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M. Yoshida et al. / Bioorg. Med. Chem. 18 (2010) 8501–8511
5.1.14. Ethyl 5-(4-ethyphenyl)-7-(trifluoromethyl)-4,5,6,7-
tetrahydropyrazolo-[1,5-a]pyrimidine-3-carboxylate (7f)
Compound 7f was prepared in a manner similar to that de-
5.1.21. 5-(4-Chlorophenyl)-7-(trifluoromethyl)-4,5,6,7-
tetrahydropyrazolo[1,5-a]-pyrimidine-3-carboxylic acid (8d)
Compound 8d was prepared in a manner similar to that de-
scribed for 8a. Yield 83%, mp 186–187 °C. 1H NMR (CDCl3): d
2.25–2.43 (1H, m), 2.50–2.60 (1H, m), 4.59 (1H, dd, J = 10.8,
2.8 Hz), 4.79–4.90 (1H, m), 6.07 (1H, br s), 7.36–7.45 (4H, m),
7.78 (1H, s). Anal. Calcd for C14H11N3O2ClF3: C, 48.68; H, 3.21; N,
12.15. Found: C, 48.53; H, 3.09; N, 11.98.
scribed for 7a. Yield 73%. 1H NMR (CDCl3):
d 1.26 (3H, t,
J = 7.6 Hz), 1.32 (3H, t, J = 7.0 Hz), 2.26–2.45 (1H, m), 2.48–2.60
(1H, m), 2.68 (2H, q, J = 7.4 Hz), 4.25 (2H, q, J = 7.4 Hz), 4.55 (1H,
dd, J = 11.2, 2.8 Hz), 4.75–4.89 (1H, m), 6.11 (1H, br s), 7.25 (2H,
d, J = 8.4 Hz), 7.36 (2H, d, J = 8.0 Hz), 7.73 (1H, s).
5.1.22. 5-(4-Methoxyphenyl)-7-(trifluoromethyl)-4,5,6,7-
tetrahydropyrazolo[1,5-a]-pyrimidine-3-carboxylic acid (8e)
Compound 8e was prepared in a manner similar to that de-
scribed for 8a. Yield 91%, mp 154.5–155.1 °C. 1H NMR (CDCl3): d
2.25–2.43 (1H, m), 2.45–2.60 (1H, m), 3.83 (3H, s), 4.50–4.58
(1H, m), 4.78–4.89 (1H, m), 6.03 (1H, br s), 6.94 (2H, d,
J = 8.4 Hz), 7.35 (2H, d, J = 8.8 Hz), 7.77 (1H, s). Anal. Calcd for
5.1.15. Ethyl 5-(2-furanyl)-7-(trifluoromethyl)-4,5,6,7-
tetrahydropyrazolo[1,5-a]-pyrimidine-3-carboxylate (7g)
Compound 7g was prepared in a manner similar to that de-
scribed for 7a. Yield 88%, mp 85.9–86.0 °C. 1H NMR (CDCl3): d
1.34 (3H, t, J = 7.2 Hz), 2.48–2.72 (4H, m), 4.27 (2H, q, J = 7.0 Hz),
4.68–4.88 (2H, m), 6.23 (1H, br s), 6.36–6.41 (2H, m, J = 7.2 Hz),
7.44 (1H, dd, J = 1.0 Hz), 7.72 (1H, s). Anal. Calcd for C14H14N3O3F3:
C, 51.07; H, 4.29; N, 12.76. Found: C, 51.13; H, 4.26; N, 12.99.
C15H14N3O3F3ꢀ0.3H2O: C, 51.97; H, 4.24; N, 12.12. Found: C,
51.95; H, 4.31; N, 12.13.
