Synthesis of N-substituted-6-alkoxypteridin-4-amine

Article abstract of DOI:10.1002/jhet.883

A novel seven-step methodology for the synthesis of N-substituted-6- alkoxypteridin-4-amine has been developed with the total yields of 35.4-41%. Twenty new compounds were synthesized by heterocyclization of easily prepared 3-amino-6-bromopyrazine-2-carboxamide, subsequent alkoxylation, chlorination, and nucleophilic substitution. Their structures were confirmed by ¹H-NMR, ¹³C-NMR, ESI-MS, and elemental analysis. The structure of N-(3-chloro-4-fluorophenyl)-6-ethoxypteridin-4-amine was further determined by X-ray crystallographic analysis. It was found that different chlorinating reagents gave different products. The possible chlorination mechanism was discussed.

Full text of DOI:10.1002/jhet.883

July 2012
Synthesis of N-Substituted-6-alkoxypteridin-4-amine
865
a
b
b
b
*
Chonggang Duan, Jiong Jia, Rongxiu Zhu, and Jianwu Wang
aKey Laboratory of Chemical Drugs of Shandong Province, Shandong Institute of Pharmaceutical
Industry, Jinan 250101, People’s Republic of China
bCollege of Chemistry and Chemical Engineering, Shandong University, Jinan 250100,
People’s Republic of China
*
E-mail: jwwang@sdu.edu.cn
Received December 3, 2010
DOI 10.1002/jhet.883
View this article online at wileyonlinelibrary.com.
A novel seven-step methodology for the synthesis of N-substituted-6-alkoxypteridin-4-amine has been
developed with the total yields of 35.4–41%. Twenty new compounds were synthesized by heterocycli-
zation of easily prepared 3-amino-6-bromopyrazine-2-carboxamide, subsequent alkoxylation, chlorina-
tion, and nucleophilic substitution. Their structures were confirmed by 1H-NMR, 13C-NMR, ESI-MS,
and elemental analysis. The structure of N-(3-chloro-4-fluorophenyl)-6-ethoxypteridin-4-amine was
further determined by X-ray crystallographic analysis. It was found that different chlorinating reagents
gave different products. The possible chlorination mechanism was discussed.
J. Heterocyclic Chem., 49, 865 (2012).
INTRODUCTION
Although 6(7)-alkyl or aryl substituted pteridines can be
conveniently obtained by Isay and Taylor method [27], there
has been no report on the synthesis of 6(7)-alkoxyl substituted
pteridines. Previously, we have tried to obtain 6(7)-alkoxyl
substituted pteridines by cyclization of 4-[(un)substituted
anilino]-5,6-diaminopyrimidine 3 with oxalic acid [28].
However, we didn’t get 4-arylamiopteridine-6,7-dione 5,
but got the unexpected 4-amino-8-arylpteridine-6,7-dione
4 due to the regioselectivity of the cyclization, as shown in
Scheme 1.
The protein kinases (PKs) regulate many cellular func-
tions, such as cell growth, proliferation, mitosis, and
death [1]. PKs, therefore, have become primary targets
for drug discovery for the treatment of tumour and many
other diseases [2–6]. In recent years, great efforts have
been devoted to the discovery of therapeutically useful
inhibitors of PKs, and a variety of templates which pro-
vide selective inhibition both within and across different
PK families have been identified [7,8]. Among these
templates, 4-anilinoquinazolines and related 4-anilinopyrido
[d]-pyrimidines have served as the core template for a va-
riety of ATP-competitive epidermal growth factor recep-
tor (EGFr) tyrosine kinase inhibitors [9]. The leading
example is the clinically approved anticancer agent Iressa
(ZD1839) 1 (Fig. 1) [10,11]. Additionally, purine deriva-
tives have been reported as kinase inhibitors for mainly
cyclin-dependent kinases [12], quinoxalines as potent ki-
nase inhibitors of platelet derived growth factor receptor
tyrosine kinase [13,14], and pteridine-like molecules 2
(Fig. 1) from Abbott compound library as an adenosine
kinase inhibitor [15,16].
In this article, we developed a novel method to get the de-
sired compounds 14–33, and their structures were confirmed
by 1H-NMR, 13C-NMR, ESI-MS, and elemental analysis.
RESULTS AND DISCUSSION
The synthesis of pteridine-liked compounds are de-
scribed in Scheme 2. The intermediates 7–10 can be
obtained by the reported methods [29–31]. The key inter-
mediates 12a–c were prepared by the alkoxylation of
10, followed by chlorination of the resulting 6-alkoxy-4-
pteridinone 11a–c with thionyl chloride under catalytic
amount of DMF. Finally, the desired compounds 14–31
were obtained by the reactions of 12a–c with equimolar an-
iline or substituted aniline in isopropanol in 79.4–86.2%
yields, and 32, 33 were prepared by reactions of 12a with
equimolar piperidine and morpholine.
To search for novel lead PKs inhibitors, based on the
structure and activity relationship of the EGFr inhibitors
[17–26], we designed and synthesized a series of N-
substituted-6-alkoxypteridine-4-amine compounds 14–33
(Fig. 1, Table 1).
© 2012 HeteroCorporation

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C. Duan, J. Jia, R. Zhu, and J. Wang
Vol 49
Figure 1. Comparison of reported kinase inhibitors and designed compounds.
The influence of amino group on the reactivity.
In
proposed mechanism of DMA involved chlorination was
shown in Scheme 4. The generated HCl results in the
demethylation effect but has no influence on the other
groups (R1¼CH3).
3-amino-6-bromopyrazine-2-carboxamide 9, the 6-bromo
is inert to sodium alkoxylate because of the electronic
effects of 3-amino group. Therefore, it is better to cyclize 9
to form 10 first, and the subsequent nucleophilic reaction
can take place smoothly.
The chlorination of 6-alkoxyl-4 (3H)-pteridinone 11a-c. To
obtain the 6-alkoxyl-4-chloropteridine 12a–c, we used
different chlorinating reagents, and the results are shown in
Table 2.
The chlorination reactions can be carried out in good
yields by using thionyl chloride and catalytic amount of
DMF, and the products were pure enough to be used
directly in the next reaction. The possible reaction
mechanism is shown in Scheme 5.
