Journal of Medicinal Chemistry
ARTICLE
(57.0 g, 89%) as a solid. 1H NMR (DMSO-d6) δ 3.33ꢀ3.43 (2H, m),
4.94 (2H, t, J = 8.9 Hz), 6.33 (1H, d, J = 9.6 Hz), 7.37 (1H, d, J = 6.9 Hz),
7.65 (2H, s), 7.78 (1H, dd, J = 9.6, 3.2 Hz), 8.49ꢀ8.53 (1H, m),
8.56ꢀ8.61 (2H, m).
[3,2-c]pyrazolo[1,5-a]pyridine-1-carboxylate21c (770 mg, 2.96mmol) in
THF (30 mL) was added to a suspension of 80% LiAlH4 (548 mg, 11.8
mmol) in THF (30 mL) at 0 °C. The reaction mixture was stirred at room
temperature for 30 min. Sodium sulfate decahydrate (10 g) was added to
the reaction mixture at 0 °C, and the mixture was filtered and evaporated.
The residue was washed with diisopropyl ether to afford 23c (485 mg,
75%) as a solid. Mp 119ꢀ120 °C (EtOAc/diisopropyl ether); 1H NMR
(CDCl3) δ 1.35 (3H, t, J = 7.7 Hz), 2.83 (2H, q, J = 7.7 Hz), 3.48 (2H, t,
J = 9.1 Hz), 4.70ꢀ4.79 (4H, m), 6.42 (1H, d, J = 7.4 Hz), 8.17 (1H, d,
J = 7.4 Hz). Anal. (C11H14N2O2) C, H, N.
(2-Cyclopropyl-8,9-dihydrofuro[3,2-c]pyrazolo[1,5-a]pyridin-
1-yl)methanol (23d). By a similar procedure to that for 23c, 23d
(93%) was obtained from 21d as a solid. Mp 170ꢀ172 °C (EtOAc); 1H
NMR (CDCl3) δ 0.96ꢀ1.06 (4H, m), 1.43 (1H, brs), 1.99ꢀ2.12 (1H,
m), 3.47 (2H, t, J = 9.1 Hz), 4.73 (2H, t, J = 9.1 Hz), 4.81 (2H, s), 6.38
(1H, d, J = 7.4 Hz), 8.06ꢀ8.13 (1H, m). Anal. (C13H14N2O2) C, H, N.
[2-(Trifluoromethyl)-8,9-dihydrofuro[3,2-c]pyrazolo[1,5-a]
pyridin-1-yl]methanol (23e). By a similar procedure described for
23c, 23e (49%) was obtained from 21e as a solid. Mp 144ꢀ145 °C
(EtOH/hexane); 1H NMR (CDCl3) δ 3.56 (2H, t, J = 9.2 Hz),
4.73ꢀ4.89 (4H, m), 6.65 (1H, d, J = 7.4 Hz), 8.27 (1H, d, J = 7.4 Hz).
Anal. (C11H9N2F3O2) C, H, N.
(2-Phenyl-8,9-dihydrofuro[3,2-c]pyrazolo[1,5-a]pyridin-1-yl)
acetonitrile (24a). By a similar procedure described for 24c, 24a
(83%) was obtained from 23a as a solid. Mp 188ꢀ189 °C (EtOAc/
hexane); 1H NMR (CDCl3) δ 3.66 (2H, t, J = 9.1 Hz), 3.85 (2H, s), 4.82
(2H, t, J = 9.1 Hz), 6.55 (1H, d, J = 7.4 Hz), 7.41ꢀ7.55 (3H, m),
7.60ꢀ7.67 (2H, m), 8.26ꢀ8.30 (1H, m); MS (ESI) m/z 276 (M þ H)þ.
Anal. (C17H13N3O) C, H, N.
(2-Methyl-8,9-dihydrofuro[3,2-c]pyrazolo[1,5-a]pyridin-
1-yl)acetonitrile (24b). By a similar procedure described for 24c,
24b (46%) was obtained from 23b as a solid. Mp 173ꢀ174 °C (EtOAc/
hexane); 1H NMR (CDCl3) δ 2.43 (3H, s), 3.55 (2H, t, J = 9.1 Hz), 3.72
(2H, s), 4.77 (2H, t, J = 9.1 Hz), 6.44 (1H, d, J = 7.4 Hz), 8.12ꢀ8.17 (1H,
m); MS (ESI) m/z 214 (M þ H)þ. Anal. (C12H11N3O) C, H, N.
