Journal of Medicinal Chemistry
Article
amine (0.05 mL). After purification by flash chromatography (CH2Cl2
+ 2% MeOH) 6c was obtained as an off-white solid (43.0 mg, 69%).
Mp: 97 °C. IR (NaCl): 3106, 2944, 2811, 1647, 1578, 1291, 1240,
1199, 1043, 781 cm−1. 1H NMR (CDCl3, 360 MHz): δ 1.72−1.81 (m,
2 H), 1.85−1.93 (m, 2 H), 2.54 (t, J = 7.6 Hz, 2 H), 2.68−2.73 (m, 4
H), 3.10−3.12 (m, 4 H), 4.00 (t, J = 6.3 Hz, 2 H), 6.44−6.45 (m, 1
H), 6.92 (dd, J = 9.6, 2.2 Hz, 1 H), 6.96 (dd, J = 6.9, 2.6 Hz, 1 H),
7.14−7.16 (m, 2 H), 7.41 (d, J = 9.6 Hz, 1 H), 7.84 (d, J = 2.2 Hz, 1
H), 8.07−8.08 (m, 1 H). 13C NMR (CDCl3, 360 MHz): δ 23.2, 27.1,
51.1, 53.3, 58.1, 68.7, 96.7, 111.8, 117.8, 118.7, 119.1, 124.7, 127.5,
127.6, 134.1, 136.4, 140.8, 148.3, 151.2. HPLC: tR = 19.0 min, purity
99%. APCI-MS: m/z 419 [M+], 421 [M+ + 2]. Anal. Calcd (%) for
C21H24N4OCl2·0.6H2O: C 58.64, H 5.91, N 13.03. Found: C 58.86, H
5.81, N 12.78.
97.7, 109.6, 113.2, 118.6, 124.6, 127.4, 127.5, 130.1, 134.0, 141.6,
147.5, 151.3, 160.6, 183.2. HPLC: tR = 17.1 min, purity 98%. APCI-
MS: m/z 446 [M+ − 1], 448 [M+ + 1]. Anal. Calcd (%) for
C22H24N4O2Cl2·0.3H2O: C 58.36, H 5.48, N 12.37. Found: C 58.34, H
5.43, N 12.27.
6-{4-[4-(2,3-Dichlorophenyl)piperazin-1-yl]butoxy}pyrazolo-
[1,5-a]pyridine-3-carbaldehyde (7c). Compound 7c was prepared
according to the protocol of 7a using a solution of 6c (60.0 mg, 0.14
mmol) in DMF (0.46 mL) as well as POCl3 (0.04 mL, 0.44 mmol).
The crude compound was purified by flash chromatography (CH2Cl2
+ 2% MeOH) to give 7c as off-white solid (40.0 mg, 63%). Mp: 99 °C.
IR (NaCl): 3096, 2946, 2818, 1663, 1578, 1519, 1278, 1242, 1185,
1044, 780 cm−1. 1H NMR (CDCl3, 360 MHz): δ 1.71−1.79 (m, 2 H),
1.88−1.95 (m, 2 H), 2.51 (t, J = 7.6 Hz, 2 H), 2.64−2.70 (m, 4 H),
3.06−3.11 (m, 4 H), 4.05 (t, J = 6.4 Hz, 2 H), 6.96 (dd, J = 6.6, 3.0 Hz,
1 H), 7.14−7.15 (m, 2 H), 7.30 (dd, J = 9.7, 2.2 Hz, 1 H), 8.16−8.18
(m, 2 H), 8.29 (s, 1 H), 9.98 (s 1 H). 13C NMR (CDCl3, 360 MHz): δ
23.3, 27.0, 51.4, 53.4, 58.0, 69.1, 112.8, 113.9, 118.7, 119.1, 123.7,
124.6, 127.5, 127.6, 134.1, 135.5, 146.2, 150.6, 151.3, 183.1. HPLC: tR
= 17.0 min, purity 95%. APCI-MS: m/z 447 [M+], 449 [M+ + 2]. Anal.
