A. Egorova et al. / European Journal of Medicinal Chemistry 188 (2020) 112007
11
7.75 (2H, s, H3, H5) ppm.
4.1.4.10. 3-(4-(3-(3-Carbethoxy-isoxazol-5-yl)propoxy)pyridin-3-yl)-
5-trifluoromethyl-1,2,4-oxadiazole 19. White solid, yield 10%, mp
45e48 ꢀC (hexane). Mass (EI), m/z (Irelat.(%)): 412.3200 [M]þ (62).
4.1.4.3. 3-(4-(3-(3-Carbethoxy-isoxazol-5-yl)propoxy)phenyl)-5-
trifluoromethyl-1,2,4-oxadiazole 6c. White solid, yield 58%, mp
71e75 ꢀC (EtOH). Mass (EI), m/z (Irelat.(%)): 411.3319 [M]þ (53).
C
17H15F3N4O5. 1H NMR (DMSO‑d6):
d
1.28 (3H, t, J ¼ 7.1, CH3CH2O),
2.18 (2H, dt, J ¼ 6.5, 7.6, CH2CH2CH2O), 3.00 (2H, t, J ¼ 7.6,
CH2CH2CH2O), 4.28 (2H, q, J ¼ 7.1, CH3CH2O), 4.45 (2H, t, J ¼ 6.5,
CH2CH2CH2O), 6.75 (1H, s, isoxazole), 7.01 (1H, d, J ¼ 7.8, H3), 8.29
(1H, dd, J ¼ 1.5, 7.8, H4), 8.80 (d, 1H, J ¼ 1.5, H6) ppm.
C
18H16F3N3O5. 1H NMR (DMSO‑d6):
d
1.31 (3H, t, J ¼ 7.1, CH3CH2O),
2.16 (2H, dt, J ¼ 6.5, 7.5 CH2CH2CH2O), 3.00 (2H, t, J ¼ 7.5,
CH2CH2CH2O), 4.14 (2H, t, J ¼ 6.5, CH2CH2CH2O), 4.35 (2H, q, J ¼ 7.1,
CH3CH2O), 6.76 (1H, s, isoxazole), 7.15 (2H, d, J ¼ 8.8, H2, H6), 8.00
(2H, d, J ¼ 8.8, H3, H5) ppm.
4.1.5. Synthesis of 3-(3,5-dimethyl-4-(3-(3-carbisopropoxy-
isoxazol-5-yl)propoxy)phenyl)-5-trifluoromethyl-1,2,4-oxadiazole 7
1) A solution of 6b (0.1 mmol) and LiOH (0.16 mmol) in ethanol-
water mixture (1:1) was stirred for 3 h at room temperature. Re-
action mixture was concentrated in vacuo. The remaining aqueous
solution was acidified by the addition of 6 M hydrochloric acid. The
precipitated white solid was collected and washed with water. The
acid obtained was used without other purification. 2) A solution of
acid obtained previously, one-two drops of H2SO4 and isopropanol
was refluxed for 4 h. After completion of reaction (monitored by
TLC) the reaction mixture was concentrated in vacuo. The precipi-
tate was collected, washed with water and recrystallized from
ethanol. White solid, yield 78%, mp 69e74 ꢀC (EtOH). Mass (EI), m/z
(Irelat.(%)): 453.4117 [M]þ (54). C21H22F3N3O5. 1H NMR (DMSO‑d6):
4.1.4.4. 3-(3-Methyl-4-(3-(3-carbethoxy-isoxazol-5-yl)propoxy)
phenyl)-5-trifluoromethyl-1,2,4-oxadiazole 6d. White solid, yield
91%, mp 66e68 ꢀC (EtOH). Mass (EI), m/z (Irelat.(%)): 425.3585 [M]þ
(47). C19H18F3N3O5. 1H NMR (DMSO‑d6):
d
1.27 (3H, t, J ¼ 7.1,
CH3CH2O), 2.15e2.25 (5H, m, CH2CH2CH2O, CH3Ph), 3.02 (2H, t,
J ¼ 7.5, CH2CH2CH2O), 4.18 (2H, t, J ¼ 6.5, CH2CH2CH2O), 4.35 (2H, q,
J ¼ 7.1, CH3CH2O), 6.78 (1H, s, isoxazole), 7.18 (1H, d, J ¼ 8.3, H6),
7.80e7.90 (2H, m, H3, H5) ppm.