(2-Ethyl-8,9-dihydrofuro[3,2-c]pyrazolo[1,5-a]pyridin-1-
yl)acetonitrile (24c). A solution of (2-ethyl-8,9-dihydrofuro[3,2-c]-
pyrazolo[1,5-a]pyridin-1-yl)methanol 23c (480 mg, 2.20 mmol) in
Methyl 2-Phenyl-8,9-dihydrofuro[3,2-c]pyrazolo[1,5-a]-
pyridine-1-carboxylate (21a). By a similar procedure described
for 21c, 21a (16%) was obtained from 19 and ethyl 2-butynoate 20a as a
solid. Mp 174ꢀ175 °C (EtOAc/hexane); 1H NMR (CDCl3) δ
3.69ꢀ3.80 (5H, m), 4.76 (2H, t, J = 9.2 Hz), 6.63 (1H, d, J = 7.1 Hz),
7.39ꢀ7.47 (3H, m), 7.63ꢀ7.69 (2H, m), 8.29ꢀ8.34 (1H, m); MS (ESI)
m/z 295 (M þ H)þ. Anal. (C17H14N2O3) C, H, N.
Ethyl 2-Methyl-8,9-dihydrofuro[3,2-c]pyrazolo[1,5-a]pyridine-
1-carboxylate (21b). By a similar procedure described for 21c, 21b
(12%) was obtained from 19 and ethyl 2-butynoate 20b as a solid. Mp
132ꢀ133 °C (EtOAc); 1H NMR (CDCl3) δ 1.39 (3H, t, J = 7.2 Hz),
2.60 (3H, s), 3.73 (2H, t, J = 9.2 Hz), 4.32 (2H, q, J = 7.2 Hz), 4.72 (2H, t,
J = 9.2 Hz), 6.54 (1H, d, J = 7.4 Hz), 8.16ꢀ8.21 (1H, m); MS (ESI) m/z
247 (M þ H)þ. Anal. (C13H14N2O3) C, H, N.
Ethyl 2-Ethyl-8,9-dihydrofuro[3,2-c]pyrazolo[1,5-a]pyridine-
1-carboxylate (21c) and Ethyl 7-Ethyl-2,3-dihydrofuro[2,3-
d]pyrazolo[1,5-a]pyridine-8-carboxylate (22c). Ethyl 2-pentyno-
ate 20c (0.91 mL, 6.87 mmol) was added to a mixture of 19 (2.00 g, 6.24
mmol) and potassium carbonate (1.21 g, 8.75 mmol) in DMF (40 mL) at
0 °C. The reaction mixture was stirred at room temperature overnight. After
addition of water, the mixture was extracted with EtOAc. The extract was
dried over sodium sulfate and evaporated. Purification by silica gel column
chromatography (EtOAc/hexane) afforded less polar 21c (284 mg, 17%) as
a solid and polar 22c (244 mg, 15%) as a solid. 21c: 1H NMR (CDCl3) δ
1.33 (3H, t, J = 7.4 Hz), 1.39 (3H, t, J = 7.1 Hz), 3.05 (2H, q, J = 7.4 Hz),
3.74 (2H, t, J = 9.2 Hz), 4.32 (2H, q, J = 7.1 Hz), 4.72 (2H, t, J = 9.2 Hz),
6.54 (1H, d, J = 7.1 Hz), 8.19ꢀ8.23 (1H, m). 22c: 1H NMR (CDCl3) δ
1.32 (3H, t, J = 7.4 Hz), 1.40 (3H, t, J = 7.1 Hz), 3.04 (2H, q, J = 7.4 Hz),
3.24ꢀ3.34 (2H, m), 4.34 (2H, q, J = 7.1 Hz), 4.71 (2H, t, J = 8.2 Hz), 7.30
(1H, s), 8.14ꢀ8.20 (1H, m).
Methyl 2-Cyclopropyl-8,9-dihydrofuro[3,2-c]pyrazolo[1,5-
a]pyridine-1-carboxylate (21d). By a similar procedure described
for 21c, 21d (12%) was obtained from 19 and methyl 3-cyclopropylprop-
2-ynoate 20d as a solid. Mp 171ꢀ172 °C (EtOAc); 1H NMR (CDCl3) δ
1.00ꢀ1.06 (4H, m), 2.71ꢀ2.82 (1H, m), 3.70 (2H, t, J = 9.2 Hz), 3.85
(3H, s), 4.71 (2H, t, J = 9.2 Hz), 6.51 (1H, d, J = 7.1 Hz), 8.10ꢀ8.15 (1H,
m); MS (ESI) m/z 259 (M þ H)þ. Anal. (C14H14N2O3) C, H, N.
Ethyl 2-(Trifluoromethyl)-8,9-dihydrofuro[3,2-c]pyrazolo-
[1,5-a]pyridine-1-carboxylate (21e). By a similar procedure de-
scribed for 21c, 21e (38%) was obtained from 19 and ethyl 4,4,4-
trifluoro-2-butynoate 20e as a solid. Mp 162ꢀ163 °C (EtOAc/hexane);
1H NMR (CDCl3) δ 1.39 (3H, t, J = 7.2 Hz), 3.78 (2H, t, J = 9.3 Hz),
4.35 (2H, q, J = 7.2 Hz), 4.78 (2H, t, J = 9.3 Hz), 6.74 (1H, d, J = 7.5 Hz),
8.33 (1H, d, J = 7.5 Hz); MS (ESI) m/z 301 (M þ H)þ. Anal.