The single crystal structure of compound 26.
The
From Table 2, it can be seen that the requisite 4-
chloropteridines were obtained in poor yields when
11a–c were treated with POCl3 alone. Catalytic amount
of DMA could reduce the yields of 4-chloropteridines
due to the formation of impurities 13a–c (Scheme 3).
When equivalent amount of DMA was added to the sys-
tem, no desired products were obtained but only the by-
products 13a–c. While SOCl2/DMF could give the
corresponding products in excellent yields, hardly influ-
enced by the 6-substituent group.
single crystal structure of compound 26 was shown
in Figure 2. The formula of 26 is C14H11ClFN5O,
Mr = 319.73, Monoclinic; P2(1)/c; a = 12.677(3) Å;
b = 16.172(4) Å; c = 6.8673(15) Å; a = 90.00ꢀ;
b = 92.009(4)ꢀ; g= 90.00ꢀ; V = 1407.0(5) Å3; Z = 4;
Dc = 1.509 g cmꢁ3; m = 0.292 mmꢁ1; F(000) = 656;
T = 298(2) K; yellow block; 0.28 mm ꢂ 0.23 mm ꢂ
0.06 mm.
In summary, we have developed an original route for
the synthesis of N-substituted-6-alkoxypteridin-4-amine.
The seven-step procedure, using very inexpensive start-
ing materials and involving 6-alkoxy-4-chloropteridine
Based on the above results, we concluded that DMA
is not a catalyst but a reactant in these reactions. The
Table 1
Structures of compounds 14–33.
No.
R1
R2
No.
R1
R2
14
15
16
17
18
19
20
21
22
CH3ꢁ
CH3ꢁ
CH3ꢁ
CH3ꢁ
CH3ꢁ
CH3ꢁ
CH3ꢁ
CH3ꢁ
4-OCH3
4-CH3
H
4-F
4-Cl
3-Cl-4-F
3-Cl
3-Br
24
25
26
27
28
29
30
31
32
CH3CH2ꢁ
3-Cl
3-Br
3-Cl-4-F
3-Cl
4-Cl
3-Br
CH3CH2ꢁ
CH3CH2ꢁ
CH3OCH2CH2ꢁ
CH3OCH2CH2ꢁ
CH3OCH2CH2ꢁ
CH3OCH2CH2ꢁ
CH3OCH2CH2ꢁ
CH3ꢁ
4-F
3-Cl-4-F
CH3CH2ꢁ
CH3CH2ꢁ
4-NO2
23
4-Cl
33
CH3ꢁ
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Synthesis of N-Substituted-6-alkoxypteridin-4-amine
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Scheme 1. The regioselectivity of cyclization of compound 3.
was discussed. Efforts to explore the biological activities
of the compounds are ongoing in our group.
EXPERIMENTAL
All starting materials were obtained commercially, and all
solvents were dried using standard laboratory procedures.
Melting points were determined using a WRS-1B digital melt-
ing point apparatus and were reported uncorrected. 1H and
13C-NMR spectra were recorded on a Bruker AV 300 spec-
trometer. ESI-MS were recorded on an ABI API 4000
spectrometers. Elemental analyses were recorded on Elementar
Vario EL-III elemental analysis apparatus. Analytical thin-layer
chromatography was performed on silica gel 60 F-254 plates for
routine monitoring of reaction mixtures.
Compounds 7–10 were prepared according to literatures
[29–31].
General procedure for the synthesis of 11a–b. 6-
Methoxypteridin-4(3H)-one (11a) [30]. To a 250 mL flask with
a mechanical stirrer, a thermometer and a reflux condenser
attached to a CaCl2 dry tube, was added 100 mL methanol.
as the key intermediates, is very straightforward and
gives the overall yields of 35.4–41% under mild reaction
conditions. SOCl2 and catalytic amount of DMF were
used as the chlorinating reagents to get the 6-alkoxy-4-
chloropteridine conveniently, and its possible mechanism
Scheme 2. Synthesis of compounds 14–33.
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Table 2
Chlorination of 6-alkoxylpteridin-4(3H)-one with different reagents.
Entry
R1
Reagent
POCl3
POCl3
POCl3
Temperature (ꢀC)
Time (h)
Yield (%)
1
2
3
4
5
6
7
8
9
CH3ꢁ
100
82
82
82
82
90
100
82
90
82
82
82
4
6
6
6
6
6
3
5
6
5
5
6
53.5
55.8
57.4
26.4
20.7
22.6
_
_
_
87.9
86.5
85.8
CH3CH2ꢁ
CH3OCH2CH2ꢁ
CH3ꢁ
POCl3/DMAa
POCl3/DMAa
POCl3/DMAa
POCl3/DMAb
POCl3/DMAb
POCl3/DMAb
SOCl2/DMFc
SOCl2/DMFc
SOCl2/DMFc
CH3CH2ꢁ
CH3OCH2CH2ꢁ
CH3ꢁ
CH3CH2ꢁ
CH3OCH2CH2ꢁ
CH3ꢁ
10
11
12
CH3CH2ꢁ
CH3OCH2CH2ꢁ
aDMA(N,N-dimethylaniline) is catalytic amount.
bDMA: 6-alkoxypteridin-4(3H)-one = 1:1.
cDMF(N,N-Dimethylformamide) is catalytic amount.
Sodium (1.2 g, 0.052 mol) was carefully dissolved in the
methanol to get the sodium methoxide solution. Then 6-
bromopteridin-4(3H)-one 10 (4.54 g, 0.02 mol) was charged.
The mixture was refluxed for 6 h. When the starting material
disappeared, the mixture was cooled to room temperature,
poured into 150 mL water, and adjusted the pH to 3–4. The
white precipitate was filtered, washed with water, and
recrystalized with isopropanol and water to give 3.1 g white
11a. yield: 91.2%; m.p. 278–281ꢀC. 1H-NMR (300 MHz,
DMSO-d6) d: 8.69 (s, 1H, ArH), 8.24 (s, 1H, ArH), 4.02 (s, 3H,
OCH3); 13C-NMR (300MHz, DMSO-d6) d: 160.6, 158.4, 151.3,
146.6, 143.5, 130.4, 54.7; ESI-MS m/z: 179.07 [M+H]+. Anal.
calcd for C7H6N4O2: C, 47.19; H, 3.39; N, 31.45. found: C,
47.23; H, 3.35; N, 31.39.
