4466 Journal of Medicinal Chemistry, 2006, Vol. 49, No. 15
Xin et al.
mL), and washed with 0.5 M NaOH (2 × 100 mL). The mixture
was stirred vigorously, and then the resulting precipitate was filtered,
providing 6-benzyloxymethyl-5-(4-nitrophenyl)-pyrimidine-2,4-di-
was dissolved in MeOH (1 mL)/AcOH (50 µL). Formaldehyde 37%
solution (27 µL, 0.36 mmol) was added and the mixture stirred for
15 min. NaBH3CN (28 mg, 0.45 mmol) was then added, and the
reaction mixture was stirred for 16 h at 25 °C. EtOAc (50 mL)
was added, and the mixture was washed with saturated NaHCO3
(20 mL) and brine (20 mL). The crude material was purified by
reverse phase HPLC providing 12 as pale yellow solid (40 mg,
40%). 1H NMR (300 MHz, DMSO-d6) δ 7.33-7.18 (m, 5H), 6.93
(d, J ) 8.5 Hz, 2H), 6.57 (d, J ) 8.5 Hz, 2H), 5.88 (s, 2H), 5.71
(q, J ) 5.1 Hz, 1H), 5.51 (brs, 2H), 4.35 (s, 2H), 3.97 (s, 2H),
2.70 (d, J ) 5.1 Hz, 3H). MS (ESI) m/e 336 (M + H)+.
1
amine 10 (8.78 g, 80% over 3 steps) as a light brown solid. H
NMR (300 MHz, DMSO-d6) δ 8.19 (d, J ) 8.8 Hz, 2H), 7.48 (d,
J ) 9.2 Hz, 2H), 7.18-7.31 (m, 3H), 7.05-7.17 (m, 2H), 6.13 (s,
2H), 5.90 (s, 2H), 4.30 (s, 2H), and 3.99 (s, 2H); MS (ESI) m/e )
352 (M + H)+.
5-(4-Amino-phenyl)-6-benzyloxymethyl-pyrimidine-2,4-di-
amine (11). To a solution of 20 wt % Pd(OH)2/C (wet, 600 mg) in
MeOH (140 mL) was added 6-benzyloxymethyl-5-(4-nitrophenyl)-
pyrimidine-2,4-diamine 10 (5.00 g, 14.25 mmol) in a heavy walled
high-pressure reaction vessel. The vessel was charged with H2 (60
psi) and the mixture was stirred at room temperature for 14 h. The
reaction mixture was filtered through a nylon membrane and the
solution was concentrated in vacuo followed by trituration with
MeOH (20 mL). 5-(4-Amino-phenyl)-6-benzyloxymethyl-pyrimi-
dine-2,4-diamine (11, 4.34 g, 95%) was obtained as a light yellow
Cyclopentanecarboxylic Acid [4-(2,4-Diamino-6-benzyloxy-
methyl-pyrimidin-5-yl)-phenyl]-methyl-amide (compound 13f).
This compound was prepared in a fashion similar to that for 13a
1
substituting intermediate 12 for 11. H NMR (300 MHz, DMSO-
d6) δ 7.22-7.33 (m, 7H), 7.14-7.20 (m, 2H), 6.06 (brs, 2H), 5.80
(brs, 2H), 4.28 (s, 2H), 3.98 (s, 2H), 3.17 (s, 3H), 2.74-2.55 (m,
1H), 1.12-1.72 (m, 8H). HRMS (ESI) calcd for C25H30N5O2 (M
+ H)+ 432.2394, found 432.2397.
Tetrahydro-furan-2-carboxylic Acid [4-(2,4-Diamino-6-ben-
zyloxymethyl-pyrimidin-5-yl)-phenyl]-amide (compound 13g).
1H NMR (300 MHz, DMSO-d6) δ 9.73 (s, 1H), 7.55 (d, J ) 8.5
Hz, 2H), 7.31-7.13 (m, 5H), 7.15 (d, J ) 8.5 Hz, 2H), 6.01 (brs,
2H), 5.67 (brs, 2H), 4.43-4.36 (m, 1H), 4.33 (s, 2H), 4.03-3.96-
(m, 1H), 3.96 (s, 2H), 3.88-3.81 (m, 1H), 2.24-2.15 (m, 1H),
2.05-1.83 (m, 3H). MS (APCI) m/e 420 (M + H)+. Anal.
(C23H25N5O3 ‚ 0.25 CH3CN ‚ 1.2 H2O) C, H, N.
N-[4-(2,4-Diamino-6-benzyloxymethyl-pyrimidin-5-yl)-phen-
yl]-isonicotinamide (compound 13h). 1H NMR (500 MHz,
DMSO-d6) δ 10.65 (s, 1H), 8.85-8.76 (m, 2H), 7.94-7.80 (m,
4H), 7.36-7.23 (m, 7H), 4.49 (s, 2H), 4.20 (s, 2H). HRMS (ESI)
calcd for C24H23N6O2 (M + H)+ 427.1877, found 427.1883.