5.1.23. 5-(4-Ethyphenyl)-7-(trifluoromethyl)-4,5,6,7-
5.1.16. Ethyl 7-methyl-5-phenyl-4,5,6,7-
tetrahydropyrazolo[1,5-a]-pyrimidine-3-carboxylic acid (8f)
Compound 8f was prepared in a manner similar to that de-
scribed for 8a. Yield 74%, mp 165–168 °C. 1H NMR (CDCl3): d 1.25
(3H, t, J = 7.5 Hz), 2.26–2.45 (1H, m), 2.48–2.60 (1H, m), 2.68 (2H,
q, J = 7.6 Hz), 4.56 (2H, dd, J = 11.6, 2.8 Hz), 4.75–4.90 (1H, m),
6.06 (1H, br s), 7.25 (2H, d, J = 8.6 Hz), 7.35 (2H, d, J = 8.0 Hz),
7.77 (1H, s). Anal. Calcd for C16H16N3O2F3: C, 56.64; H, 4.75; N,
12.38. Found: C, 56.62; H, 4.98; N, 12.56.
tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxylate (7k)
Compound 7k was prepared in a manner similar to that de-
scribed for 7a. Yield 96%. 1H NMR (CDCl3):
d 1.31 (3H, t,
J = 6.9 Hz), 1.60 (3H, d, J = 6.3 Hz), 1.95–2.07 (1H, m), 2.30–2.37
(1H, m), 4.24 (2H, q, J = 10.8 Hz), 4.22–4.38 (1H, m), 4.58 (1H, dd,
J = 11.1, 3.0 Hz), 5.95 (1H, br s), 7.32–7.45 (5H, m), 7.65 (1H, s).
5.1.17. Ethyl 5-methyl-7-phenyl-4,5,6,7-
tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxylate (7l)
Compound 7l was prepared in a manner similar to that de-
5.1.24. 5-(2-Furanyl)-7-(trifluoromethyl)-4,5,6,7-
tetrahydropyrazolo[1,5-a]pyrimi-dine-3-carboxylic acid (8g)
Compound 8g was prepared in a manner similar to that de-
scribed for 8a. Yield 92%, mp 156–157 °C; 1H NMR (CDCl3): d
2.50–2.72 (4H, m), 4.71–4.91 (2H, m), 6.19 (1H, br s), 6.38–6.43
(2H, m), 7.45 (1H, dd, J = 1.8, 1.0 Hz), 7.78 (1H, s). Anal. Calcd for
scribed for 7a. Yield 78%, 1H NMR (CDCl3):
d 1.34 (3H, t,
J = 7.0 Hz), 1.92–2.10 (1H, m), 2.30–2.41 (1H, m), 3.65–3.78 (1H,
m), 4.27 (2H, q, J = 7.0 Hz), 5.17 (1H, dd, J = 11.4, 5.2 Hz), 5.79
(1H, br s), 7.18–7.42 (5H, m), 7.59 (1H, s).
C12H10N3O3F3: C, 47.85; H, 3.35; N, 13.95. Found: C, 47.99; H,
3.44; N, 13.86.
5.1.18. 5-Phenyl-7-(trifluoromethyl)-4,5,6,7-
tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxylic acid (8a)
A mixture of 7a (2.2 g, 6.5 mmol), 1.5 N KOH solution (14 mL,
21 mmol) in EtOH (20 mL) was stirred at 60 °C for 12 h, acidified
with saturated citric acid solution, and the precipitated solid was
collected by filtration, which was washed with water and IPE to
give the title compound (1.59 g, 76%) as colorless prisms, mp
202–204 °C; 1H NMR (CDCl3): d 2.31–2.44 (1H, m), 2.50–2.59
(1H, m), 4.59 (1H, dd, J = 11.4, 3.0 Hz), 4.79 (1H, m), 6.10 (1H, s),
7.20–7.26 (5H, m), 7.78 (1H, s). Anal. Calcd for C14H12F3N3O2: C,
54.02; H, 3.89; N, 13.50. Found: C, 54.05; H, 3.82; N, 13.67.