6-Ethoxypteridin-4(3H)-one (11b). White powder, yield
89.7%; m.p. 260–261ꢀC; 1H-NMR (300 MHz, DMSO-d6) d:
8.66 (s, 1H, ArH), 8.22 (s, 1H, ArH), 4.46 (q, J = 7.2 Hz, 2H,
CH2CH3), 1.40 (t, J = 7.2 Hz, 3H, CH2CH3); 13C-NMR (300
MHz, DMSO-d6) d: 160.6, 158.0, 151.2, 146.5, 143.5, 130.4,
63.3, 14.6; ESI-MS m/z: 193.08 [M+H]+. Anal. calcd for
C8H8N4O2: C, 50.00; H, 4.20; N, 29.15. found C, 49.96; H,
4.22; N, 29.09.
OCH2CH2O), 3.33 (s, 3H, OCH3); 13C-NMR (300 MHz,
DMSO-d6) d: 160.5, 157.9, 151.3, 146.6, 143.5, 130.3, 70.2,
66.4, 58.6; ESI-MS m/z: 222.12 [M+H]+. Anal. calcd for
C9H10N4O2: C, 48.65; H, 4.54; N, 25.21. found C, 48.59; H,
4.58; N, 25.24.
General procedure for the synthesis of 12a–c. 4-Chloro-6-
methoxypteridine (12a). Compound 11a (3.0 g, 16.8 mmol),
20 mL thionyl chloride and 2 drops of N,N-dimethyl formamide
was charged into a 50 mL single necked round-bottom flask
with a magnetic stir bar, a thermometer and a refluxing
condensor. The mixture was refluxed with stirring for 5 h, then
distilled to dry under reduced pressure and the residue was
dissolved in 30 mL ethyl acetate. The mixture was washed with
water, saturated sodium bicarbonate, and water, dried with
anhydrous magnesium sulphate and distilled to dry to obtain 2.9
1
g 12a in 87.9% yield. Yellow powder. m.p. 140.2–141.5ꢀC. H-
NMR (300 MHz, DMSO-d6) d: 8.71 (s, 1H, ArH), 8.44 (s, 1H,
ArH), 4.04 (s, 3H, OCH3); 13C-NMR (300 MHz, DMSO-d6) d:
160.2, 158.6, 149.8, 147.1, 143.5, 130.3, 54.8; ESI-MS m/z:
197.2 [M(35Cl)+H]+, 199.1 [M(37Cl)+H]+.Anal. calcd for
Scheme 3. The chlorination of 11a-c by POCl3 and DMA.
6-(2-Methoxyethoxy)pteridin-4(3H)-one (11c). Ethylene glycol
monomethyl ether (3.5 g, 0.046 mol) was mixtured with 100
mL dry tetrahydrofuran in a 250 mL flask equipped with a
magnetic stir bar, a thermometer and a refluxing condensor.
Sodium hydride (60%) (1.8 g, 0.046 mol) was added and stired
for 30 mins at room temperature to get the sodium
methoxyethoxlate. 10 (4.54 g, 0.02 mol) was then charged and
the mixture was refluxed for 6 h. The solvent was distilled to
dry under reduced pressure, the residue was dissolved in 10 mL
water. The pH was adjusted to 3–4 with 4N hydrochloride acid
and the precipatated white solid was filtered, washed with water
and dried to give 3.89 g 11c, yield: 87.6%. m.p. 236.5–237ꢀC.
1H-NMR (300 MHz, DMSO-d6) d: 8.71 (s, 1H, ArH), 8.24 (s,
1H, ArH), 4.55–4.52 (m, 2H, OCH2CH2O), 3.76–3.73 (m, 2H,
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Scheme 4. The proposed mechanism of chlorination of 11a-c by POCl3 and DMA.
C7H5ClN4O: C, 42.77; H, 2.56; N, 28.50. found C, 42.83; H,
2.51; N, 28.47.
General procedure for the synthesis of compounds 13a–c.
N-(4-(6-Hydroxypteridin-4(3H)-ylidene)cyclohexa-2,5-dienylidene)-
N-methyl methanaminium chloride (13a). 11a (2.0 g, 0.011 mol)
and 20 mL phosphorus oxychloride were charged into a 100 mL
four-necked round-bottom flask. N,N-dimethylaniline (1.34 g,
0.012 mol) was added dropwise with stirring and the mixture was
heated to 100ꢀC for 3 h. The exceeding POCl3 was removed by
distillation under reduced pressure, the residue was dissolved in 30
mL ethyl acetate and then 20 mL cool water was added while
stirring. The organic layer was seperated and the aqueous layer was
extracted with ethyl acetate (20 mL ꢂ 2). The combined ethyl
acetate was dried with anhydrous magnesium sulphate and
decoloured with active carbon. The filtrate was distilled to dry
to get the title compound 2.55 g in 76.2% yield. Brown powder.
1H-NMR (300MHz, DMSO-d6) d: 10.44 (s, 1H, OH), 8.75
(d, J = 1.8 Hz 1H, ArH), 8.00 (s, 1H, ArH), 7.07 (d, J =
8.7 Hz, 2H, ArH), 6.69 (d, J = 8.7 Hz, 2H, ArH), 5.11 (d,
J = 2.1 Hz, 1H, NH), 2.86 (s, 6H, N(CH3)2); 13C-NMR (300
MHz, CDCl3) d: 163.4, 153.8, 152.5, 151.2, 150.6, 140.4,
4-Chloro-6-ethoxypteridine (12b). Yellowish powder, yield:
86.5%. m.p. 156–157ꢀC. 1H-NMR (300 MHz, DMSO-d6)
d: 9.16 (s, 1H, ArH), 9.03 (s, 1H, ArH), 4.60 (q, J = 7.2 Hz,
2H, OCH2CH3), 1.47 (t, J = 7.2 Hz, 3H, OCH2CH3); 13C-NMR
(300 MHz, DMSO-d6) d: 160.4, 158.7, 150.2, 147.2, 143.5,
129.9, 64.4, 14.6; ESI-MS m/z: 211.1 [M(35Cl)+H]+, 213.1
[M(37Cl)+H]+. Anal. calcd for C8H7ClN4O: C, 45.62; H, 3.35;
N, 26.60. found C, 45.57; H, 3.38; N, 26.64.
