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to give a brown residue. This residue, dissolved in a minimal
amount of DMSO and AcOH, was then loaded onto a RediSep
C18Aq (30 g) column primed with H2O+0.1% AcOH. The column
was then eluted with 2 CV of H2O+0.1% AcOH and then the
eluent was gradually changed to CH3CN+0.1% AcOH over 10 CV.
The fractions containing the desired product were pooled and
stripped of solvent under vacuum to provide a yellow solid (2a,
55 mg, 28%); mp: 126–1288C; 1H NMR (400 MHz, [D6]DMSO): d=
2.33 (s, 3H), 2.39–2.49 (m, 5H), 3.44 (m, J=4.40 Hz, 4H), 3.53 (brs,
2H), 4.36–4.47 (m, 1H), 6.00 (s, 1H), 7.31–7.39 (m, 1H), 7.53 (t, J=
7.83 Hz, 2H), 7.62 (d, J=7.83 Hz, 2H), 7.68 (s, 1H) 8.08 (d, J=
1.47 Hz, 1H), 9.17–9.24 (m, 1H); IR: n˜ =3580–2827 cmÀ1 (NH+OH);
MS (ESI+) m/z: 380.4 [M+H]+ (C20H25N7O).
1H NMR (400 MHz, [D6]DMSO): d=2.23 (s, 3H), 3.03 (t, J=7.34 Hz,
2H), 3.16–3.26 (m, 2H), 3.48 (t, J=5.62 Hz, 2H), 4.16 (t, J=7.34 Hz,
2H), 4.75 (brs, 1H), 5.73 (s, 1H), 6.47 (brs, 1H), 7.09 (s, 1H), 7.19–
7.32 (m, 6H), 8.73 ppm (brs, 1H); IR: n˜ =3360–2838 cmÀ1 (NH+
OH); MS (ESI+) m/z: 339.3 [M+H]+ (C18H22N6O).
N-4-(2-Methoxyethyl)-2-methyl-N6-(1-phenethyl-1H-imidazol-4-
yl)pyrimidine-4,6-diamine (2e): 6-Chloro-2-methyl-N-(1-phenethyl-
1H-imidazol-4-yl)pyrimidin-4-amine 7b (80 mg, 0.25 mmol) and 2-
methoxyethanamine (0.029 mL, 0.33 mmol) were reacted in diethy-
lene glycol monomethyl ether (2 mL) using the same procedure as
described for the synthesis of 2d, providing 2e as a yellow solid
1
(46 mg, 51%); mp: 129–1318C; H NMR (400 MHz, [D6]DMSO): d=
2.23 (s, 3H), 3.03 (s, 2H), 3.26 (s, 3H), 3.39–3.46 (m, 2H), 4.16 (t, J=
7.34 Hz, 2H), 5.74 (s, 1H), 6.54 (brs, 1H), 7.08 (s, 1H), 7.19–7.32 (m,
6H), 8.71 ppm (brs, 1H), (2H under solvent peak); IR: n˜ =
3231 cmÀ1 (NH); MS (ESI+) m/z: 353.3 [M+H]+ (C19H24N6O).