5.1.25. 7-Methyl-5-phenyl-4,5,6,7-tetrahydropyrazolo[1,5-
a]pyrimidine-3-carboxyli-c acid (8k)
Compound 8k was prepared in a manner similar to that de-
scribed for 8a. Yield 83%, mp 165–167 °C. 1H NMR (CDCl3): d 1.60
(3H, d. J = 6.3 Hz), 1.94–2.06 (1H, m), 2.30–2.37 (1H, m), 4.26–
4.36 (1H, m), 4.58 (1H, dd, J = 11.1, 3.0 Hz), 5.91 (1H, br s), 7.32–
7.42 (5H, m), 7.69 (1H, s). Anal. Calcd for C14H15N3O2: C, 65.35;
H, 5.88; N, 16.33. Found: C, 65.28; H, 6.13; N, 16.36.
5.1.26. 5-Methyl-7-phenyl-4,5,6,7-tetrahydropyrazolo[1,5-
a]pyrimidine-3-carboxyli-c acid (8l)
5.1.19. 5-(2-Chlorophenyl)-7-(trifluoromethyl)-4,5,6,7-
tetrahydropyrazolo[1,5-a]-pyrimidine-3-carboxylic acid (8b)
Compound 8b was prepared in a manner similar to that de-
scribed for 8a. Yield 88%, mp 177–179 °C. 1H NMR (DMSO-d6): d
2.09–2.17 (1H, m), 2.54–2.65 (1H, m), 5.02–5.08 (1H, m), 5.33–
5.44 (1H, m), 6.76 (1H, br s), 7.32–7.52 (3H, m), 7.59–7.63 (1H,
m), 7.64 (1H, s). Anal. Calcd for C14H11N3O2ClF3: C, 48.68; H,
3.21; N, 12.15. Found: C, 48.73; H, 2.97; N, 12.19.
Compound 8l was prepared in a manner similar to that de-
scribed for 8a. Yield 92%, mp 159.2–159.3 °C. 1H NMR (CDCl3): d
1.35 (3H, t, J = 6.2 Hz), 1.93–2.11 (1H, m), 2.33–2.42 (1H, m),
3.69–3.80 (1H, m), 5.18 (1H, dd, J = 11.2, 5.0 Hz), 5.79 (1H, br s),
7.19–7.43 (5H, m), 7.66 (1H, s). Anal. Calcd for C14H15N3O2: C,
65.35; H, 5.88; N, 16.33. Found: C, 65.10; H, 5.90; N, 16.00.
5.1.27. N-(1-Adamantyl)-5-phenyl-7-(trifluoromethyl)-4,5,6,7-
tetrahydropyrazolo-[1,5-a]pyrimidine-3-carboxamide (9a)
A mixture of 8a (0.35 g, 1.12 mmol), 1-adamantylamine (0.17 g,
1.12 mmol), WSC (0.24 g, 1.25 mmol), HOBt (0.25 g, 0.56 mmol)
and DMF (10 mL) was stirred at room temperature for 3 h, and con-
centrated to dryness. The residue was dissolved in EtOAc, and the
organic layer was successively washed with aqueous NaHCO3,
water and brine, dried over MgSO4, and then concentrated. The res-
idue was chromatographed on silica gel using EtOAc–hexane (1:2)
to give 9a (1.34 g, 73%) as colorless crystals: mp 210–212 °C; 1H
5.1.20. 5-(3-Chlorophenyl)-7-(trifluoromethyl)-4,5,6,7-
tetrahydropyrazolo[1,5-a]-pyrimidine-3-carboxylic acid (8c)
Compound 8c was prepared in a manner similar to that de-
scribed for 8a. Yield 51%, mp 194–195 °C. 1H NMR (DMSO-d6): d
1.99–2.33 (1H, m), 2.50–2.60 (1H, m), 4.68–5.75 (1H, m), 5.17–
5.31 (1H, m), 6.74 (1H, br s), 7.36–7.50 (4H, m), 7.62 (1H, s). Anal.
Calcd for C14H11N3O2ClF3: C, 48.68; H, 3.21; N, 12.15. Found: C,
48.63; H, 2.99; N, 12.05.