Journal of Medicinal Chemistry
Article
further purification. A solution of the intermediate in DMA, containing
guanidine carbonate (130 mg, 0.72 mmol), was stirred at 140 °C for 8 h,
cooled to room temperature, diluted with water (40 mL), and
extracted with DCM (3 × 50 mL). The extracts were dried over
Na2SO4 and concentrated in vacuo to give a residue that was subjected
to silica gel chromatography (15:1 DCM/MeOH, 1% NH3·H2O) to
preparation of 4k as a colorless powder (127 mg, 76% over 2 steps).
1H NMR (300 MHz, CDCl3): δ 1.53 (s, 9 H), 4.78 (brs, 2 H), 5.60
(brs, 1 H), 6.75 (d, J = 7.70 Hz, 1 H), 7.07 (d, J = 7.98 Hz, 1 H), 7.40
(t, J = 8.11 Hz, 1 H), 7.74 (brs, 1 H). 13C NMR (100 MHz, DMSO-
d6): δ 28.45, 81.59, 104.62, 110.56, 117.92, 132.04, 153.60, 154.09,
159.95, 162.00. HRMS (EI) calcd for C12H16N4O, 232.1324; found,
232.1326. The purity of the compound was >95% by HPLC.
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afford 4j as a colorless powder (146 mg, 81% over two steps). H
NMR (300 MHz, CDCl3): δ 4.83 (brs, 2 H), 6.34 (dd, J = 7.98, 1.10
Hz, 1 H), 7.13 (t, J = 7.84 Hz, 3 H), 7.21−7.29 (m, 3 H), 7.36 (t, J =
8.25 Hz, 1 H), 7.43 (t, J = 7.84 Hz, 2 H). 13C NMR (100 MHz,
DMSO-d6): δ 102.47, 107.09, 118.97, 120.15, 124.71, 130.18, 132.36,
154.96, 155.03, 155.45, 160.63, 161.34. HRMS (EI) calcd for
C14H12N4O, 252.1011; found, 252.1010. The purity of the compound
was >95% by HPLC.
5-(Neopentyloxy)quinazoline-2,4-diamine (4p). Compound 4p
was obtained from neopentanol using the general method described
for the preparation of 4k as a colorless powder (141 mg, 80% over two
1
steps). H NMR (300 MHz, CDCl3): δ 1.12 (s, 9 H), 3.79 (s, 2 H),
4.87 (brs, 2 H), 6.53 (d, J = 7.98 Hz, 1 H), 7.03 (d, J = 8.53 Hz, 1 H),
7.44 (t, J = 8.25 Hz, 1 H). 13C NMR (100 MHz, DMSO-d6): δ 26.55,
31.49, 78.50, 101.20, 101.83, 116.83, 132.68, 154.56, 156.92, 160.43,
161.94. HRMS (EI) calcd for C13H18N4O, 246.1481; found, 246.1479.
The purity of the compound was >95% by HPLC.
5-(Cyclopentyloxy)quinazoline-2,4-diamine (4q). Compound 4q
was obtained from cyclopentanol using the general method described
for the preparation of 4k as a colorless powder (136 mg, 77% over two
steps). 1H NMR (300 MHz, MeOH-d4): δ 1.68−1.87 (m, 4 H), 1.87−
2.14 (m, 4 H), 4.98−5.09 (m, 1 H), 6.67 (d, J = 8.25 Hz, 1 H), 6.86
(d, J = 8.25 Hz, 1 H), 7.45 (t, J = 8.25 Hz, 1 H). 13C NMR (100 MHz,
DMSO-d6): δ 23.56, 32.28, 80.31, 101.64, 103.12, 116.26, 132.58,
154.45, 155.45, 160.21, 161.98. HRMS (EI) calcd for C13H16N4O,
244.1324; found, 244.1328. The purity of the compound was >95% by
HPLC.