4-Chloro-6-(2-methoxyethoxy)pteridine (12c). Yellowish
powder, yield: 85.8%. m.p. 97.5–98ꢀC. 1H-NMR (300 MHz,
DMSO-d6) d: 8.73 (s, 1H, ArH), 8.65 (s, 1H, ArH), 4.55 (q,
2H, OCH2CH2O), 3.75 (t, J = 4.5 Hz, 2H, OCH2CH2O), 3.34
(s, 3H, OCH3); 13C-NMR (300 MHz, DMSO-d6) d: 159.0,
157.7, 149.5, 148.2, 143.2, 128.8, 69.6, 66.1, 58.0; ESI-MS
m/z: 241.1 [M(35Cl)+H]+, 243.1 [M(37Cl)+H]+.Anal. calcd for
C9H9ClN4O2: C, 44.92; H, 3.77; N, 23.28. found C, 44.87; H,
3.83; N, 23.31.
Scheme 5. The proposed mechanism of chlorination by SOCl2/DMF.
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Vol 49
6-Methoxy-N-p-tolylpteridin-4-amine (15). Yellow powder,
1
yield: 83.2%. m.p. 180–181ꢀC. H-NMR (300 MHz, DMSO-d6)
d: 8.85 (s, 1H, ArH), 8.67 (s, 1H, ArH), 8.36 (s, 1H, NH), 7.78
(d, J = 8.4 Hz, 2H, ArH), 7.24 (d, J = 8.4 Hz, 2H, ArH), 4.20
(s, 3H, OCH3), 2.33 (s, 3H, CH3); 13C-NMR (300 MHz,
DMSO-d6) d: 158.3, 157.9, 155.1, 149.01, 145.9, 136.0,
134.1, 129.5, 122.9, 122.1, 55.5, 21.0; ESI-MS m/z: 269.3
[M+H]+. Anal. calcd for C14H13N5O: C, 62.91; H, 4.90; N,
26.20. found: C, 62.85; H, 4.94; N, 26.27.
6-Methoxy-N-phenylpteridin-4-amine (16). Yellow powder,
1
yield: 79.5%. m.p. 148.5–150.5ꢀC. H-NMR (300 MHz, CDCl3)
d: 8.82 (s, 1H, ArH), 8.71 (s, 1H, ArH), 8.49 (s, 1H, NH), 7.86 (t,
J = 7.8 Hz, 2H, ArH), 7.42 (t, J = 7.8 Hz, 2H, ArH), 7.17 (t,
J = 8.4 Hz, 1H, ArH), 4.15 (s, 3H, OCH3); 13C-NMR (300
MHz, CDCl3) d: 157.5, 157.3, 155.9, 149.9, 145.5, 137.9,
129.2, 124.5, 121.6, 120.7, 54.6; ESI-MS m/z: 254.2 [M+H]+.
Anal. calcd for C13H11N5O: C, 61.65; H, 4.38; N, 27.65.
found: C, 61.57; H, 4.42; N, 27.61.
Figure 2. The single crystal structure of compound 26.
N-(4-Fluorophenyl)-6-methoxypteridin-4-amine (17). Yellow
powder, yield: 81.7%. m.p. 176–177ꢀC. 1H-NMR (300 MHz,
CDCl3) d: 8.79 (s, 1H, ArH), 8.72 (s, 1H, ArH), 8.42 (s, 1H, NH),
7.82-7.77 (m, 2H, ArH), 7.14–7.09 (m, 2H, ArH), 4.15 (s, 3H,
OCH3); 13C-NMR (300 MHz, CDCl3) d: 157.9, 157.4, 155.9,
150.0, 145.6, 133.9, 122.7, 121.6, 116.0, 115.7, 54.6; ESI-MS m/z:
272.4 [M+H]+. Anal. calcd for C14H14N6O: C, 57.56; H, 3.72; N,
25.82. found: C, 57.49; H, 3.85; N, 25.90.
N-(4-Chlorophenyl)-6-methoxypteridin-4-amine (18). Yellow
powder, yield: 84.6%. m.p. 163–165ꢀC. 1H-NMR (300 MHz,
CDCl3) d: 8.82 (s, 1H, ArH), 8.73 (s, 1H, ArH), 8.48 (s, 1H, NH),
7.86–7.82 (m, 2H, ArH), 7.40–7.37 (m, 2H, ArH), 4.17 (s, 3H,
OCH3); 13C-NMR (300 MHz, CDCl3) d: 157.6, 157.1, 155.7,
149.9, 145.7, 136.5, 129.4, 129.2, 121.8, 121.5, 54.6; ESI-MS m/z:
288.2 [M(35Cl)+H]+, 290.4 [M(37Cl)+H]+. Anal. calcd for
C13H10ClN5O: C, 54.27; H, 3.50; N, 24.34. found: C, 54.35; H,
3.53; N, 24.28.
N-(3-Chloro-4-fluorophenyl)-6-methoxypteridin-4-amine
(19). Yellow powder, yield: 86.2%. m.p. 170.5–172.5ꢀC.
1H-NMR (300 MHz, CDCl3) d: 8.84 (s, 1H, ArH), 8.75 (s, 1H,
ArH), 8.43 (s, 1H, NH), 8.10–8.07 (m, 2H, ArH), 7.71–7.66
(m, 1H, ArH), 7.27–7.16 (m, 1H, ArH), 4.17 (s, 3H, OCH3);
13C-NMR (300 MHz, CDCl3) d: 157.6, 157.1, 155.7, 150.0,
145.9, 134.6, 130.9, 122.7, 121.5, 120.3, 116.9, 54.7; ESI-MS
m/z: 306.1 [M(35Cl)+H]+, 308.1 [M(37Cl)+H]+. Anal. calcd for
C13H9ClFN5O: C, 51.08; H, 2.97; N, 22.91. found: C, 50.98;
H, 3.04; N, 22.85.