Calcd (%) for C22H24N4O2Cl2: C 59.07, H 5.41, N 12.52. Found: C
58.68 H 5.43, N 12.16.
5-{4-[4-(2,3-Dichlorophenyl)piperazin-1-yl]butoxy}pyrazolo-
[1,5-a]pyridine-2-carbaldehyde (7f). To a solution of 6g (56.8 mg,
0.126 mmol) in CH2Cl2 (5.0 mL) was added MnO2 (110 mg, 1.26
mmol). After stirring at room temperature for 14 h, the remaining
MnO2 was removed by filtration over Celite and the solvent was
evaporated to yield 7f as white solid (55.9 mg, 99%). Mp: 121 °C. IR
(NaCl): 3093, 2946, 2876, 2816, 2359, 2248, 1699, 1648, 1577, 1540,
1493, 1447, 1421, 1257, 1207, 1138, 1044, 1016 cm−1. 1H NMR
(CDCl3, 600 MHz): δ 1.71−1.80 (m, 2 H), 1.87−1.94 (m, 2 H), 2.52
(t, J = 7.3 Hz, 2 H), 2.64−2.72 (m, 4 H), 3.04−3.13 (m, 4 H), 4.05 (t,
J = 6.4 Hz, 2 H), 6.64 (dd, J = 7.6, 2.6 Hz, 1 H), 6.79 (d, J = 2.6 Hz, 1
H), 6.82 (d, J = 0.8 Hz, 1 H), 6.96 (dd, J = 7.4, 2.3 Hz, 1 H), 7.13−
7.18 (m, 2 H), 8.31 (ddd, J = 7.6, 0.8, 0.8 Hz, 1 H), 10.16 (s, 1 H). 13C
NMR (CDCl3, 360 MHz): δ 23.4, 26.9, 51.4, 53.3, 58.0, 68.3, 95.5,
96.3, 110.3, 118.6, 124.6, 127.4, 127.5, 129.6, 134.1, 142.3, 151.3,
152.5, 156.2, 187.7. HPLC: tR = 16.6 min, purity 97%. HR-EIMS:
calcd 446.1276; found 446.1276.
Ethyl 5-{4-[4-(2,3-Dichlorophenyl)piperazin-1-yl]butoxy}-
pyrazolo[1,5-a]pyridine-2-carboxylate (6f). Compound 6f was
prepared according to the protocol of 6a using a solution of 5f (504
mg, 1.48 mmol) and NaI (332 mg, 2.21 mmol) in acetonitrile (12.0
mL) as well as a solution of 1-(2,3-dichlorophenyl)piperazine (375
mg, 1.62 mmol) and triethylamine (0.23 mL, 1.66 mmol) in
acetonitrile (6.0 mL). The crude compound was purified by flash
chromatography (CH2Cl2 + 1% MeOH) to afford 6f as white solid
(297 mg, 41%). Mp: 144 °C. IR (NaCl): 3062, 2945, 2878, 2818,
1
1725, 1649, 1577, 1540, 1495, 1448, 1240, 1221, 1139, 963 cm−1. H
NMR (CDCl3, 600 MHz): δ 1.44 (t, J = 7.1 Hz, 3 H), 1.71−1.78 (m, 2
H), 1.86−1.89 (m, 2 H), 2.50 (t, J = 7.6 Hz, 2 H), 2.63−2.71 (m, 4
H), 3.05−3.13 (m, 4 H), 4.04 (t, J = 6.3 Hz, 2 H), 4.47 (q, J = 7.1 Hz,
2 H), 6.57 (dd, J = 7.6, 2.6 Hz, 1 H), 6.76 (d, J = 2.4 Hz, 1 H), 6.85 (d,
J = 0.8 Hz, 1 H), 6.95 (dd, J = 7.3, 2.4 Hz, 1 H), 7.13 (t, J = 7.7 Hz, 1
H), 7.16 (dd, J = 7.6, 2.0 Hz, 1 H), 8.34 (ddd, J = 7.3, 0.6, 0.6 Hz, 1
H). 13C NMR (CDCl3, 360 MHz): δ 14.4, 23.4, 26.9, 51.3, 53.3, 58.0,
61.3, 68.2, 95.9, 98.6, 109.5, 118.6, 124.6, 127.4, 127.5, 129.6, 134.0,
141.9, 145.9, 151.3, 156.0, 162.9. HPLC: tR = 17.0 min, purity 98%.