2-(4-(6-((1-Benzyl-1H-imidazol-4-yl)amino)-2-methylpyrimidin-4-
yl)piperazin-1-yl)ethanol (2b): To N-(1-benzyl-1H-imidazol-4-yl)-6-
chloro-2-methylpyrimidin-4-amine 7a (60 mg, 0.20 mmol) in dry
DMSO (1 mL), 2-(piperazin-1-yl)ethanol (0.037 mL, 0.30 mmol) and
DIPEA (0.070 mL, 0.40 mmol) were added. The resulting mixture
was heated at 1008C overnight. DIPEA was then evaporated, AcOH
(0.5 mL) was added, and the resulting solution was loaded onto
a RediSep C18Aq (30 g) column primed with H2O+0.1% AcOH. The
column was then eluted with 2 CV of H2O+0.1% AcOH and then
the eluent was gradually changed to CH3CN+0.1% AcOH over
10 CV. The fractions containing the desired product were pooled
and stripped of solvent under vacuum to give a brown solid. This
solid was then loaded onto a Biotage KP-NH column (11 g) primed
with CH2Cl2 only. The column was then run for 2 CV with CH2Cl2
only and then changed to CH2Cl2/MeOH 8:2 over 3 CV. The frac-
tions containing the desired product were pooled and stripped of
solvent under vacuum to provide, on drying under high vacuum,
a yellow solid. 2-(4-(6-((1-Benzyl-1H-imidazol-4-yl)amino)-2-methyl-
pyrimidin-4-yl)piperazin-1-yl)ethanol 2b (31 mg, 40%); mp: 173–
1768C; 1H NMR (400 MHz, [D6]DMSO): d=2.24 (s, 3H), 2.38–2.48
(m, 6H), 3.36–3.45 (m, 4H), 3.49–3.56 (m, 2H), 4.41 (t, J=5.38 Hz,
1H), 5.15 (s, 2H), 5.96 (s, 1H), 7.14 (s, 1H), 7.26–7.40 (m, 5H), 7.55
(d, J=1.47 Hz, 1H), 8.97 ppm (s, 1H); IR: n˜ =3440–2827 cmÀ1
(NH+OH); MS (ESI+) m/z: 394.4 [M+H]+ (C21H27N7O).
2-((2-Methyl-6-((1-phenethyl-1H-imidazol-4-yl)amino)pyrimidin-
4-yl)oxy)ethanol (2 f): To 6-Chloro-2-methyl-N-(1-phenethyl-1H-imi-
dazol-4-yl)pyrimidin-4-amine 7b (80 mg, 0.255 mmol) was added
ethylene glycol (2 mL, 0.255 mmol) followed by NaH 60% disper-
sion in mineral oil (30.6 mg, 1.275 mmol). Once gas evolution had
stopped, the mixture was heated at 1308C for 2 h. The mixture
was then cooled to RT. H2O (0.25 mL) and AcOH (0.25 mL) were
added. The solution was then loaded onto RediSep C18Aq column
(50 g) primed with H2O+0.1% AcOH. The column was then eluted
with 2 CV of H2O+0.1% AcOH and then the eluent was gradually
changed to CH3CN+0.1% AcOH over 10 CV. The fractions contain-
ing the desired product were pooled and stripped of solvent
under vacuum to give, on drying under high vacuum, 2-((2-methyl-
6-((1-phenethyl-1H-imidazol-4-yl)amino)pyrimidin-4-yl)oxy)ethanol
2 f as a white solid (65 mg, 75%); mp: 154–1578C; 1H NMR
(400 MHz, [D6]DMSO): d=2.36 (s, 3H), 3.04 (t, J=7.34 Hz, 2H), 3.66
(q, J=5.38 Hz, 2H), 4.16–4.24 (m, 4H), 4.80 (t, J=5.62 Hz, 1H), 6.04
(brs, 1H), 7.12–7.35 (m, 7H), 9.22–9.35 ppm (m, 1H); IR: n˜ =3370–
2860 cmÀ1 (NH+OH); MS (ESI+) m/z: 340.6 [M+H]+ (C18H21N5O2).
6-(2-Ethoxyethoxy)-2-methyl-N-(1-phenethyl-1H-imidazol-4-yl)-
pyrimidin-4-amine (2g): 6-Chloro-2-methyl-N-(1-phenethyl-1H-imi-
dazol-4-yl)pyrimidin-4-amine (80 mg, 0.255 mmol) and NaH 60%
dispersion in mineral oil (30.6 mg, 1.27 mmol) were reacted in eth-
ylene glycol monoethyl ether (2 mL, 0.255 mmol) using the same
procedure as described for the synthesis of 2 f, providing 2g as
a brown solid (60 mg, 60%); mp: 118–1218C; 1H NMR (400 MHz,
[D6]DMSO): d=1.12 (t, J=6.85 Hz, 3H), 2.36 (s, 3H), 3.04 (t, J=
7.09 Hz, 2H), 3.48 (d, J=6.85 Hz, 2H), 3.61–3.67 (m, 2H), 4.19 (t, J=
7.34 Hz, 2H), 4.28–433 (m, 2H), 6.02 (brs, 1H), 7.12–7.33 (m, 7H),
9.22–9.37 ppm (m, 1H); IR: n˜ =3283 cmÀ1 (NH); MS (ESI+) m/z:
368.3 [M+H]+ (C20H25N5O2).