N-(3-Chlorophenyl)-6-methoxypteridin-4-amine (20). Yellow
powder, yield: 83.6%. m.p. 151–153ꢀC. 1H-NMR (300 MHz,
CDCl3) d: 8.85 (s, 1H, ArH), 8.74 (s, 1H, ArH), 8.48 (s, 1H,
NH), 8.03 (m, 1H, ArH), 7.72–7.69 (m, 1H, ArH), 7.36–7.27
(m, 1H, ArH), 7.14–7.11 (m, 1H, ArH), 4.17 (s, 3H, OCH3);
13C-NMR (300 MHz, CDCl3) d: 157.6, 157.0, 155.7, 150.0,
145.8, 139.1, 134.8, 130.1, 124.2, 121.5, 120.4, 118.4, 54.7;
ESI-MS m/z: 288.1 [M(35Cl)+H]+, 290.2 [M(37Cl)+H]+. Anal.
calcd for C13H10ClN5O: C, 54.27; H, 3.50; N, 24.34. found: C,
54.32; H, 3.47; N, 24.29.
128.2, 127.7, 118.3, 112.5, 58.8; ESI-MS m/z: 304.3 [M(35Cl)
+H]+, 306.4 [M(37Cl)+H]+.
N-(4-(6-ethoxypteridin-4(3H)-ylidene)cyclohexa-2,5-dienylidene)-
N-methyl methanaminium chloride (13b). Brown powder, yield:
1
72.5%. H-NMR (300 MHz, CDCl3) d: 7.93 (s, 1H, ArH), 7.10
(d, J = 8.7 Hz, 2H, ArH), 6.66 (d, J = 8.7 Hz, 2H, ArH), 6.40 (s,
1H, ArH), 5.27(s, 1H, NH), 4.37(q, 2H, OCH2CH3), 2.95 (s, 6H,
N(CH3)2), 1.27(t, J = 7.2 Hz, 3H, OCH2CH3); 13C-NMR (300
MHz, CDCl3) d: 161.8, 154.1, 153.7, 151.5, 151.2, 141.3, 128.0,
127.3, 120.2, 112.9, 63.9, 57.3, 14.4; ESI-MS m/z: 332.6
[M(35Cl)+H]+, 334.1 [M(37Cl)+H]+.
N-(4-(6- methoxyethoxy pteridin-4(3H)-ylidene)cyclohexa-
2,5-dienylidene)-N-methyl methanaminium chloride (13c). Brown
1
powder, yield: 70.8%. H-NMR (300 MHz, CDCl3) d: 8.02 (s, 1H,
ArH), 7.24 (d, J = 8.7 Hz 2H, ArH), 6.70 (d, J = 8.7 Hz, 2H, ArH),
6.54 (s, 1H, ArH), 5.31(s, 1H, NH), 4.69(t, J = 7.2 Hz, 2H,
OCH2CH2O), 3.82(t, J = 7.2 Hz, 2H, OCH2CH2O), 3.46(s, 3H,
OCH3), 2.92 (s, 6H, N(CH3)2); 13C-NMR (300 MHz, CDCl3) d:
163.4, 153.6, 152.8, 151.9, 151.3, 140.7, 128.2, 127.5, 116.6, 112.8,
71.3, 65.3, 58.2, 40.8; ESI-MS m/z: 362.5 [M(35Cl)+H]+, 364.3
[M(37Cl)+H]+.
General procedure for the synthesis of compounds 14–33.
6-Methoxy-N-(4-methoxyphenyl)pteridin-4-amine (14). A 50 mL
flask was charged with 6-methoxy-4-chloropteridine 12a (0.5 g,
2.54 mmol), 4-methoxyaniline (0.37 g, 3.0 mmol), triethylamine
(0.30 g, 3.0 mmol) and 25 mL isopropanol. The mixture was
refluxed for 8 h with stirring. When the starting material
disappeared, the mixture was cooled to room temperature and
poured into 50 mL water, then extracted with ethyl acetate
(50 mL ꢂ 3). The extracted solution was dried with anhydrous
magnesium sulphate and distilled to dry under reduced
pressure. The residue was dissolved in small amount of
chloroform and chromatographied on a silica gel column (ethyl
acetate: petroleum ether = 1:2) to give 0.58 g 14 as a
1
yellowish powder, yield: 81.6%. m.p. 161.5–162.5ꢀC. H-NMR
(300 MHz, CDCl3) d: 8.76 (s, 1H, ArH), 8.69 (s, 1H, ArH),
8.38 (s, 1H, NH), 7.71–7.67 (t, J = 9.0 Hz, 2H, ArH), 6.97–
6.94 (d, J = 9.0 Hz, 2H, ArH), 4.14 (s, 3H, OCH3), 3.82 (s,
3H, OCH3); 13C-NMR (300 MHz, CDCl3) d: 157.5, 157.4,
156.7, 156.0, 149.8, 145.2, 130.7, 122.8, 121.6, 114.3, 55.5,
54.6; ESI-MS m/z: 283.2 [M+H]+. Anal. calcd for
C14H13N5O2: C, 59.36; H, 4.63; N, 24.72. found: C, 59.41; H,
4.58; N, 24.70.
N-(3-Bromophenyl)-6-methoxypteridin-4-amine (21). Yellow
powder, yield: 85.1%. m.p. 160.5–161.5ꢀC. 1H-NMR (300 MHz,
CDCl3) d: 8.85 (s, 1H, ArH), 8.73 (s, 1H, ArH), 8.48 (s, 1H, NH),
8.15 (s, 1H, ArH), 7.80–7.76 (m, 1H, ArH), 7.28–7.26 (m, 2H,
ArH), 4.17 (s, 3H, OCH3); 13C-NMR (300 MHz, CDCl3) d:
157.6, 157.0, 155.7, 149.9, 145.8, 139.2, 130.4, 127.1, 123.2,
122.7, 121.5, 118.9, 54.7; ESI-MS m/z: 332.0 [M(79Br)+H]+,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

July 2012
Synthesis of N-Substituted-6-alkoxypteridin-4-amine
871
334.1 [M(81Br)+H]+. Anal. calcd for C13H10BrN5O: C, 47.01; H,
3.03; N, 21.08. found: C, 46.95; H, 3.10; N, 20.99.
m/z: 332.4 [M(35Cl)+H]+, 334.3 [M(37Cl)+H]+. Anal. calcd
for C15H14ClN5O2: C, 54.30; H, 4.25; N, 21.11. found: C,
54.27; H, 4.28; N, 21.06.
