jϭ8.5 Hz), 6.90 (2H, d, Jϭ8.5 Hz), 7.35—7.5 (3H,
m), 7.85—8.0 (2H, m). Anal. Calcd for C23H25N5O2: C, 68.47; H, 6.25; N, 17.74. 55; 1H-NMR (CDCl3) d: 1.9—2.1 (2H, m), 2.54 (2H, t, Jϭ7 Hz),
2.82 (2H, t, Jϭ7.5 Hz), 4.02 (3H, s), 5.23 (2H, s), 6.79 (2H, d, Jϭ8.5 Hz),
for C21H21N5O2S: C, 64.43; H, 5.41; N, 17.89. Found: C, 64.24; H, 5.40; N,
17.36. Found: C, 68.54; H, 6.26; N, 17.15. 34; 1H-NMR (CDCl3) d: 2.42
(3H, s), 2.99 (2H, t, Jϭ6.5 Hz), 4.20 (2H, t, Jϭ6.5 Hz), 6.77 (2H, d, 6.94 (2H, d, Jϭ8.5 Hz), 7.35—7.5 (3H, m), 7.95—8.1 (2H, m). Anal. Calcd
Jϭ9 Hz), 6.96 (1H, d, Jϭ16.5 Hz), 7.31 (2H, d, Jϭ9 Hz), 7.35—7.5 (3H, m), for C20H21N7O: C, 63.98; H, 5.64; N, 26.12. Found: C, 63.87; H, 5.52; N,
1
7.65 (2H, d, Jϭ16.5 Hz), 7.9—8.05 (2H, m). Anal. Calcd for C21H19N5O2: C,
26.03. 58; H-NMR (CDCl3) d: 1.45—1.75 (4H, m), 2.50 (2H, t, Jϭ7 Hz),
1
67.55; H, 5.13; N, 18.75. Found: C, 67.20; H, 5.21; N, 18.19. 35; H-NMR 2.56 (3H, s), 2.80 (2H, t, Jϭ7 Hz), 5.14 (2H, s), 6.5—6.6 (2H, m), 6.81 (2H,
(CDCl3) d: 2.22 (3H, s), 2.36 (3H, s), 2.82 (2H, t, Jϭ6.5 Hz), 2.85—3.15 d, Jϭ8.5 Hz), 6.95 (2H, d, Jϭ8.5 Hz), 7.3—7.45 (3H, m), 7.55—7.65 (2H,
(4H, m), 4.11 (2H, t, Jϭ6.5 Hz), 6.77 (2H, d, Jϭ8.5 Hz), 7.09 (2H, d, m). Anal. Calcd for C22H23N5O2: C, 67.85; H, 5.95; N, 17.98. Found: C,
Jϭ8.5 Hz). Anal. Calcd for C16H18N5O2Na·1/2H2O: C, 55.81; H, 5.56; N, 67.51; H, 5.99; N, 17.79. 59; 1H-NMR (DMSO-d6) d: 2.48 (3H, s), 5.08
1
20.34. Found: C, 56.01; H, 5.82; N, 20.68. 36; H-NMR (CDCl3) d: 1.15— (2H, s), 7.12 (2H, d, Jϭ8.5 Hz), 7.16 (1H, d, Jϭ16.5 Hz), 7.45—7.55 (3H,
2.1 (10H, m), 2.26 (3H, s), 2.71 (1H, tt, Jϭ11, 3.5 Hz), 2.85 (2H, t, Jϭ6.5
m), 7.61 (1H, d, Jϭ16.5 Hz), 7.68 (2H, d, Jϭ8.5 Hz), 7.9—8.0 (2H, m).
