T. Saito et al. / Bioorg. Med. Chem. 19 (2011) 5955–5966
5963
6.68 Hz, 4H), 2.33 (s, 3H), 1.49 (m, 4H), 0.85 (t, J = 7.32 Hz, 6H); mp
165–168 °C.
21.19, 50.41, 52.80, 55.76, 80.74, 91.66, 113.91, 115.69, 132.21,
134.00, 135.22, 142.94, 149.42, 151.32, 157.03, 159.09; IR (KBr)
580, 627, 752, 842, 880, 903, 938, 1033, 1047, 1103, 1138, 1161,
1181, 1226, 1260, 1285, 1326, 1380, 1390, 1441, 1463, 1497,
1525, 1550, 1615, 2873, 2962, 3094 cmꢂ1; .
5.1.39. N7-(2-chloro-4-methoxyphenyl)-6-methyl-N5,N5-di-
propylimidazo[1,2-a]pyrimidine-5,7-diamine (24)
11% yield in 2 steps; a white powder. TLC Rf = 0.42 (MeOH/
CH2Cl2, 1/9); MS (APCI, Pos) m/z 388 (M+H)+; FABHRMS calcd for
C
5.1.44. N5-(2-chloro-4-methoxyphenyl)-N5-(2-methyl-2-propen
yl)-N7,N7-dipropylpyrazolo[1,5-a]pyrimidine-5,7-diamine (15)
95% yield; a yellow oil. TLC Rf = 0.25 (EtOAc/hexane, 1/8); MS
(APCI, Pos) m/z 428 (M+H)+; FABHRMS calcd for C23H31ClN5O:
428.2217. Found: 428.2218; 1H NMR (300 MHz, CDCl3) d 7.80 (d,
J = 2.20 Hz, 1H), 7.22 (d, J = 8.79 Hz, 1H), 7.06 (d, J = 2 .93 Hz, 1H),
6.86 (dd, J = 8.79, 2.93 Hz, 1H), 6.10 (d, J = 2.20 Hz, 1H), 5.07 (m,
1H), 4.80 (m, 3H), 3.99 (m, 1H), 3.84 (s, 3H), 3.42 (m, 4H), 1.82
(s, 3H), 1.55 (m, 4H), 0.77 (t, J = 7.41 Hz, 6H).
20H27ClN5O: 388.1904. Found: 388.1905; 1H NMR (300 MHz,
CDCl3) d 8.95 (d, J = 9.15 Hz, 1H), 7.40 (d, J = 1.46 Hz, 1H), 7.27 (d,
J = 1.46 Hz, 1H), 7.03 (s, 1H), 6.96 (d, J = 2.93 Hz, 1H), 6.90 (dd,
J = 9.15, 2.93 Hz, 1H), 3.81 (s, 3H), 3.18 (m, 4H), 2.29 (s, 3H), 1.52
(m, 4H), 0.87 (t, J = 7.32 Hz, 6H); mp 189–191 °C.
5.1.40. N5-(2-Chloro-4-methoxyphenyl)-N5-(methoxymethyl)-
N7,N7-dipropylpyrazolo[1,5-a]pyrimidine-5,7-diamine (19)
To a stirred solution of 4 (200 mg, 536
lmol) in DMF (3.0 mL)
was added NaH (26 mg, 643 mol, 60% in mineral oil) at ambient
l
5.1.45. N5-allyl-N5-(2-chloro-4-methoxyphenyl)-N7,N7-dipropyl
pyrazolo[1,5-a]pyrimidine-5,7-diamine (16)
temperature under argon atmosphere. After stirring for 30 min,
the reaction mixture was treated with methoxymethylchloride
(49 lL, 643 lmol), then stirred for 1 h, quenched with water and
100% yield; a white powder. TLC Rf = 0.21 (EtOAc/hexane, 1/8);
MS (APCI, Pos) m/z 414 (M+H)+; 1H NMR (300 MHz, DMSO-d6) d
7.81 (d, J = 2.20 Hz, 1H), 7.34 (d, J = 8.79 Hz, 1H), 7.22 (d,
J = 2.93 Hz, 1H), 7.02 (dd, J = 8.79, 2.93 Hz, 1H), 6.00 (d,
J = 2.20 Hz, 1H), 5.92 (m, 1H), 5.09 (m, 2H), 4.73 (m, 2H), 4.16 (m,
1H), 3.80 (s, 3H), 3.43 (m, 4H), 1.46 (m, 4H)0.69 (t, J = 7.41 Hz,
6H); Anal. Calcd for C22H28ClN5O; C, 63.83; H, 6.82; N, 16.92.