N-(4-Nitrophenyl)-6-ethoxypteridin-4-amine (22). Yellow
1
powder, yield: 79.4%. m.p. 146–146.5ꢀC. H-NMR (300 MHz,
N-(4-Chlorophenyl)-6-(2-methoxyethoxy)pteridin-4-amine
(28). Yellow powder, yield: 81.7%. m.p. 145–146ꢀC. 1H-
NMR (300 MHz, CDCl3) d: 8.82 (s, 1H, ArH), 8.78 (s, 1H,
ArH), 8.45 (s, 1H, NH), 7.83–7.79 (m, 2H, ArH), 7.40–7.36
(m, 2H, ArH), 4.66 (t, J = 7.2 Hz, 2H, OCH2CH2), 3.87 (t,
J = 7.2 Hz, 2H, CH2CH2O), 3.49 (s, 3H, OCH3); 13C-NMR
(300 MHz, CDCl3) d: 157.1, 157.0, 155.8, 150.0, 145.8,
136.5, 129.3, 129.1, 121.8, 121.4, 70.2, 66.7, 59.3; ESI-MS
m/z: 332.3 [M(35Cl)+H]+, 334.1 [M(37Cl)+H]+. Anal. calcd
for C15H14ClN5O2: C, 54.30; H, 4.25; N, 21.11. found: C,
54.34; H, 4.22; N, 21.16.
CDCl3) d: 8.82 (s, 1H, ArH), 8.71 (s, 1H, ArH), 8.52 (s, 1H,
NH), 7.85–7.81 (m, 2H, ArH), 7.44–7.66 (m, 2H, ArH), 4.57
(q, J = 7.2 Hz, 2H, OCH2CH3), 1.56 (t, J = 7.2 Hz, 3H,
OCH2CH3); 13C-NMR (300 MHz, CDCl3) d: 157.4, 157.1,
155.8, 149.8, 145.9, 141.7, 127.7, 126.9, 121.8, 121.6, 63.7,
14.2; ESI-MS m/z: 313.4 [M+H]+. Anal. calcd for C14H12N6O3:
C, 53.85; H, 3.87; N, 26.91. found: C, 53.78; H, 3.94; N, 26.83.
N-(4-Chlorophenyl)-6-ethoxypteridin-4-amine (23). Yellow
powder, yield: 84.3%. m.p. 172–174ꢀC. 1H-NMR (300 MHz,
CDCl3) d: 8.81 (s, 1H, ArH), 8.71 (s, 1H, ArH), 8.45 (s, 1H, NH),
7.85–7.80 (m, 2H, ArH), 7.40–7.35 (m, 2H, ArH), 4.56 (q, J = 7.2
Hz, 2H, OCH2CH3), 1.55 (t, J = 7.2 Hz, 3H, OCH2CH3);
13C-NMR (300 MHz, CDCl3) d: 157.2, 157.1, 155.6, 149.8,
145.9, 136.5, 129.3, 129.1, 121.8, 121.5, 63.6, 14.2; ESI-MS
m/z: 302.8 [M(35Cl)+H]+, 304.6 [M(37Cl)+H]+. Anal. calcd for
C14H12ClN5O: C, 55.73; H, 4.01; N, 23.21. found: C, 55.68; H,
4.07; N, 23.26.
N-(3-Chlorophenyl)-6-ethoxypteridin-4-amine (24). Yellow
powder, yield: 82.6%. m.p. 161–163ꢀC. 1H-NMR (300 MHz,
CDCl3) d: 8.85 (s, 1H, ArH), 8.72 (s, 1H, ArH), 8.47 (s, 1H,
NH), 8.03–8.017 (m, 1H, ArH), 7.72–7.69 (m, 1H, ArH), 7.36–
7.27 (m, 1H, ArH), 7.14–7.11 (m, 1H, ArH), 4.57 (q, J = 7.2
Hz, 2H, OCH2CH3), 1.55 (t, J = 7.2 Hz, 3H, OCH2CH3); 13C-
NMR (300 MHz, CDCl3) d: 157.3, 157.0, 155.6, 149.8, 146.0,
139.1, 134.8, 130.1, 124.2, 121.5, 120.3, 118.3, 63.7, 14.1; ESI-
MS m/z: 302.6 [M(35Cl)+H]+, 304.7 [M(37Cl)+H]+. Anal. calcd
for C14H12ClN5O: C, 55.73; H, 4.01; N, 23.21. found: C, 55.72;
H, 3.97; N, 23.17.
N-(3-Bromophenyl)-6-ethoxypteridin-4-amine (25). Yellow
powder, yield: 85.2%. m.p. 154–156ꢀC. 1H-NMR (300 MHz,
CDCl3) d: 8.84 (s, 1H, ArH), 8.71 (s, 1H, ArH), 8.45 (s, 1H,
NH), 8.14 (s, 1H, ArH), 7.80–7.76 (m, 1H, ArH), 7.28–7.26 (m,
2H, ArH), 4.57 (q, J = 7.2 Hz, 2H, OCH2CH3), 1.55 (t, J = 7.2
Hz, 3H, OCH2CH3); 13C-NMR (300 MHz, CDCl3) d: 157.3,
157.0, 155.5, 149.8, 146.0, 139.3, 130.4, 127.0, 123.1, 122.7,
121.5, 118.8, 63.7, 14.2; ESI-MS m/z: 346.4 [M(79Br)+H]+,
348.3 [M(81Br)+H]+. Anal. calcd for C14H12BrN5O: C, 48.57;
H, 3.49; N, 20.23. found: C, 48.59; H, 3.45; N, 20.19.
N-(3-Chloro-4-fluorophenyl)-6-ethoxypteridin-4-amine
(26). Yellow powder, yield: 83.8%. m.p. 192.5–194.5ꢀC.