N-[4-(2,4-Diamino-6-benzyloxymethyl-pyrimidin-5-yl)-phen-
yl]-2-pyridin-3-yl-acetamide (compound 13i). 1H NMR (300
MHz, DMSO-d6) δ 10.30 (s, 1 H), 8.55 (d, J ) 1.7 Hz, 1H), 8.47
(dd, J ) 4.7, 1.7 Hz, 1H), 7.72-7.80 (m, 1H), 7.63 (d, J ) 8.5
Hz, 2H), 7.37 (dd, J ) 7.5, 4.4 Hz, 1H), 7.09-7.31 (m, 7H), 5.95
(s, 2H), 5.60 (s, 2H), 4.32 (s, 2H), 3.95 (s, 2H), 3.72 (s, 2H). MS
(ESI) m/e 441 (M + H)+. Anal. (C25H24N6O2 ‚ 0.3 CF3COOH ‚
0.75 H2O) C, H, N.
1
solid. H NMR (300 MHz, DMSO-d6) δ 7.16-7.37 (m, 5H) 6.85
(d, J ) 8.1 Hz, 2H) 6.60 (d, J ) 8.5 Hz, 2H) 5.86 (s, 2H) 5.49 (s,
2H) 5.12 (s, 2H) 4.35 (s, 2H) 3.97 (s, 2H); MS (ESI) m/e ) 322
(M + H)+.
General Procedure for Synthesis of Amide Derivative: N-[4-
(2,4-Diamino-6-benzyloxymethyl-pyrimidin-5-yl)-phenyl]-aceta-
mide (compound 13a). To a stirred solution of HOAc (9.3 mg,
0.16 mmol) and TBTU (70 mg, 0.22 mmol) in DMF (1 mL) were
added 5-(4-amino-phenyl)-6-benzyloxymethyl-pyrimidine-2,4-di-
amine 11 (50 mg, 0.16 mmol) and N,N′-diisopropylethylamine (0.27
mL, 1.56 mmol). After stirring at RT for 12 h, the product was
precipitated by addition of H2O (25 mL), dissolved in 2:1 MeOH/
DMSO, and separated by preparative RP-HPLC to yield 13a as an
1
off-white solid (20 mg, 35%). H NMR (300 MHz, DMSO-d6) δ
9.99 (s, 1H), 7.61 (d, J ) 8.5 Hz, 2H), 7.22-7.32 (m, 3H), 7.15-
7.20 (m, 2H), 7.12 (d, J ) 8.5 Hz, 2H), 6.03 (s, 2H), 5.68 (s, 2H),
4.33 (s, 2H), 3.96 (s, 2H), 2.06 (s, 3H). HRMS (ESI) calcd for
C20H22N5O2 (M + H)+ 364.1768, found 364.1768. Anal. (C20H21N5O2
‚ 0.35 CF3COOH) C, H, N.
The following compounds were prepared in a fashion similar to
that for 13a starting from common intermediate 11.
N-[4-(2,4-Diamino-6-benzyloxymethyl-pyrimidin-5-yl)-phen-
yl]-propionamide (compound 13b). 1H NMR (300 MHz, DMSO-
d6) δ 9.91 (s, 1H), 7.63 (d, J ) 8.5 Hz, 2H), 7.35-7.15 (m, 5H),
7.12 (d, J ) 8.5 Hz, 2H), 5.99 (s, 2H), 5.64 (s, 2H), 4.33 (s, 2H),
3.96 (s, 2H), 2.34 (q, J ) 7.6 Hz, 2H), 1.10 (d, J ) 7.6 Hz, 3H).
MS (ESI) 378 (M + H)+. Anal. (C21H23N5O2 ‚ 0.4 CF3COOH ‚
1.45 H2O) C, H, N.
N-[4-(2,4-Diamino-6-benzyloxymethyl-pyrimidin-5-yl)-phen-
yl]-3-methyl-butyramide (compound 13c). 1H NMR (300 MHz,
DMSO-d6) δ 11.69 (s, 1H), 10.01 (s, 1H), 8.26 (s, 1H), 7.71 (d, J
) 8.4 Hz, 2H), 7.26-7.35 (m, 5H), 7.14 (d, J ) 8.7 Hz, 2H), 6.96
(s, 1H), 4.48 (s, 2H), 4.18 (s, 2H), 2.21 (d, J ) 7.2 Hz, 2H), 2.05-
2.14 (m, 1H), 0.95 (d, J ) 6.9 Hz, 6H). HRMS (ESI) calcd for
C23H28N5O2 (M + H)+ 406.2238, found 406.2236.
Cyclopropanecarboxylic Acid [4-(2,4-Diamino-6-benzyloxy-
methyl-pyrimidin-5-yl)-phenyl]-amide (compound 13d). 1H NMR
(300 MHz, DMSO-d6) δ 10.23 (s, 1 H), 7.63 (d, J ) 8.5 Hz, 2H),
7.15-7.33 (m, 5H), 7.12 (d, J ) 8.5 Hz, 2H), 5.95 (brs, 2H), 5.60
(brs, 2H), 4.33 (s, 2H), 3.96 (s, 2H), 1.73-1.87 (m, 1H), 0.75-
0.85 (m, 4H). HRMS (ESI) calcd for C22H24N5O2 (M + H)+
390.1925, found 390.1925.
