Efficient synthesis of flupirtine analogues derived from pyrimidine

Article abstract of DOI:10.1002/jhet.725

The synthesis of novel N²-substituted 5-alkoxycarbonylamino-2,4- diaminopyrimidines, 5-acylamino-2,4-diaminopyrimidines, and 2,4-diamino-5- ureidopyrimidines as analogues of the analgesic flupirtine is described. Copyright

Full text of DOI:10.1002/jhet.725

March 2012
Efficient Synthesis of Flupirtine Analogues Derived from
Pyrimidine
321
Finn K. Hansen* and Detlef Geffken
Institute of Pharmacy, University of Hamburg, 20146 Hamburg, Germany
*E-mail: hansen@chem.ufl.edu
Received June 26, 2010
DOI 10.1002/jhet.725
Published online 19 December 2011 in Wiley Online Library (wileyonlinelibrary.com).
The synthesis of novel N2-substituted 5-alkoxycarbonylamino-2,4-diaminopyrimidines, 5-acylamino-
2,4-diaminopyrimidines, and 2,4-diamino-5-ureidopyrimidines as analogues of the analgesic flupirtine is
described.
J. Heterocyclic Chem., 49, 321 (2012).
INTRODUCTION
The synthesis of polysubstituted pyrimidine deriva-
tives is usually achieved by (i) cyclization, (ii) ring
transformation, (iii) aromatization, and (iv) substituent
modification, and various efficient preparations have
been published [15]. However, the synthesis of pyrimi-
dine-2,4,5-triamine derivatives is still challenging
because of the low stability of the latter. Pyrimidine-4,5-
diamines with an enolizable group in the 2-position can
easily form pyrimidopteridines by oxidative self-conden-
sation [16,17]. Hence, there is a need for efficient syn-
thetic procedures for the preparation of pyrimidine-
2,4,5-triamine derivatives. We herein report on a facile
and convenient synthesis of N5-acylated pyrimidine-
2,4,5-triamines (6–8).
Flupirtine, a centrally acting nonopiate analgesic, has
been effectively and safely used in therapy for over 20
years. From a subsequent drug design resulted retigabine
(Fig. 1), the desaza analogue of flupirtine, as a highly
active anticonvulsant, which is currently in late-stage
development as a novel antiepileptic drug [1–3]. Both
flupirtine and retigabine display their biological activity
by activating neuronal KCNQ channels [4–10], which
have been recently discovered as attractive targets for
novel therapeutics against chronic and neuropathic pain,
epilepsy, and other neuronal hyperexcitability disorders
[11–14].
The development of simple and efficient methods for
the preparation of new bioactive heterocyclic com-
pounds represents an important challenge in organic and
heterocyclic chemistry. As part of our research directed
to novel polyaminosubstituted pyrimidine derivatives,
we became interested in flupirtine/retigabine analogues
with a pyrimidine core.
RESULTS AND DISCUSSION
Starting from commercially available 5-nitrouracil (1),
chlorination [18], and subsequent ammonolysis [19] of 2
according
to
literature
furnished
2-chloro-5-
C
V
2011 HeteroCorporation

322
F. K. Hansen and D. Geffken
Vol 49
Figure 1. Chemical structure of flupirtine and retigabine.
Scheme 1. Synthesis of N2-substituted 5-nitropyrimidine-2,4-diamines
(4a–g). Reagents and conditions: (i) POCl3, N,N-dimethylaniline,
reflux; (ii) NH3, ethanol, 0ꢀC; (iii) R1R2NH, ethanol, reflux.
Table 1
N2-Substituted 5-nitropyrimidine-2,4-diamines (4a–g) prepared.
Compound
R1
R2
H
Yield (%)
4a
4b
4c
4d
4e
4f
4-FC6H4CH2
81
84
93
80
92
84
70
A(CH2)2O(CH2)2A
4-MeC6H4CH2
PhCH2CH2
H
H
Ph
Bn
Bn
H
H
Me
4g
Catalytic hydrogenation of the key intermediates 4
delivered the corresponding pyrimidine-2,4,5-triamines 5
as labile compounds. All attempts to isolate the triami-
nopyrimidines 5 as free bases, hydrochlorides or sulfates
failed. Consequently, the intermediates 5 were in situ
reacted with alkyl chlorofomates to produce the desired
6a–g as stable, amorphous hydrochlorides in 41–64%
overall yield (Scheme 2, Table 2). The N2-substituted 5-
alkoxycarbonylamino-2,4-diaminopyrimidines (6a–g) are
characterized by a strong (C¼¼O)-absorption band at
nitropyrimidin-4-amine (3). Treatment of 3 with 2 equiv.
of primary or secondary amines in refluxing ethanol
afforded the N2-substituted 5-nitropyrimidine-2,4-dia-
mines 4a–g in 70–93% yield (Scheme 1, Table 1).
Scheme 2. Synthesis of N2-substituted 5-alkoxycarbonylamino-2,4-diaminopyrimidines (6a–h), 5-acylamino-2,4-diaminopyrimidines (7a–l), and
2,4-diamino-5-ureidopyrimidines (8a–h). Reagents and conditions: (i) Pd/C, H2, RT; (ii) alkyl chloroformate, dioxane, RT; (iii) acid chloride, diox-
ane, RT; (iv) isocyanate, THF, RT.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