Found: C, 63.70; H, 6.82; N, 16.61; mp 85–86 °C.
extracted with EtOAc. The combined organic layers were washed
with water, brine, dried over MgSO4 and evaporated. The resulting
residue was purified by column chromatography on silica gel
(EtOAc/hexane, 1/9–1/3) to give 19 (207 mg, 92% yield) as a yellow
oil. TLC Rf = 0.57 (EtOAc/hexane, 1/2); MS (APCI, Pos) m/z 418
(M+H)+; FABHRMS calcd for C21H29ClN5O2: 418.2010. Found:
418.2002; 1H NMR (300 MHz, CDCl3) d 7.82 (d, J = 2.4 Hz, 1H),
7.34 (d, J = 9.0 Hz, 1H), 7.07 (d, J = 3.0 Hz, 1H), 6.90 (dd, J = 3.0,
9.0 Hz, 1H), 6.13 (d, J = 2.4 Hz, 1H), 4.81 (s, 1H), 3.84 (s, 3H), 3.48
(s, 3H), 3.46 (m, 4H), 1.53 (m, 4H), 0.77 (t, J = 7.2 Hz, 6H); 13C
NMR (75 MHz, CDCl3) d 11.26, 20.73, 53.02, 55.81, 56.50, 79.57,
79.96, 92.12, 113.84, 115.54, 132.25, 133.12, 134.51, 143.01,
149.65, 150.88, 156.71, 159.23; IR (neat) 2962, 2934, 1614, 1550,
5.1.46. N5-(2-chloro-4-methoxyphenyl)-N5-(cyclopropylmethyl)
-N7,N7-dipropylpyrazolo[1,5-a]pyrimidine-5,7-diamine (17)
90% yield; a pink powder. TLC Rf = 0.50 (EtOAc/hexane, 1/6); MS
(APCI, Pos) m/z 428 (M+H)+; FABHRMS calcd for C23H31ClN5O:
428.2217. Found: 428.2222; 1H NMR (300 MHz, CDCl3) d 7.80 (d,
J = 2.20 Hz, 1H), 7.29 (d, J = 8.60 Hz, 1H), 7.06 (d, J = 2.93 Hz, 1H),
6.89 (dd, J = 8.79, 2.93 Hz, 1H), 6.11 (d, J = 2.20 Hz, 1H), 4.73 (s,
1H), 4.03–4.23 (m, 1H), 3.85 (s, 3H), 3.33–3.56 (dd, J = 8.33,
6.87 Hz, 5H), 1.42–1.60 (m, 4H), 1.00–1.18 (m, 1H), 0.76 (t,
J = 7.41 Hz, 6H), 0.34–0.46 (m, 2H), 0.06–0.20 (m, 2H); IR (KBr)
772, 789, 834, 880, 905, 1020, 1039, 1072, 1105, 1149, 1181,
1202, 1226, 1259, 1289, 1329, 1388, 1439, 1461, 1499, 1518,
1469, 1465, 1442, 1383, 1283, 1231, 1119, 1068 cmꢂ1
.
5.1.41. N5-(2-chloro-4-methoxyphenyl)-N5-methyl-N7,N7-
dipropylpyrazolo[1,5-a]pyrimidine-5,7-diamine (12)
61% yield; a pale yellow powder. TLC Rf = 0.30 (EtOAc/hexane,
1/4); MS (APCI, Pos) m/z 388 (M+H)+; FABHRMS calcd for
C
20H27ClN5O: 388.1904. Found: 388.1901; 1H NMR (300 MHz,
1550, 1614, 2873, 2962, 3007, 3433 cmꢂ1
; Anal. Calcd for
CDCl3) d 7.81 (d, J = 2.20 Hz, 1H), 7.23 (d, J = 8.60 Hz, 1H), 7.06 (d,
J = 2.93 Hz, 1H), 6.89 (dd, J = 8.60, 2.93 Hz, 1H), 6.15 (d,
J = 2.20 Hz, 1H), 4.78 (s, 1H), 3.85 (s, 3H), 3.41 (m, 7H), 1.53 (m,
4H), 0.77 (t, J = 7.41 Hz, 6H); mp 95–96 °C.
C23H30ClN5O; C, 64.55; H, 7.07; N, 16.36. Found: C, 64.73; H,
7.13; N, 16.26; mp 61–66 °C.