N-(4-{2,4-Diamino-6-[(benzyloxy)methyl]pyrimidin-5-yl}phenyl)-
1
thiophene-3-carboxamide (compound 13j). H NMR (300 MHz,
DMSO-d6) δ 10.11 (s, 1H), 8.33-8.39 (m, 1H), 7.81 (d, J ) 8.5
Hz, 2H), 7.69-7.62 (m, 2H), 7.15-7.33 (m, 7H), 5.97 (s, 2H),
5.64 (brs, 2H), 4.34 (s, 2H), 3.98 (s, 2H). MS (ESI) m/e 432 (M +
H)+. Anal. (C23H21N5O2S ‚ 0.9 H2O) C, H, N.
N-(4-{2,4-Diamino-6-[(benzyloxy)methyl]pyrimidin-5-yl}-
1
phenyl)-2-thien-3-ylacetamide (compound 13k). H NMR (300
MHz, DMSO-d6) δ 10.19 (s, 1H), 7.63 (d, J ) 8.5 Hz, 2H), 7.49
(dd, J ) 4.9, 2.9 Hz, 1H), 7.08-7.36 (m, 9H), 5.95 (s, 2H), 5.61
(brs, 2H), 4.32 (s, 2H), 3.95 (s, 2H), 3.67 (s, 2H). MS (ESI) m/e
441 (M + H)+. Anal. (C24H23N5O2 ‚ 0.1 CF3COOH) C, H, N.
2-(2-Bromothien-3-yl)-N-(4-{2,4-diamino-6-[(benzyloxy)meth-
yl]pyrimidin-5-yl}phenyl)-acetamide (compound 13l). 1H NMR
(300 MHz, DMSO-d6) δ 10.27 (s, 1H), 7.64 (d, J ) 8.5 Hz, 2H),
7.58 (d, J ) 5.8 Hz, 1H), 7.32-7.16 (m, 5H), 7.14 (d, J ) 8.5 Hz,
2H), 7.06 (d, J ) 5.4 Hz, 1H), 5.96 (s, 2H), 5.62 (s, 2H), 4.33 (s,
2H), 3.95 (s, 2H), 3.68 (s, 2H). HRMS (ESI) calcd for C24H22-
BrN5O2S (M + H)+ 524.0750, found 524.0759.
N-(4-{2,4-Diamino-6-[(benzyloxy)methyl]pyrimidin-5-yl}-
phenyl)-2-phenylacetamide (compound 13m). 1H NMR (300
MHz, DMSO-d6) δ 10.22 (s, 1H), 7.64 (d, J ) 8.5 Hz, 2H), 7.09-
7.40 (m, 12H), 5.95 (s, 2H), 5.60 (s, 2H), 4.32 (s, 2H), 3.94 (s,
2H), 3.65 (s, 2H). MS (ESI) m/e 440 (M + H)+. Anal. (C26H25N5O2
‚ 0.95 H2O) C, H, N.
Cyclopentanecarboxylic Acid [4-(2,4-Diamino-6-benzyloxy-
methyl-pyrimidin-5-yl)-phenyl]-amide (compound 13e). 1H NMR
(300 MHz, DMSO-d6) δ 9.90 (s, 1 H), 7.65 (d, J ) 8.7 Hz, 2H),
7.15-7.32 (m, 5H), 7.12 (d, J ) 8.7 Hz, 2H), 5.93 (brs, 2H), 5.59
(brs, 2H), 4.33 (s, 2H), 3.96 (s, 2H), 2.74-2.85 (m, 1H), 1.50-
1.91 (m, 8H). HRMS (ESI) calcd for C24H28N5O2 (M + H)+
418.2238, found 418.2242.
6-Benzyloxymethyl-5-(4-methylamino-phenyl)-pyrimidine-
2,4-diamine (compound 12). This intermediate was prepared by
reductive amination of formaldehyde with 11. 5-(4-amino-phenyl)-
6-benzyloxymethyl-pyrimidine-2, 4-diamine 11 (96 mg, 0.3 mmol)
N-(4-{2,4-Diamino-6-[(benzyloxy)methyl]pyrimidin-5-yl}-
1
phenyl)-3-phenylpropanamide (compound 13n). H NMR (300
MHz, DMSO-d6) δ 11.68 (s, 1H), 10.07 (s, 1H), 8.26 (s, 1H), 7.69
(d, J ) 8.4 Hz, 2H), 7.17-7.37 (m, 10H), 7.14 (d, J ) 8.4 Hz,
2H), 4.47 (s, 2H), 4.17 (s, 2H), 2.93 (t, J ) 7.5 Hz, 2H), 2.67 (t,