Hz), 2.95—3.3 (4H, m), 4.04 (2H, t, Jϭ6.5 Hz), 6.64 (2H, d, Jϭ8.5 Hz), Anal. Calcd for C20H17N5O2: C, 66.84; H, 4.77; N, 19.49. Found: C, 66.50;
1
6.93 (2H, d, Jϭ8.5 Hz). Anal. Calcd for C21H27N5O2: C, 66.12; H, 7.13; N,
H, 4.75; N, 19.46. 60; H-NMR (DMSO-d6) d: 2.48 (3H, s), 5.06 (2H, s),
18.36. Found: C, 66.14; H, 7.41; N, 18.39. 37; 1H-NMR (CDCl3) d: 2.38 6.75—7.05 (3H, m), 7.15—7.55 (8H, m), 7.9-8.0 (2H, m). Anal. Calcd for
(6H, s), 2.8—3.2 (6H, m), 4.15 (2H, t, Jϭ6.5 Hz), 6.64 (2H, d, Jϭ9 Hz), C22H19N5O2: C, 68.56; H, 4.97; N, 18.17. Found: C, 68.24; H, 4.64; N,
6.84 (2H, d, Jϭ9 Hz), 7.23 (1H, br d, Jϭ8 Hz), 7.31 (1H, t, Jϭ7.5 Hz), 7.7— 17.99. 61; H-NMR (DMSO-d6) d: 2.46 (3H, s), 5.11 (2H, s), 6.72 (1H, d,
7.8 (2H, m). Anal. Calcd for C22H23N5O2: C, 67.85; H, 5.95; N, 17.97. Jϭ15.5 Hz), 6.95—7.7 (10H, m), 7.9—8.05 (2H, m). Anal. Calcd for
1
1
Found: C, 68.13; H, 6.14; N, 18.26. 38; H-NMR (CDCl3) d: 2.41 (3H, s), C22H19N5O2: C, 68.56; H, 4.97; N, 18.17. Found: C, 68.25; H, 4.91; N,
2.8—3.2 (6H, m), 4.16 (2H, t, Jϭ6.5 Hz), 6.67 (2H, d, Jϭ8.5 Hz), 6.87 (2H, 18.33.
d, Jϭ8.5 Hz), 7.25—7.5 (3H, m), 7.8—7.9 (2H, m). Anal. Calcd for
General Procedure for Method B. 5-[2-[4-(5-Methyl-2-phenyl-4-oxa-
C21H20ClN5O2: C, 61.54; H, 4.92; N, 17.09. Found: C, 61.53; H, 4.89; N, zolylmethoxy)phenyl]ethyl]-1H-tetrazole (42) A mixture of 5-[2-[4-(5-
17.24. 39; 1H-NMR (DMSO-d6) d: 2.32 (3H, s), 2.8—3.2 (6H, m), 4.14
(2H, t, Jϭ6.5 Hz), 6.82 (2H, d, Jϭ8.5 Hz), 7.09 (2H, d, Jϭ8.5 Hz), 7.19 (1H,
methyl-2-phenyl-4-oxazolylmethoxy)phenyl]vinyl]-1H-tetrazole (59, 1.00 g,
2.8 mmol), 5% Pd–C (50% wet, 0.50 g), and 1,4-dioxane (100 ml) was hy-
dd, Jϭ5, 3.5 Hz), 7.58 (1H, dd, Jϭ3.5, 1 Hz), 7.70 (1H, dd, Jϭ5, 1 Hz). drogenated at 1 atm. After removal of the catalyst by filtration and the filtrate
Anal. Calcd for C19H19N5O2S: C, 59.83; H, 5.02; N, 18.36. Found: C, 59.78;
was concentrated in vacuo to give the title compound (42, 810 mg, 81%).