HR-EIMS: calcd 490.1539; found 490.1535.
(5-{4-[4-(2,3-Dichlorophenyl)piperazin-1-yl]butoxy}-
pyrazolo[1,5-a]pyridin-2-yl)methanol (6g). To an ice-cooled
solution of 6f (56.2 mg, 0.12 mmol) in Et2O (10.0 mL) was added
a 4 M solution of LiAlH4 in Et2O (29 μL, 0.12 mmol). After stirring at
0 °C for 1 h the cooling was removed and the solution was stirred at
room temperature for 2 h. Then saturated NaHCO3 solution (30 mL)
was added, the organic layer was separated, and the aqueous layer was
extracted with CH2Cl2. The combined organic layers were dried over
MgSO4 and concentrated. The residue was purified by flash
chromatography (CH2Cl2 + 1% MeOH) to afford 6g as a rose solid
(43.8 mg, 85%). Mp: 116 °C. IR (NaCl): 3298, 2926, 2823, 1646,
(E)-5-{4-[4-(2,3-Dichlorophenyl)piperazin-1-yl]butoxy}-
pyrazolo[1,5-a]pyridine-3-carbaldehyde Oxime (8a,b). A sol-
ution of hydroxylamine hydrochloride (18.0 mg, 0.26 mmol) in water
(0.74 mL) and 2 M NaOH (0.07 mL, 0.14 mmol) was adjusted to pH
5.0 by the addition of 2 M HCl and cooled to 0 °C. Subsequently, a
solution of 7a (57.8 mg, 0.13 mmol) in ethanol (6.45 mL) was added
and the mixture was refluxed for 2 h. After cooling, saturated NaHCO3
solution was added and the aqueous layer was extracted with
dichloromethane. The combined organic layers were dried over
Na2SO4 and evaporated. Purification of the residue by flash
chromatography (CH2Cl2/MeOH 2%) yielded the isomers 8a (s-
trans, 25.0 mg, 42%) and 8b (s-cis, 23.5 mg, 39%) as white solids.
Isomer 8a: Mp: 189 °C. IR (KBr): 3446, 3078, 2956, 2831, 1647,
1
1577, 1541, 1228, 1421, 1241, 1203, 1044 cm−1. H NMR (CDCl3,
600 MHz): δ 1.72−1.80 (m, 2 H), 1.86−1.92 (m, 2 H), 1,92−2.06 (bs,
1H, OH) 2.53 (t, J = 6.7 Hz, 2 H), 2.65−2.75 (m, 4 H), 3.07−3.14 (m,
4 H), 4.02 (t, J = 6.3 Hz, 2 H), 4.85 (s, 2 H), 6.28 (s, 1 H), 6.43 (dd, J
= 7.6 Hz, 2.7 Hz, 1 H), 6.67 (d, J = 2.5 Hz, 1 H), 6.96 (dd, J = 7.4, 2.1
Hz, 1 H), 7.14−7.21 (m, 2 H), 8.21 (ddd, J = 7.6, 0.5, 0.5 Hz, 1 H);
signal for free OH not detected. 13C NMR (CDCl3, 600 MHz): δ 23.3,
26.9, 51.3, 53.3, 58.1, 59.4, 68.0, 93.6, 95, 106.7, 118.6, 124.6, 127.4,
127.5, 129.2, 134.1, 142.2, 151.3, 155.7, 155.9. HPLC: tR = 15.9 min,
purity 95%. HR-EIMS: calcd 448.1433; found 448.1434.