1H-NMR (300 MHz, CDCl3) d: 8.83 (s, 1H, ArH), 8.72 (s, 1H,
ArH), 8.41 (s, 1H, NH), 8.09–8.06 (m, 1H, ArH), 7.71–7.67 (m,
1H, ArH), 7.22–7.16 (m, 1H, ArH), 4.57 (q, J = 6.9 Hz, 2H,
OCH2CH3), 1.55 (t, J = 6.9 Hz, 3H, OCH2CH3); 13C-NMR
(300 MHz, CDCl3) d: 157.3, 157.0, 155.5, 149.8, 146.1, 134.6,
122.8, 121.4, 120.3, 120.2, 116.9, 116.6, 63.7, 14.2; ESI-MS
m/z: 320.0 [M(35Cl)+H]+, 322.1 [M(37Cl)+H]+. Anal. calcd
for C14H11ClFN5O: C, 52.59; H, 3.47; N, 21.90. found: C,
52.53; H, 3.51; N, 21.88.
N-(3-Bromophenyl)-6-(2-methoxyethoxy)pteridin-4-amine
1
(29). Yellow powder, yield: 83.6%. m.p. 136.5–137.5ꢀC. H-
NMR (300 MHz, CDCl3) d: 8.85 (s, 1H, ArH), 8.79 (s, 1H,
ArH), 8.45 (s, 1H, NH), 8.14 (s, 1H, ArH), 7.80-7.76 (m,
1H, ArH), 7.28–7.26 (m, 2H, ArH), 4.66 (t, J = 6.9 Hz, 2H,
OCH2CH2), 3.88 (t, J = 6.9 Hz, 2H, CH2CH2O), 3.50 (s,
3H, OCH3); 13C-NMR (300 MHz, CDCl3) d: 157.0, 157.0,
155.8, 150.0, 145.9, 139.2, 130.4, 127.1, 123.2, 122.7, 121.3,
118.9, 70.2, 66.8, 59.3; ESI-MS m/z: 376.4 [M(79Br)+H]+,
378.1 [M(81Br)+H]+. Anal. calcd for C15H14BrN5O2: C,
47.89; H, 3.75; N, 18.62. found: C, 47.81; H, 3.83; N, 18.67.
N-(4-Fluorophenyl)-6-(2-methoxyethoxy)pteridin-4-amine
(30). Yellow powder, yield: 82.9%. m.p. 120–121ꢀC. 1H-NMR
(300 MHz, CDCl3) d: 8.80 (s, 1H, ArH), 8.78 (s, 1H, ArH),
8.42 (s, 1H, NH), 7.83–7.78 (m, 2H, ArH), 7.16–7.10 (m,
2H, ArH), 4.66 (t, J = 4.8 Hz, 2H, OCH2CH2), 3.87 (t, J =
4.8 Hz, 2H, CH2CH2O), 3.50 (s, 3H, OCH3); 13C-NMR (300
MHz, CDCl3) d: 157.9, 157.0, 155.9, 150.0, 145.7, 133.8,
122.7, 121.3, 116.9, 116.6, 70.2, 66.8, 59.3; ESI-MS m/z:
316.2 [M+H]+. Anal. calcd for C15H14FN5O2: C, 57.14; H,
4.48; N, 22.21. found: C, 57.21; H, 4.42; N, 22.17.
N-(3-Chloro-4-fluorophenyl)-6-(2-methoxyethoxy)pteridin-4-
amine (31). Yellow powder, yield: 84.4%. m.p. 138–140.5ꢀC.
1H-NMR (300 MHz, CDCl3) d: 8.85 (s, 1H, ArH), 8.80 (s, 1H,
ArH), 8.40 (s, 1H, NH), 8.09-8.06 (m, 1H, ArH), 7.72-7.66 (m,
1H, ArH), 7.23–7.17 (m, 1H), 4.67 (t, J = 7.2 Hz, 2H,
OCH2CH2), 3.87 (t, J = 7.2 Hz, 2H, CH2CH2O), 3.50 (s, 3H,
OCH3); 13C-NMR (300 MHz, CDCl3) d: 157.1, 157.0, 155.8,
153.1, 150.1, 146.0, 134.6, 122.7, 121.3, 120.3, 116.9, 116.6,
70.2, 66.8, 59.3; ESI-MS m/z: 350.1 [M(35Cl)+H]+, 352.1
[M(37Cl)+H]+. Anal. calcd for C15H13ClFN5O2: C, 51.51; H,
3.75; N, 20.02. found: C, 51.47; H, 3.80; N, 19.96.
6-Methoxy-4-(piperidin-1-yl)pteridine (32). Tan powder,
1
yield: 82.3%. m.p. 103–106ꢀC. H-NMR (300 MHz, DMSO-d6)
d: 8.74 (s, 1H, ArH), 8.52 (s, 1H, ArH), 4.24 (t, J = 4.8 Hz, 4H,
NCH2), 3.98 (s, 3H, OCH3), 1.71 (t, J = 4.8 Hz, 6H, CH2);
13C-NMR (300 MHz, DMSO-d6) d: 159.3, 155.1, 154.9,
151.7, 144.2, 123.4, 54.6, 49.0, 26.5, 24.6 ; ESI-MS m/z:
246.2 [M+H]+. Anal. calcd for C12H15N5O: C, 58.76; H, 6.16;
N, 28.55. found: C, 58.72; H, 6.19; N, 28.61.
N-(3-Chlorophenyl)-6-(2-methoxyethoxy)pteridin-4-amine
(27). Yellow powder, yield: 86.1%.m.p. 131–131.5ꢀC. 1H-
NMR (300 MHz, CDCl3) d: 8.85 (s, 1H, ArH), 8.79 (s, 1H,
ArH), 8.46 (s, 1H, NH), 8.03–8.02 (m, 1H, ArH), 7.72–7.68
(m, 1H, ArH), 7.36–7.28 (m, 1H, ArH), 7.14–7.11 (m, 1H,
ArH), 4.67 (t, J = 6.8 Hz, 2H, OCH2CH2), 3.88 (t, J = 6.8 Hz,
2H, CH2CH2O), 3.50 (s, 3H, OCH3); 13C-NMR (300 MHz,
CDCl3) d: 157.0, 157.0, 155.8, 150.0, 145.9, 139.1, 134.8,
130.1, 124.2, 121.3, 120.4, 118.4, 70.2, 66.8, 59.3; ESI-MS
6-Methoxy-4-morpholinopteridine (33). Yellowish powder,
1
yield: 85.4%. m.p. 179–181ꢀC. H-NMR(300 MHz, DMSO-d6)
d:8.79 (s, 1H, ArH), 8.60 (s, 1H, ArH), 4.32 (t, J = 4.8 Hz, 4H,
OCH2), 3.98 (s, 3H, OCH3), 3.79 (t, J = 4.8 Hz, 4H, NCH2);
13C-NMR (300 MHz, DMSO-d6) d: 159.4, 155.3, 154.5, 151.3,
144.8, 123.4, 66.8, 54.9, 48.3; ESI-MS m/z: 248.4 [M+H]+.