1
H, 4.96; N, 18.18. 40; H-NMR (CDCl3) d: 2.34 (3H, s), 2.85—3.05 (4H, 1H-NMR (CDCl3) d: 2.46 (3H, s), 2.95—3.3 (4H, m), 4.93 (2H, s), 6.82
m), 3.18 (2H, t, Jϭ7 Hz), 4.43 (2H, t, Jϭ6.5 Hz), 6.52 (1H, d, Jϭ8.5 Hz), (2H, d, Jϭ8.5 Hz), 6.96 (2H, d, Jϭ8.5 Hz), 7.4—7.5 (3H, m), 7.95—8.1
7.23 (1H, dd, Jϭ8.5, 2.5 Hz), 7.35—7.5 (3H, m), 7.79 (1H, d, Jϭ2.5 Hz), (2H, m). Anal. Calcd for C20H19N5O2: C, 66.47; H, 5.30; N, 19.38. Found: C,
7.85—8.0 (2H, m). Anal. Calcd for C20H20N5O2S: C, 63.82; H, 5.36; N, 66.30; H, 5.33; N, 19.25. Compounds 44, 51, 56, and 57 were obtained simi-
22.33. Found: C, 63.53; H, 5.33; N, 22.23. 41; 1H-NMR (CDCl3) d: 2.45 larly. The yields, recrystallization solvents, and melting points were listed in
1
(3H, s), 4.17 (2H, s), 4.87 (2H, s), 6.74 (2H, d, Jϭ8.5 Hz), 7.04 (2H, d, Table 1. 44; H-NMR (CDCl3) d: 1.5—1.8 (4H, m), 2.45 (3H, s), 2.49 (2H,
Jϭ8.5 Hz), 7.35—7.5 (3H, m), 7.9—8.0 (2H, m). Anal. Calcd for t, Jϭ7 Hz), 2.91 (2H, t, Jϭ7.5 Hz), 4.92 (2H, s), 6.75 (2H, d, Jϭ8.5 Hz),
C19H17N5O2: C, 65.70; H, 4.93; N, 20.16. Found: C, 65.65; H, 4.77; N,
6.93 (2H, d, Jϭ8.5 Hz), 7.35—7.5 (3H, m), 7.9—8.05 (2H, m). Anal. Calcd
20.18. 43; 1H-NMR (CDCl3) d: 1.15—1.35 (2H, m), 1.45—1.85 (4H, m), for C22H23N5O2: C, 67.85; H, 5.95; N, 17.98. Found: C, 67.39; H, 5.80; N,
2.46 (3H, s), 2.48 (2H, t, Jϭ7.5 Hz), 2.92 (2H, t, Jϭ7.5 Hz), 4.96 (2H, s), 17.70. 51; 1H-NMR (CDCl3) d: 1.5—1.85 (4H, m), 2.44 (3H, s), 2.50 (2H, t,
6.81 (2H, d, Jϭ8.5 Hz), 6.98 (2H, d, Jϭ8.5 Hz), 7.4—7.5 (3H, m), 7.95—
8.05 (2H, m). Anal. Calcd for C21H21N5O2: C, 67.18; H, 5.64; N, 18.65.
Found: C, 67.15; H, 5.96; N, 18.56. 45; 1H-NMR (CDCl3) d: 1.95—2.15
Jϭ7.5 Hz), 2.91 (2H, t, Jϭ7.5 Hz), 3.73 (3H, s), 4.98 (2H, s), 6.5—6.6 (2H,
m), 6.80 (1H, d, Jϭ8 Hz), 7.35—7.5 (3H, m), 7.85—8.05 (2H, m). Anal.
Calcd for C23H25N5O3: C, 65.86; H, 6.01; N, 16.70. Found: C, 65.59; H,
(2H, m), 2.47 (3H, s), 2.57 (2H, t, Jϭ7 Hz), 2.83 (2H, t, Jϭ8 Hz), 4.93 (2H, 5.92; N, 16.73. 56; 1H-NMR (CDCl3) d: 1.5—1.8 (4H, m), 2.46 (3H, s),
s), 6.74 (2H, d, Jϭ9 Hz), 6.92 (2H, d, Jϭ9 Hz), 7.4—7.5 (3H, m), 7.9—8.05 2.50 (2H, t, Jϭ6.5 Hz), 2.92 (2H, t, Jϭ7.5 Hz), 4.94 (2H, s), 6.53 (1H, br t,
(2H, m). Anal. Calcd for C23H25N5O2: C, 68.47; H, 6.25; N, 17.36. Found: C,
Jϭ1.5 Hz), 6.65—6.8 (2H, m), 7.13 (1H, t, Jϭ8 Hz), 7.4—7.5 (3H, m),
7.9—8.0 (2H, m). Anal. Calcd for C22H231N5O2: C, 67.85; H, 5.95; N, 17.98.
68.36; H, 6.34; N, 17.50. 46; 1H-NMR (CDCl3) d: 2.49 (3H, s), 4.99 (2H, s),
6.45—6.75 (3H, m), 6.94 (2H, d, Jϭ9 Hz), 7.34 (2H, d, Jϭ9 Hz), 7.4—7.55 Found: C, 67.58; H, 6.07; N, 17.99. 57; H-NMR (DMSO-d6) d: 1.45—1.8