5-Ethoxyquinazoline-2,4-diamine (4k). A solution of ethanol
(40 mg, 0.86 mmol) in dry THF (1 mL) was added to a cooled (0 °C)
THF solution (2 mL) containing sodium hydride (80% oil dispersion,
32 mg, 1.08 mmol) suspended in under nitrogen atmosphere. A
solution of 2,6-difluorobenzolitrile (5b, 100 mg, 0.72 mmol) in THF
(2 mL) was added at 0 °C, and the resulting mixture was stirred for 6 h
at room temperature, poured on to crushed ice−water, and extracted
with DCM (3 × 40 mL). The extracts were dried over Na2SO4 and
concentrated in vacuo to afford intermediate without further
purification. The solution of the intermediate in DMA, containing
guanidine carbonate (130 mg, 0.72 mmol), was stirred at 140 °C for
8 h, cooled to room temperature, diluted with water (40 mL), and
extracted with DCM (3 × 50 mL). The extracts were dried over
Na2SO4 and concentrated in vacuo to give a residue that was subjected
to silica gel chromatography (15:1 DCM/MeOH, 1% NH3·H2O) to
afford 4k as a colorless powder (97 mg, 66% over two steps). 1H NMR
(300 MHz, DMSO-d6): δ 1.41 (t, J = 6.89 Hz, 3 H), 4.17 (q, J =
7.13 Hz, 2 H), 6.07 (s, 2 H), 6.55 (d, J = 8.21 Hz, 1 H), 6.77 (d, J =
8.21 Hz, 1 H), 7.34 (s, 2 H), 7.36 (t, J = 8.21 Hz, 1 H). 13C NMR
(100 MHz, DMSO-d6): δ 14.43, 64.40, 101.09, 102.08, 116.06, 132.87,
153.61, 156.60, 159.96, 161.97. HRMS (EI) calcd for C10H17N4O,
204.1011; found, 204.1007. The purity of the compound was >95% by
HPLC.
5-Butoxyquinazoline-2,4-diamine (4l). Compound 4l was ob-
tained from n-butanol using the general method described for the
preparation of 4k as a colorless powder (155 mg, 93% over two steps).
1H NMR (300 MHz, DMSO-d6): δ 0.94 (t, J = 7.33 Hz, 3 H), 1.37−
1.51 (m, 2 H), 1.73−1.85 (m, 2 H), 4.11 (t, J = 6.16 Hz, 2 H), 5.99 (s,
2 H), 6.54 (d, J = 7.33 Hz, 1 H), 6.76 (d, J = 7.92 Hz, 1 H), 7.25 (s,
2 H), 7.34 (t, J = 7.92 Hz, 1 H). 13C NMR (100 MHz, DMSO- d6): δ
13.66, 18.89, 30.43, 68.38, 101.08, 102.14, 116.05, 132.88, 153.59,
156.70, 159.90, 161.96. HRMS (EI) calcd for C12H16N4O, 232.1324;
found, 232.1321. The purity of the compound was >95% by HPLC.
5-Octoxyquinazoline-2,4-diamine (4m). Compound 4m was
obtained from n-octanol using the general method described for the
preparation of 4k as a colorless powder (143 mg, 69% over two steps).
1H NMR (300 MHz, CDCl3): δ 0.89 (t, J = 7.33 Hz, 3 H), 1.26−1.42
(m, 8H), 1.43−1.57 (m, 2 H), 1.84−1.96 (m, 2 H), 4.12 (t, J =
6.60 Hz, 2 H), 4.93 (brs, 2 H), 6.53 (d, J = 8.21 Hz, 1 H), 7.02 (d, J =
8.50 Hz, 1 H), 7.44 (t, J = 8.21 Hz, 1 H). 13C NMR (100 MHz,
DMSO-d6): δ 13.94, 22.06, 25.58, 28.31, 28.63, 28.66, 31.20, 68.72,
100.96, 102.55, 115.44, 133.17, 152.48, 156.72, 159.45, 162.00. HRMS
(EI) calcd for C16H24N4O, 288.1950; found, 288.1954. The purity of
the compound was >95% by HPLC.
5-(Cyclohexyloxy)quinazoline-2,4-diamine (4r). Compound 4r
was obtained from cyclohexanol using the general method described
for the preparation of 4k as a colorless powder (178 mg, 96% over two
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steps). H NMR (300 MHz, CDCl3): δ 1.32−1.54 (m, 3 H), 1.55−
1.72 (m, 3 H), 1.73−1.89 (m, 2 H), 2.05−2.17 (m, 2 H), 4.42−4.56
(m, J = 8.97, 8.97, 4.47, 4.26 Hz, 1 H), 5.22 (brs, 2 H), 5.68 (brs, 1 H),
6.57 (d, J = 8.25 Hz, 1 H), 7.01 (d, J = 8.25 Hz, 1 H), 7.43 (t, J =
8.25 Hz, 1 H), 7.77 (s, 1 H). 13C NMR (100 MHz, DMSO-d6): δ
23.07, 24.94, 30.90, 75.77, 101.76, 103.29, 115.89, 132.76, 153.93,
155.29, 159.98, 162.06. HRMS (EI) calcd for C14H18N4O, 258.1481;
found, 258.1480. The purity of the compound was >95% by HPLC.