(C13H11N2F3O3) C, H, N.
(2-Phenyl-8,9-dihydrofuro[3,2-c]pyrazolo[1,5-a]pyridin-1-yl)
methanol (23a). By a similar procedure described for 23c, 23a (91%)
was obtained from 21a as a solid. Mp 188ꢀ190 °C (EtOH/diisopropyl
ether); 1H NMR (CDCl3) δ 3.55 (2H, t, J = 9.1 Hz), 4.78 (2H, t, J = 9.1
Hz), 4.83 (2H, d, J = 4.9 Hz), 6.51 (1H, d, J = 7.1 Hz), 7.37ꢀ7.52 (3H,
m), 7.80ꢀ7.85 (2H, m), 8.25ꢀ8.30 (1H, m); MS (ESI) m/z 267 (M þ
H)þ. Anal. (C16H14N2O2) C, H, N.
dichloromethane (10 mL) was added to a solution of BF3 Et2O (836 μL,
3
6.60 mmol) and TMSCN (1.17 mL, 8.77 mmol) in dichloromethane
(5 mL) at 0 °C under argon atmosphere. The reaction mixture was
stirred at room temperature for 30 min. After addition of saturated
aqueous sodium bicarbonate solution, the mixture was extracted with
EtOAc. The extract was dried over sodium sulfate and evaporated.
Purification by silica gel column chromatography (EtOAc/hexane)
afforded 24c (296 mg, 59%) as a solid. Mp 179ꢀ180 °C (EtOAc/
hexane); 1H NMR (CDCl3) δ 1.35 (3H, t, J = 7.7 Hz), 2.80 (2H, q, J =
7.7 Hz), 3.56 (2H, t, J = 9.1 Hz), 3.73 (2H, s), 4.76 (2H, t, J = 9.1 Hz),
6.44 (1H, d, J = 7.4 Hz), 8.14ꢀ8.19 (1H, m); MS (ESI) m/z 228 (M þ
H)þ. Anal. (C13H13N3O) C, H, N.
(2-Cyclopropyl-8,9-dihydrofuro[3,2-c]pyrazolo[1,5-a]pyridin-
1-yl)acetonitrile (24d). By a similar procedure described for 24c,
24d (55%) was obtained from 23d as a solid. Mp 139ꢀ140 °C (EtOAc/
hexane); 1H NMR (CDCl3) δ 0.95ꢀ1.08 (4H, m), 1.85ꢀ1.97 (1H, m),
3.55 (2H, t, J = 9.1 Hz), 3.83 (2H, s), 4.76 (2H, t, J = 9.1 Hz), 6.41 (1H, d,
J = 7.4 Hz), 8.08ꢀ8.13 (1H, m); MS (ESI) m/z 240 (M þ H)þ. Anal.
(C14H13N3O) C, H, N.
(2-Methyl-8,9-dihydrofuro[3,2-c]pyrazolo[1,5-a]pyridin-
1-yl)methanol (23b). By a similar procedure described for 23c, 23b
(92%) was obtained from 21b as a solid. Mp 173ꢀ174 °C (EtOH/
diisopropyl ether); 1H NMR (CDCl3) δ 1.29 (1H, t, J = 5.1 Hz), 2.45
(3H, s), 3.48 (2H, t, J = 9.1 Hz), 4.68ꢀ4.81 (4H, m), 6.42 (1H, d, J = 7.4
Hz), 8.11ꢀ8.17 (1H, m). Anal. (C11H12N2O2) C, H, N.
[2-(Trifluoromethyl)-8,9-dihydrofuro[3,2-c]pyrazolo[1,5-a]
pyridin-1-yl]acetonitrile (24e). By a similar procedure described
for 24c, 24e (96%) was obtained from 23e as a solid. Mp 151ꢀ153 °C
1
(EtOAc/hexane); H NMR (CDCl3) δ 3.66 (2H, t, J = 9.3 Hz), 3.89
(2H, s), 4.84 (2H, t, J = 9.3 Hz), 6.70 (1H, d, J = 7.6 Hz), 8.29 (1H, d,
J = 7.6 Hz); MS (ESI) m/z 268 (M þ H)þ. Anal. (C12H8N3F3O)
C, H, N.
(2-Ethyl-8,9-dihydrofuro[3,2-c]pyrazolo[1,5-a]pyridin-
1-yl)methanol (23c). A solution of ethyl 2-ethyl-8,9-dihydrofuro
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dx.doi.org/10.1021/jm200385u |J. Med. Chem. 2011, 54, 4207–4218