4.1.4.5. 3-(3-Methoxy-4-(3-(3-carbethoxy-isoxazol-5-yl)propoxy)
phenyl)-5-trifluoromethyl-1,2,4-oxadiazole 6e. White solid, yield
64%, mp 75e77 ꢀC (EtOH). Mass (EI), m/z (Irelat.(%)): 441.3579 [M]þ
(45). C19H18F3N3O6. 1H NMR (DMSO‑d6):
d
1.31 (3H, t, J ¼ 7.1,
d
1.42 (6H, d, J ¼ 7.0, (CH3)2CH), 2.18 (2H, dt, J ¼ 6.5, 7.5,
CH3CH2O), 2.18 (2H, dt, J ¼ 6.5, 7.5, CH2CH2CH2O), 3.02 (2H, t,
J ¼ 7.5, CH2CH2CH2O), 3.86 (3H, s, CH3O), 4.13 (2H, t, J ¼ 6.5,
CH2CH2CH2O), 4.35 (2H, q, J ¼ 7.1, CH3CH2O), 6.78 (1H, s, isoxazole),
7.18 (1H, d, J ¼ 8.1, H3), 7.51 (1H, d, J ¼ 2.0, H6), 7.65 (1H, dd, J ¼ 2.0,
8.1, H4) ppm.
CH2CH2CH2O), 2.30 (6H, s, (CH3)2Ph), 3.11 (2H, t, 7.7,
CH2CH2CH2O), 3.84 (2H, t, J ¼ 6.5, CH2CH2CH2O), 4.87 (1H, sept,
J ¼ 7.0, (CH3)2CH), 6.80 (1H, s, isoxazole), 7.75 (2H, s, H3, H5) ppm.
J
¼
4.1.6. General procedure for the synthesis of compounds 9a-c
To a solution of NCS (2 mmol) and 1e2 drops of pyridine in DMF
was added a solution of the corresponding benzaldehyde oximes
8a-c (1 mmol) in DMF for 20 min and stirred for 1h at room tem-
perature, then to a solution was added a solution 4a in DMF for
20 min. To resulted mixture was added Et3N (2 mmol) in DMF for
1h at 80e90 ꢀC and stirred for 3e4h at 80e90 ꢀC. The reaction
mixture was diluted with water and extracted with ethyl acetate
(3-times). The combined organic phases were washed with water,
dried over anhydrous Na2SO4 and concentrated in vacuo. The res-
idue was recrystallized from the corresponding solvent.
4.1.4.6. 3-(3-Nitro-4-(3-(3-carbethoxy-isoxazol-5-yl)propoxy)
phenyl)-5-trifluoromethyl-1,2,4-oxadiazole 6f. White solid, yield
60%, mp 98e100 ꢀC (EtOH). Mass (EI), m/z (Irelat.(%)): 456.0893 [M]þ
(41). C18H15F3N4O7. 1H NMR (DMSO‑d6):
d
1.31 (3H, t, J ¼ 7.1,
CH3CH2O), 2.25 (2H, dt, J ¼ 6.5, 7.5, CH2CH2CH2O), 3.02 (2H, t,
J ¼ 7.5, CH2CH2CH2O), 4.35 (2H, q, J ¼ 7.1, CH3CH2O), 4.42 (2H, t,
J ¼ 6.5, CH2CH2CH2O), 6.75 (1H, s, isoxazole), 7.52 (1H, d, J ¼ 8.3,
H6), 8.26 (1H, dd, J ¼ 1.5, 8.3, H5), 8.50 (1H, d, J ¼ 1.5, H3) ppm.
4.1.4.7. 3-(3-Fluoro-4-(3-(3-carbethoxy-isoxazol-5-yl)propoxy)
phenyl)-5-trifluoromethyl-1,2,4-oxadiazole 6g. White solid, yield
57%, mp 68e75 ꢀC (EtOH). Mass (EI), m/z (Irelat.(%)): 429.3224 [M]þ
4.1.6.1. 3-(3,5-Dimethyl-4-(3-(3-phenylisoxazol-5-yl)propoxy)
phenyl)-5-(trifluoromethyl)-1,2,4-oxadiazole 9a. White solid, yield
24%, mp 74e76 ꢀC (hexane). Mass (EI), m/z (Irelat.(%)): 443.4184 [M]þ
(49). C18H15F4N3O5. 1H NMR (DMSO‑d6):
d
1.27 (3H, t, J ¼ 7.1,
CH3CH2O), 2.20 (2H, dt, J ¼ 6.5, 7.5, CH2CH2CH2O), 3.01 (2H, t,
J ¼ 7.5, CH2CH2CH2O), 4.24 (2H, t, J ¼ 6.5, CH2CH2CH2O), 4.36 (2H, q,
J ¼ 7.1, CH3CH2O), 6.78 (1H, s, isoxazole), 7.45 (1H, t, J ¼ 8.6, H3),
7.79e7.91 (2H, m, H4, H6) ppm.