Anal. calcd for C11H13N5O2: C, 53.43; H, 5.30, N; 28.32. found:
C, 53.38; H, 5.36; N, 28.35.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

872
C. Duan, J. Jia, R. Zhu, and J. Wang
Vol 49
[16] Chih-Hung, L.; Meiqun, J.; Marlon, C.; Grey, G.; Richard, P.;
Ki, H. K.; Yu-Gui, G.; Michael, W.; Michael, F. J.; Elizabeth, A.K.;
Andrew, O. S.; Shripad, S. B. J Med Chem 2001, 44, 2133.
[17] Fry, D. W.; Kracker, A. J.; McMichael, A.; Ambroso, L. A.;
Nelson, J. M.; Leopold, W. R.; Connors, R. W.; Bridges, A. J. Science
1994, 265, 1093.
REFERENCES AND NOTES
[1] Aaronson, S. A. Science 1991, 254, 1146.
[2] Levitzki, A. Pharmacol Ther 1999, 82, 231.
[3] Traxler, P.; Furet, R. S. Pharmacol Ther 1999, 82, 195.
[4] Hamby, J. M.; Showalter, H. D. Pharmacol Ther 1999, 82,
[18] Lawrence, D. S.; Niu, J. Pharmarcol Ther 1998, 77, 81.
[19] Bridges, A. J Curr Med Chem 1999, 6, 825.
169.
[5] Fry, D. W.; Kraker, A. J.; Conners, R. C.; Elliott, W. L.;
[20] Traxler, P. Furet, P. Pharmacol Ther 1999, 82, 195.
[21] Peng, T.; Pei, J. F.; Zhou, J. J. Acta Chim Sinica 2003, 61, 29.
[22] Jiang, Y.; Guo, Z. R. Chinese J Org Chem 2004, 24, 1640.
[23] Boschelli, D. H.; Wang, Y. D.; Johnson, S.; Wu, B.; Ye, F.;
Sosa, A. C. B.; Golas, J. M.; Boschelli, F. J Med Chem 2004, 47, 1599.
[24] Gazit, A.; Chen, J.; App, H.; McMahon, G.; Hirth, P.; Chen, I.;
Levitzki, A. Bioorg Med Chem 1996, 4, 1203.
[25] Rewcastle, G. W.; Denny, W. A.; Bridges, A. J.; Zhou, H.;
Cody, D. R.; McMicheal, A. Fry, D. W. J Med Chem 1995, 38, 3482.
[26] Rusnak, D. W.; Affleck, K.; Cockerill, S. G.; Stubberfield, C.;
Harris, R.; Page, M.; Smith, K. J.; Guntrip, S. B.; Carter, M. C.; Shaw, R.
J.; Jowett, A.; Stables, J.; Topley, P.; Wood, E. R.; Brignola, P. S.;
Kadwell, S. H.; Reep, B. R.; Mullin, R. J.; Alligood, K. J.; Keith, B. R.;
Crosby, R. M.; Murray, D. M.; Knight, W. B.; Gilmer, T. M.;
Lackey, K. Cancer Res 2001, 61, 7196.
Nelson, J. M.; Showalter, H. D.; Leopold, W. R. Anti Cancer Drug Des
1994, 9, 331.
[6] Levitzki, A.; Gazit, A. T. Science 1995, 267, 1782.
[7] Garcia-Echeverria, C.; Traxler, P.; Evans, D. B. Med Res Rev
2000, 20, 28.
[8] Dumas, J. Expert Opin Ther Pat 2001, 11, 405.
[9] Ward, W. H. J.; Cook, P. N.; Slater, A. M.; Davies, D. H.;
Holdgate, G. A. Biochem Pharmacol 1994, 48, 659.
[10] Barker, A. J.; Gibson, K. H.; Grundy, W.; Godfrey, A. A.;
Barlow, J. J Bioorg Med Chem 2001, 11, 1911.
[11] Baselga, J.; Herbst, R.; LoRusso, P.; Rischin, D.; Ranson, M.;
Plummer, R.; Raymond, E.; Maddox, A.; Kaye, S. B.; Kieback, D. G.;
Harris, A.; Ochs, J. Proc Am Soc Clin Oncol 2000, 19, 177a (abstract 686).
[12] Meijer, L; Raymond, E. Acc Chem Res 2003, 36, 417.
[13] Kovalenko, M.; Gazit, A.; Bohmer, A.; Rorsman, C.;
Ronnstrand, L.; Heldin, C. H.; Waltenberger, J.; Bohmer, F. D.; Levitzki,
A. Cancer Res 1994, 54, 6106.
[27] Zhao, X. Y.; Qin, Z. L. Chinese J Synth Chem 2002, 10, 477.
[28] Duan, C. G.; Xu, W. R.; Tang, L. D.; Jia, J.; Wang, J. W.
Chinese J Org Chem 2008, 28, 1830.
[29] Ellingson, R. C.; Henry, R. L.; McDonald, F. G. J Am Chem
Soc 1945, 67, 1711.
[14] Gazit, A.; App, H.; Mcmahon, G.; Chen, J.; Levitzki, A.;
Bohmer, F. D. J Med Chem 1996, 39, 2170.
[15] Richard, J. P.; Yu-Gui, G.; Chih-Hung, L.; Erol, K. B.; Jeffery, M.;
Karen, M. A.; Kathy, L. K.; Carol, T. W.; Joe, M.; Michael, F. J.;
Elizabeth, A. K.; Andrew, O. S.; Shripad, S. B. J Med Chem 2003,
46, 5249.
[30] Jones, J. H.; Bicking, J. B.; Cragoe, E. J., Jr. J Med Chem
1967, 10, 899.
[31] Albert, A.; Ohta, K. J Chem Soc C 1971, 3727.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet