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J. S. Stehouwer et al. / Bioorg. Med. Chem. 23 (2015) 4286–4302
J = 7.2 Hz); 13C NMR (75 MHz, CDCl3) d 160.13, 152.23, 147.03,
146.05, 135.79, 134.27, 133.61, 130.62, 129.76, 127.23, 104.98,
85.64, 44.01, 25.58, 22.59, 13.86, 11.69; HRMS (APCI) [MH]+
Calcd for C17H19N4Cl2: 349.0981, found: 349.0983.
J = 8.1 Hz), 5.83 (s, 1H), 3.81 (q, 2H, J = 6.9 Hz), 3.74 (t, 2H,
J = 7.8 Hz), 2.43 (s, 3H), 2.34 (s, 3H), 1.70 (pentet, 2H, J = 7.8 Hz),
1.39 (sextet, 2H, J = 7.5 Hz), 1.29 (t, 3H, J = 6.9 Hz), 0.97 (t, 3H,
J = 7.5 Hz); 13C NMR (75 MHz, CDCl3) d 159.16, 151.65, 149.53,
148.73, 135.75, 134.32, 133.42, 131.02, 129.74, 127.17, 104.11,
92.32, 50.43, 45.74, 30.03, 25.28, 20.40, 14.08, 13.10; HRMS
(APCI) [MH]+ Calcd for C20H25Cl2N4: 391.1451, found: 391.1459;
Anal. Calcd for C20H24Cl2N4: C, 61.38; H, 6.18; N, 14.32; found: C,
61.63; H, 6.19; N, 14.28; HPLC: Waters Xterra tR = 33.8 min
(70:30:0.1 v/v/v MeOH/H2O/NEt3, 9 mL/min), tR = 16.0 min
(75:25:0.1 v/v/v MeOH/H2O/NEt3, 9 mL/min), Waters NovaPak
tR = 23.5 min (75:25:0.1 v/v/v MeOH/H2O/NEt3, 1.1 mL/min).
4.8. N-Butyl-3-(2,4-dichlorophenyl)-2,5-dimethylpyrazolo[1,5-
a]pyrimidin-7-amine (20)
Compound 15 (244 mg, 7.47 Â 10À4 mol), BuNH2 (0.30 mL,
3.0 mmol, 4.0 equiv), iPr2NEt (0.30 mL, 1.7 mmol, 2.3 equiv), and
CH3CN (20 mL) were stirred at reflux under Ar(g) for 1 h, cooled,
and the solvent was removed to give a yellow residue that was
dried under vacuum. The solid was dissolved in CH2Cl2, poured
onto dry silica (43 mm h  43 mm i.d.), and eluted under vacuum:
CH2Cl2 (650 mL) to afford 20 (247 mg, 91%) as a white foam: 1H
NMR (300 MHz, CDCl3) d 7.51 (d, 1H, J = 2.1 Hz), 7.36 (d, 1H,
J = 8.1 Hz), 7.30 (dd, 1H, J = 2.1 Hz, J = 8.1 Hz), 6.17 (t, 1H,
J = 5.4 Hz), 5.81 (s, 1H), 3.39 (dt, 2H, J = 5.4 Hz, J = 7.2 Hz), 2.46 (s,
3H), 2.35 (s, 3H), 1.76 (m, 2H), 1.50 (m, 2H), 1.01 (t, 3H,
J = 7.5 Hz); 13C NMR (75 MHz, CDCl3) d 160.11, 152.18, 147.00,
146.02, 135.76, 134.26, 133.58, 130.60, 129.72, 127.20, 104.94,
85.61, 41.96, 31.25, 25.55, 20.27, 13.90, 13.85; HRMS (APCI)
[MH]+ Calcd for C18H21N4Cl2: 363.1138, found: 363.1140.
4.11. 4-((3-(2,4-Dichlorophenyl)-2,5-dimethylpyrazolo[1,5-a]-
pyrimidin-7-yl)(ethyl)amino)butan-1-ol (23)
Compound 15 (106 mg, 3.25 Â 10À4 mol), EtNHBuOH (0.15 mL,
1.16 mmol, 3.6 equiv), iPr2NEt (0.15 mL, 8.6 Â 10À4 mol, 2.6 equiv),
and CH3CN (10 mL) were stirred at reflux under Ar(g) for 2.5 h,
cooled, and the solvent was removed to give a faint yellow syrup.