(54). C23H20F3N3O3. 1H NMR (DMSO‑d6):
d
2.20 (2H, dt, J ¼ 6.5, 7.5,
CH2CH2CH2O), 2.30 (6H, s, (CH3)2Ph), 3.10 (2H, t, 7.5,
J
¼
CH2CH2CH2O), 3.92 (2H, t, J ¼ 6.5, CH2CH2CH2O), 6.93 (1H, s, iso-
xazole), 7.50 (2H, m, m-Ph, p-Ph), 7.75 (2H, s, H3, H5), 7.90 (2H, m,
o-Ph) ppm.
4.1.4.8. 3-(3-Trifluoromethyl-4-(3-(3-carbethoxy-isoxazol-5-yl)pro-
poxy)phenyl)-5-trifluoromethyl-1,2,4-oxadiazole 6h. White solid,
yield 99%, mp 76e78 ꢀC (EtOH). Mass (EI), m/z (Irelat.(%)): 479.3299
4.1.6.2. 3-(4-(3-(3-(3,4-Dimethoxyphenyl)isoxazol-5-yl)propoxy)-
3,5-dimethylphenyl)-5-(trifluoromethyl)-1,2,4-oxadiazole
9b.
[M]þ (46). C19H15F6N3O5. 1H NMR (DMSO‑d6):
d
1.31 (3H, t, J ¼ 7.1,
White solid, yield 38%, mp 112e114 ꢀC (EtOH). Mass (EI), m/z (Ire-
CH3CH2O), 2.17 (2H, dt, J ¼ 6.5, 7.5, CH2CH2CH2O), 3.01 (2H, t, J ¼ 7.6,
CH2CH2CH2O), 4.25e4.40 (4H, m, CH2CH2CH2O, CH3CH2O), 6.75
(1H, s, isoxazole), 7.51 (1H, d, J ¼ 8.0, H6), 8.20 (1H, s, H3), 8.32 (1H,
d, J ¼ 8.0, H5) ppm.
lat.(%)): 503.4704 [M]þ (67). C25H24F3N3O5. 1H NMR (DMSO‑d6):
d
2.23 (2H, dt, J ¼ 6.5, 7.5, CH2CH2CH2O), 2.30 (6H, s, (CH3)2Ph), 3.14
(2H, t, J ¼ 7.5, CH2CH2CH2O), 3.80 (3H, s, CH3O), 3.85 (3H, s, CH3O),
3.92 (2H, t, J ¼ 6.5, CH2CH2CH2O), 6.83 (1H, s, isoxazole), 7.08 (1H, d,
J ¼ 8.0, H20), 7.41 (1H, d, J ¼ 1.5, H60), 7.44 (1H, dd, J ¼ 1.5, 8.0, H5’),
7.75 (2H, s, H3, H5) ppm.
4.1.4.9. 3-(3-Methoxy-5-nitro-4-(3-(3-carbethoxy-isoxazol-5-yl)pro-
poxy)phenyl)-5-trifluoromethyl-1,2,4-oxadiazole 6i. White solid,
yield 100%, mp 48e50 ꢀC (EtOH). Mass (EI), m/z (Irelat.(%)): 486.3555
4.1.6.3. 3-(3,5-Dimethyl-4-(3-(3-(4-(trifluoromethoxy)phenyl)iso-
xazol-5-yl)propoxy)phenyl)-5-(trifluoromethyl)-1,2,4-oxadiazole 9c.
White solid, yield 39%, mp 65e67 ꢀC (EtOH/H2O). Mass (EI), m/z
(Irelat.(%)): 527.4158 [M]þ (49). C24H19F6N3O4. 1H NMR (DMSO‑d6):
[M]þ (53). C19H17F3N4O8. 1H NMR (DMSO‑d6):
d
1.32 (3H, t, J ¼ 7.1,
CH3CH2O), 2.13 (2H, dt, J ¼ 6.5, 7.5, CH2CH2CH2O), 3.01 (2H, t, J ¼ 7.5,
CH2CH2CH2O), 4.01 (3H, s, CH3O), 4.24 (2H, t, J ¼ 6.5, CH2CH2CH2O),
4.36 (2H, q, J ¼ 7.1, CH3CH2O), 6.74 (1H, s, isoxazole), 7.86 (1H, d,
J ¼ 2.0, H3), 8.08 (1H, d, J ¼ 2.0, H5) ppm.
d
2.22 (2H, dt, J ¼ 6.5, 7.7, CH2CH2CH2O), 2.30 (6H, s, (CH3)2Ph), 3.10
(2H, t, J ¼ 7.7, CH2CH2CH2O), 3.94 (2H, t, J ¼ 6.5, CH2CH2CH2O), 6.93