5-{4-[4-(2,3-Dichlorophenyl)piperazin-1-yl]butoxy}pyrazolo-
[1,5-a]pyridine-3-carbaldehyde (7a). To a solution of 6a (360 mg,
0.86 mmol) in DMF (2.75 mL) was added POCl3 (0.25 mL, 2.66
mmol). After stirring at room temperature for 1 h, the mixture was
diluted with H2O under ice cooling and alkalized by addition of 5 M
NaOH. After extraction with CHCl3, the combined organic layers were
dried over Na2SO4 and evaporated. The residue was purified by flash
chromatography (CH2Cl2 + 2% MeOH) to yield 7a as off-white solid
(361 mg, 94%). Mp: 107 °C. IR (NaCl): 2946, 2818, 1663, 1633,
1577, 1527, 1275, 1241, 1194, 1044, 774 cm−1. 1H NMR (CDCl3, 600
MHz): δ 1.70−1.78 (m, 2 H), 1.88−1.96 (m, 2 H), 2.51 (t, J = 7.6 Hz,
2 H), 2.64−2.68 (m, 4 H), 3.07−3.09 (m, 4 H), 4.16 (t, J = 6.5 Hz, 2
H), 6.71 (dd, J = 7.6, 2.6 Hz, 1 H), 6.96 (dd, J = 6.5, 3.0 Hz, 1 H),
7.14−7.15 (m, 2 H), 7.58 (d, J = 2.6 Hz, 1 H), 8.26 (s, 1 H), 9.95 (s, 1
H). 13C NMR (CDCl3, 360 MHz): δ 23.3, 26.9, 51.4, 53.3, 58.0, 68.9,
1
1578, 1535, 1267, 1244, 1038, 789 cm−1. H NMR (DMSO-d6, 360
MHz): δ 1.60−1.68 (m, 2 H), 1.79−1.86 (m, 2 H), 2.44 (t, J = 7.6 Hz,
2 H), 2.52−2.60 (m, 4 H), 2.97−3.00 (m, 4 H), 4.09 (t, J = 6.4 Hz, 2
H), 6.68 (dd, J = 7.6, 2.6 Hz, 1 H), 7.11 (dd, J = 6.5, 3.0 Hz, 1 H),
7.26−7.30 (m, 3 H), 8.08 (s, 1 H), 8.29 (s, 1 H), 8.58 (d, J = 7.6 Hz, 1
H), 10.63 (s, 1 H). 13C NMR (DMSO-d6, 360 MHz): δ 23.2, 26.9,
51.5, 53.3, 57.8, 68.6, 97.0, 104.4, 108.0, 120.1, 124.9, 126.6, 129.0,
130.9, 133.2, 138.6, 142.5, 143.1, 151.6, 157.5. HPLC: tR = 16.8 min,
purity 99%. APCI-MS: m/z 462 [M+], 464 [M+ + 2]. Anal. Calcd (%)
for C22H25N5O2Cl2·0.4H2O: C 56.27, H 5.54, N 14.91. Found: C
56.48, H 5.47, N 14.69. Isomer 8b: Mp: 165 °C. IR (NaCl): 3425,
1
2846, 1684, 1649, 1542, 1204, 1051, 764 cm−1. H NMR (DMSO-d6,
360 MHz): δ 1.60−1.68 (m, 2 H), 1.79−1.86 (m, 2 H), 2.43 (t, J = 7.6
Hz, 2 H), 2.52−2.58 (m, 4 H), 2.97−3.00 (m, 4 H), 4.14 (t, J = 6.3
Hz, 2 H), 6.68 (dd, J = 7.6, 2.6 Hz, 1 H), 7.11 (dd, J = 6.5, 3.0 Hz, 1
H), 7.27−7.30 (m, 2 H), 7.45 (d, J = 2.6 Hz, 1 H), 7.75 (s, 1 H),
8.56−8.59 (m, 2 H), 11.06 (s, 1 H). 13C NMR (DMSO-d6, 360 MHz):
δ 23.2, 26.8, 51.5, 53.3, 57.7, 68.8, 95.6, 103.1, 108.0, 120.0, 124.8,
I
dx.doi.org/10.1021/jm5004039 | J. Med. Chem. XXXX, XXX, XXX−XXX