5-(Benzyloxy)quinazoline-2,4-diamine (4s). Compound 4s was
obtained from penylmethanol using the general method described for
the preparation of 4k as a colorless powder (88 mg, 46% over two
steps). 1H NMR (300 MHz, CDCl3): δ 5.17 (s, 2 H), 5.58 (brs, 2 H),
5.94 (brs, 1 H), 6.66 (d, J = 8.25 Hz, 1 H), 7.07 (d, J = 8.53 Hz, 1 H),
7.34−7.52 (m, 6 H), 7.59 (brs, 1 H). 13C NMR (100 MHz, DMSO-
d6): δ 70.29, 101.10, 103.19, 115.54, 128.05, 128.30, 128.72, 133.12,
136.25, 152.33, 156.35, 159.40, 161.93. HRMS (EI) calcd for
C15H14N4O, 266.1168; found, 266.1171. The purity of the compound
was >95% by HPLC.
N5-tert-Butylquinazoline-2,4,5-triamine (4t). To a thick-wall
borosilicate glass vial (10 mL), 2,6-difluorobenzonirile (5b, 500 mg,
3.6 mmol), tert-butylamine (315 mg, 4.3 mmol), K2CO3 (745 mg,
5.4 mmol), and DMSO (2 mL) were added. The reaction vial was
sealed and placed in the microwave reactor and irradiated as at 110 °C
for 15 min. After it was cooled to room temperature, the mixture was
extracted with EtOAc, washed by saturated brine, and dried over
Na2SO4. The filtrate was concentrated in vacuo giving a residue that
was subjected to silica gel chromatography [petroleum ether (PE) to
7% EtOAc in PE] to afford intermediate 7a (522 mg, 76%). 1H NMR
(300 MHz, CDCl3): δ 1.43 (s, 9 H), 4.65 (brs, 1 H), 6.37 (t, J =
8.39 Hz, 1 H), 6.67 (d, J = 8.53 Hz, 1 H), 7.21−7.33 (m, 1 H).
A solution of 7a (100 mg, 0.52 mmol) and guanidine carbonate
(94 mg, 0.52 mmol) in 3 mL of DMA was stirred at 140 °C for 8 h,
cooled to room temperature, diluted with water (40 mL), and extracted
with DCM (3 × 50 mL). The extracts were dried over Na2SO4 and
concentrated in vacuo to give a residue that was subjected to silica gel
chromatography (12:1 DCM/MeOH, 1% NH3·H2O) to afford 4t as a
5-(2,2,2-Trifluoroethoxy)quinazoline-2,4-diamine (4n). Com-
pound 4n was obtained from 2,2,2-trifluoromethanol using the general
method described for the preparation of 4k as a colorless powder (102
mg, 55% over two steps). 1H NMR (300 MHz, DMSO-d6): δ 4.97 (q,
J = 8.70 Hz, 2 H), 6.23 (brs, 2 H), 6.68 (d, J = 7.92 Hz, 1 H), 6.88 (d,
J = 8.21 Hz, 1 H), 6.96 (brs, 1 H), 7.42 (t, J = 8.21 Hz, 1 H), 7.52 (brs,
1 H). 13C NMR (100 MHz, DMSO-d6): δ 65.01 (q, JC−F = 34.3 Hz),
100.91, 102.93, 117.58, 123.93 (q, JC−F = 247.9 Hz), 132.76, 153.34,
154.62, 159.90, 161.47. HRMS (EI) calcd for C10H9N4OF3, 258.0728;
found, 258.0730. The purity of the compound was >95% by HPLC.
5-tert-Butoxyquinazoline-2,4-diamine (4o). Compound 4o was
obtained from tert-butanol using the general method described for the
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colorless powder (94 mg, 78%). H NMR (300 MHz, DMSO-d6): δ
1.08 (s, 9 H), 4.52 (brs, 1 H) 5.88 (s, 2 H), 6.63 (d, J = 7.62 Hz, 1 H),
6.93 (d, J = 8.21 Hz, 1 H), 7.30 (t, J = 7.92 Hz, 1 H), 8.34 (brs, 2 H).
13C NMR (100 MHz, DMSO-d6): δ 28.41, 53.65, 109.22, 120.21,
120.53, 130.96, 143.42, 153.36, 159.68, 163.39. HRMS (EI) calcd for
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dx.doi.org/10.1021/jm2015952 | J. Med. Chem. 2012, 55, 3135−3143