2-(4-(2-Methyl-6-((1-phenethyl-1H-imidazol-4-yl)amino)pyrimi-
din-4-yl)piperazin-1-yl)ethanol (2c): 6-Chloro-2-methyl-N-(1-phe-
nethyl-1H-imidazol-4-yl)pyrimidin-4-amine 7b (50 mg, 0.16 mmol),
2-(piperazin-1-yl)ethanol (0.029 mL, 0.30 mmol), and DIPEA
(0.070 mL 0.40 mmol) were reacted in dry DMSO (1 mL) using the
same procedure as described for the synthesis of 2b, providing 2c
1
as a brown solid (16 mg, 25%); mp: 167–1698C; H NMR (400 MHz,
[D6]DMSO): d=2.27 (s, 3H), 2.39–2.48 (m, 6H), 3.04 (t, J=7.34 Hz,
2H), 3.37–3.45 (m, 4H), 3.49–3.57 (m, 2H), 4.17 (t, J=7.09 Hz, 2H),
4.41 (t, J=5.38 Hz, 1H), 5.93 (s, 1H), 7.14 (s, 1H), 7.19–7.32 (m, 6H),
8.89 ppm (s, 1H); IR: n˜ =3363–2838 cmÀ1 (NH+OH); MS (ESI+)
m/z: 408.4 [M+H]+ (C22H29N7O).
2-Chloro-3-phenylpropanal
(9):
l-(À)-proline
(8.58 mg,
0.075 mmol) was added to a stirred solution of 3-phenylpropanal
(0.099 mL, 0.745 mmol) in dry CH2Cl2 (2 mL). The solution was
cooled to 08C in an ice bath and then N-chlorosuccinimide
(129 mg, 0.969 mmol) was added. The ice bath was removed and
the mixture allowed to warm to RT overnight. CH2Cl2 was then
evaporated to give 2-chloro-3-phenylpropanal 9, which was used
directly in the next step without further purification. 1H NMR
(400 MHz, CDCl3): d=3.10 (dd, J=14.43, 8.07 Hz, 1H), 3.40 (dd, J=
14.67, 5.87 Hz, 1H), 4.41 (ddd, J=8.07, 5.87, 2.20 Hz, 1H), 7.22–7.39
(m, 5H), 9.56 ppm (d, J=1.96 Hz, 1H).
2-((2-Methyl-6-((1-phenethyl-1H-imidazol-4-yl)amino)pyrimidin-
4-yl)amino)ethanol (2d): To 6-chloro-2-methyl-N-(1-phenethyl-1H-
imidazol-4-yl)pyrimidin-4-amine 7b (80 mg, 0.255 mmol) was
added ethanolamine (0.020 mL, 0.33 mmol) followed by diethylene
glycol monomethyl ether (2 mL). The mixture was heated at 1308C
overnight and then cooled to RT. H2O (0.25 mL) and AcOH
(0.25 mL) were added. The solution was then loaded onto a
RediSep C18Aq column (50 g) primed with H2O+0.1% AcOH. The
column was then eluted with 2 CV of H2O+0.1% AcOH and then
the eluent was gradually changed to CH3CN+0.1% AcOH over
10 CV. The fractions containing the desired product were pooled
and stripped of solvent under vacuum to give, on drying under
high vacuum, a yellow solid 2d (49 mg, 57%); mp: 163–1658C;
5-Benzylthiazol-2-amine (10): 2-Chloro-3-phenylpropanal
9
(50 mg, 0.296 mol) was dissolved in EtOH (2 mL). Thiourea (113 mg,
1.491 mol) was added, and the mixture was heated at reflux for
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