The syrup was dissolved in CH2Cl2, poured onto dry silica
(43 mm h  43 mm i.d.), and eluted under vacuum: hexane
(50 mL), hexane/EtOAc/NEt3 v/v/v 90:8:2 (50 mL), 75:20:5
(100 mL), 50:45:5 (100 mL), 20:75:5 (150 mL) to give a sticky, yel-
low residue (134 mg). Purification by radial chromatography
(2 mm silica): hexane/EtOAc/NEt3 v/v/v 90:8:2 (100 mL), 75:20:5
(100 mL), 50:45:5 (100 mL), 20:75:5 (50 mL) gave an off-white
foam (123 mg) that was further purified by radial chromatography
(1 mm silica): 1% MeOH/CHCl3 (100 mL) to afford 23 (118 mg, 89%)
as a white foam: 1H NMR (300 MHz, CDCl3) d 7.50 (d, 1H,
J = 2.1 Hz), 7.35 (d, 1H, J = 8.4 Hz), 7.29 (dd, 1H, J = 2.1, J = 8.4 Hz),
5.84 (s, 1H), 3.87 (br s, 2H), 3.73 (q, 2H, J = 6.0 Hz), 3.72 (q, 2H,
J = 7.2 Hz), 2.43 (s, 3H), 2.35 (s, 3H), 2.01 (t, 1H, J = 6.0 Hz), 1.88
(pentet, 2H, J = 7.2 Hz), 1.65 (pentet, 2H, J = 7.2 Hz), 1.30 (t, 3H,
J = 7.2 Hz); 13C NMR (75 MHz, CDCl3) d 159.36, 151.90, 149.60,
148.55, 135.76, 134.30, 133.50, 130.82, 129.70, 127.18, 104.24,
92.13, 62.15, 50.05, 45.73, 29.62, 25.17, 24.68, 13.94, 12.72;
HRMS (APCI) [MH]+ Calcd for C20H25Cl2N4O: 407.1400, found:
407.1404.
4.9. 3-(2,4-Dichlorophenyl)-2,5-dimethyl-N,N-dipropylpyra-
zolo[1,5-a]pyrimidin-7-amine (21)
Compound 15 (155 mg, 4.75 Â 10À4 mol), Pr2NH (0.30 mL,
2.2 mmol, 4.6 equiv), iPr2NEt (0.23 mL, 1.3 mmol, 2.7 equiv), and
CH3CN (8 mL) were stirred at reflux under Ar(g) for 3.5 h, then
cooled, and the solvent was removed to give a residue that was
dried under vacuum briefly. The residue was dissolved in CH2Cl2,
poured onto dry silica (43 mm h  43 mm i.d.), and eluted under
vacuum: hexane (50 mL), hexane/EtOAc/NEt3 v/v/v 95:4:1
(100 mL), 90:8:2 (100 mL), 75:20:5 (200 mL) to give a yellow oil
(170 mg). Purification by radial chromatography (2 mm silica):
hexane/EtOAc/NEt3 v/v/v 98:1:1 (250 mL) gave
a yellow oil
(149 mg) that was repurified by radial chromatography (1 mm sil-
ica): hexane/EtOAc/NEt3 v/v/v 98:1:1 (150 mL) to afford 21
(129 mg, 69%) as a white solid: 1H NMR (300 MHz, CDCl3) d 7.50
(d, 1H, J = 2.1 Hz), 7.36 (d, 1H, J = 8.1 Hz), 7.29 (dd, 1H, J = 2.1 Hz,
J = 8.1 Hz), 5.80 (s, 1H), 3.71 (t, 4H, J = 7.5 Hz), 2.42 (s, 3H), 2.34
(s, 3H), 1.74 (sextet, 4H, J = 7.5 Hz), 0.96 (t, 6 H, J = 7.5 Hz); 13C
NMR (75 MHz, CDCl3) d 159.12, 151.57, 149.61, 148.78, 135.72,
134.32, 133.38, 131.06, 129.73, 127.17, 140.00, 92.05, 53.20,
25.29, 21.31, 14.13, 11.53; HRMS (APCI) [MH]+ Calcd for
4.12. 2-((3-(2,4-Dichlorophenyl)-2,5-dimethylpyrazolo[1,5-a]-
pyrimidin-7-yl)(methyl)amino)ethanol (24)
Compound 15 (144 mg, 4.41 Â 10À4 mol), CH3CN (15 mL),
iPr2NEt (0.20 mL, 1.1 mmol, 2.5 equiv), and MeNHEtOH (0.14 mL,
1.8 mmol, 4.1 equiv) were stirred at reflux under Ar(g) for 3 h, then
cooled, and the solvent was removed to give a yellow syrup.