5.1.47. N5-(2-chloro-4-methoxyphenyl)-N5-(2-methoxyethyl)-
N7,N7-dipropylpyrazolo[1,5-a]pyrimidine-5,7-diamine (18)
91% yield; a yellow oil. TLC Rf = 0.57 (EtOAc/hexane, 1/2); MS
(APCI, Pos) m/z 432 (M+H)+; FABHRMS calcd for C22H31ClN5O2:
432.2166. Found: 432.2165; 1H NMR (300 MHz, CDCl3) d 7.81 (d,
J = 2.2 Hz, 1H), 7.31 (d, J = 8.8 Hz, 1H), 7.05 (d, J = 2.7 Hz, 1H),
6.89 (dd, J = 8.8, 2.7 Hz, 1H), 6.11 (d, J = 2.2 Hz, 1H), 4.73 (s, 1H),
4.35–4.55 (m, 1H), 3.84 (s, 3H), 3.55–3.81 (m, 3H), 3.40 (dd,
J = 8.5, 6.1 Hz, 4H), 3.32 (s, 3H), 1.43–1.59 (m, 4H), 0.76 (t,
J = 7.4 Hz, 6H); 13C NMR (75 MHz, CDCl3) d11.17, 20.47, 48.29,
52.83, 55.75, 58.60, 70.45, 80.62, 91.76, 113.90, 115.52, 132.50,
134.14, 135.01, 142.95, 149.49, 151.23, 156.90, 159.17; IR (KBr)
627, 754, 861, 903, 1032, 1046, 1104, 1124, 1192, 1223, 1260,
5.1.42. N5-(2-chloro-4-methoxyphenyl)-N5-ethyl-N7,N7-
dipropylpyrazolo[1,5-a]pyrimidine-5,7-diamine (13)
94% yield; a white powder. TLC Rf = 0.20 (EtOAc/hexane, 1/8);
MS (APCI, Pos) m/z 402 (M+H)+; 1H NMR (300 MHz, CDCl3) d 7.81
(d, J = 2.20 Hz, 1H), 7.20 (d, J = 8.79 Hz, 1H), 7.08 (d, J = 2.93 Hz,
1H), 6.90 (dd, J = 8.79, 2.93 Hz, 1H), 6.12 (d, J = 2.20 Hz, 1H), 4.72
(s, 1H), 4.19 (m, 1H), 3.85 (s, 3H), 3.78 (m, 1H), 3.39 (m, 4H),
1.51 (m, 4H), 1.20 (t, J = 7.14 Hz, 3H), 0.76 (t, J = 7.41 Hz, 6H); Anal.
Calcd for C21H28ClN5O; C, 62.75; H, 7.02; N, 17.42. Found: C, 62.75;
H, 7.09; N, 17.21; mp 107–108 °C.
5.1.43. N5-(2-chloro-4-methoxyphenyl)-N5,N7,N7-tripropylpy-
razolo[1,5-a]pyrimidine-5,7-diamine (14)
1286, 1387, 1464, 1497, 1524, 1550, 1614, 2874, 2962 cmꢂ1
;
98% yield; an ivory wax. TLC Rf = 0.56 (EtOAc/hexane, 1/3); MS
(APCI, Pos) m/z 416 (M+H)+; FABHRMS calcd for C22H31ClN5O:
416.2217. Found: 416.2222; 1H NMR (300 MHz, CDCl3) d 7.80 (d,
J = 2.2 Hz, 1H), 7.20 (d, J = 8.6 Hz, 1H), 7.07 (d, J = 2.7 Hz, 1H),
6.89 (dd, J = 8.7, 2.7 Hz, 1H), 6.11 (d, J = 2.2 Hz, 1H), 4.66–4.75
(m, 1H), 3.95–4.23 (m, 1H), 3.85 (s, 3H), 3.51–3.72 (m, 1H),
3.34–3.45 (m, 4H), 1.42–1.70 (m, 6H), 0.94 (t, J = 7.4 Hz, 3H), 0.76
(t, J = 7.4 Hz, 6H); 13C NMR (75 MHz, CDCl3) d 11.18, 11.47, 20.45,
5.1.48. N5-(2-chloro-4-methoxyphenyl)-N5-(methoxymethyl)-
N7,N7-dipropylpyrazolo[1,5-a]pyrimidine-5,7-diamine (23)
90% yield; a pale yellow oil. TLC Rf = 0.57 (EtOAc/hexane, 1/2);
MS (APCI, Pos) m/z 418 (M+H)+; FABHRMS calcd for C21H29ClN5O2:
418.2010. Found: 418.2002; 1H NMR (300 MHz, DMOSO-d6) d 7.80
(d, J = 2.2 Hz, 1H), 7.38 (d, J = 8.8 Hz, 1H), 7.18 (d, J = 2.9 Hz, 1H),
7.04 (dd, J = 8.8, 2.7 Hz, 1H), 6.00 (d, J = 2.2 Hz, 1H), 5.19 (s, 2H),
4.92 (s, 1H), 3.84 (s, 3H), 3.48–3.57 (m, 4H), 3.37 (s, 3H),