Hexane was added and removed to give an off-white solid that
was dried under vacuum. The solid was dissolved in CH2Cl2, poured
onto dry silica (14 cm h  4 cm i.d.), and eluted under vacuum:
hexane/EtOAc/NEt3 v/v/v 90:8:2 (100 mL), 75:20:5 (100 mL),
50:45:5 (100 mL), 20:75:5 (400 mL) to afford 24 (152 mg, 94%) as
an off-white solid: 1H NMR (300 MHz, CDCl3) d 7.52 (d, 1H,
J = 1.8 Hz), 7.34 (d, 1H, J = 8.1 Hz), 7.31 (dd, 1H, J = 1.8 Hz,
J = 8.1 Hz), 6.23 (t, 1H, J = 3.6 Hz), 5.99 (s, 1H), 4.02 (partially
resolved dt, 2H, J = 4.5 Hz), 3.95 (br d, 2H), 3.10 (s, 3H), 2.47 (s,
3H), 2.35 (s, 3H); 13C NMR (75 MHz, CDCl3) d 160.49, 151.69,
149.83, 148.85, 135.73, 134.20, 133.87, 130.11, 129.81, 127.26,
104.92, 93.00, 59.76, 53.46, 37.89, 25.28, 13.74; HRMS (APCI)
[MH]+ Calcd for C17H19Cl2N4O: 365.0930, found: 365.0931.
C
C
20H25Cl2N4: 391.1451, found: 391.1456; Anal. Calcd for
20H24Cl2N4: C, 61.38; H, 6.18; N, 14.32; found: C, 61.65; H, 6.31;
N, 14.16.
4.10. N-Butyl-3-(2,4-dichlorophenyl)-N-ethyl-2,5-dimethylpyra-
zolo[1,5-a]pyrimidin-7-amine (22)
Compound 15 (105 mg, 3.21 Â 10À4 mol), BuNHEt (0.20 mL,
1.5 mmol, 4.7 equiv), iPr2NEt (0.15 mL, 8.6 Â 10À4 mol, 2.7 equiv),
and CH3CN (5 mL) were stirred at reflux under Ar(g) for 2.5 h,
cooled, and the solvent was removed to give a residue that was
dried under vacuum. The residue was dissolved in CH2Cl2, poured
onto dry silica (43 mm h  43 mm i.d.), and eluted under vacuum:
hexane (50 mL), hexane/EtOAc/NEt3 v/v/v 95:4:1 (50 mL), 90:8:2
(100 mL), 75:20:5 (200 mL) to give an off-white solid (96 mg).
Purification
by
radial
chromatography
(1 mm
silica):
4.13. 2-((3-(2,4-Dichlorophenyl)-2,5-dimethylpyrazolo[1,5-a]-
hexane/EtOAc/NEt3 v/v/v 98:1:1 (150 mL) afforded 22 (90 mg,
72%) as a colorless syrup that became an off-white solid when
stored in a freezer: 1H NMR (300 MHz, CDCl3) d 7.50 (d, 1H,
J = 2.1 Hz), 7.36 (d, 1H, J = 8.1 Hz), 7.29 (dd, 1H, J = 2.1 Hz,
pyrimidin-7-yl)(ethyl)amino)ethanol (25)
Compound 15 (143 mg, 4.38 Â 10À4 mol), CH3CN (15 mL),
iPr2NEt (0.20 mL, 1.1 mmol, 2.5 equiv), and EtNHEtOH (0.15 mL,