March 2012
Efficient Synthesis of Flupirtine Analogues Derived from Pyrimidine
323
Table 2
lation unambiguously (Fig. 2) [20]. These findings are
in accordance with the literature, which describes the 5-
amino group as preferred position of (alkoxy)acylation
for related polyaminosubstituted pyrimidine derivatives
[15,21,22].
N2-Substituted 5-alkoxycarbonylamino-2,4-diaminopyrimidines (6a–h),
5-acylamino-2,4-diamino-pyrimidines (7a–l), and 2,4-diamino-5-
ureidopyrimidines (8a–h) prepared.
Compound
R1
R2
R3
Yield (%)
Analogously to the preparation of 6, the reaction of
the pyrimidine-2,4,5-triamines 5 with acid chlorides pro-
duced the desired N2-substituted 5-acylamino-2,4-dia-
mino-pyrimidines 7a–l as hydrochlorides in 57–80%
yield (Scheme 2, Table 2). Compounds 7 display a sharp
(C¼¼O)-absorption band at 1670–1690 cmꢁ1 in the IR-
spectrum.
6a
6b
6c
6d
6e
6f
6g
6h
7a
7b
7c
7d
7e
7f
7g
7h
7i
7j
7k
7l
4-FC6H4CH2
4-FC6H4CH2
4-FC6H4CH2
4-FC6H4CH2
4-MeC6H4CH2
4-MeC6H4CH2
4-MeC6H4CH2
H
H
H
H
H
H
H
Et
nPr
59
53
64
47
51
41
49
35a
64
69
70
80
58
59
59
62
61
63
57
63
56
59
75
52
54
72
71
69
nBu
iBu
Et
nPr
iBu
Et
A(CH2)2O(CH2)2A
Similarly, several 5-ureidopyrimidine analogues were
obtained according to Scheme 2 by in situ reaction of
the intermediates 5 with isocyanates. A simple workup
procedure followed by recrystallization from methanol
provided the N2-substituted 2,4-diamino-5-ureidopyrimi-
dines (8a–h) in 52–75% yield.
The structure of all synthesized compounds 6–8 were
determined by IR-, 1H-NMR, 13C-NMR-spectroscopy,
and elemental analysis.
4-FC6H4CH2
4-FC6H4CH2
4-FC6H4CH2
4-FC6H4CH2
4-FC6H4CH2
4-FC6H4CH2
Bn
H
H
H
H
H
H
H
Me
H
H
H
H
H
H
H
H
H
Me
Et
nBu
c-(Pentyl)CH2
3-(MeO)Ph
3-Me-Ph
Me
Et
Bn
4-MeC6H4CH2
4-MeC6H4CH2
Ph
PhCH2CH2
4-FC6H4CH2
4-FC6H4CH2
4-FC6H4CH2
4-FC6H4CH2
4-FC6H4CH2
Me
Et
Et
Et
In summary, we have synthesized a variety of novel
N2-substituted 5-alkoxycarbonylamino-2,4-diaminopyri-
midines (6), 5-acylamino-2,4-diaminopyrimidines (7),
and 2,4-diamino-5-ureidopyrimidines (8) as potentially
bioactive pyrimidine analogues of flupirtine.
8a
8b
8c
8d
8e
8f
Et
nPr
c-Hexyl
Ph
3-Cl-Ph
Et
nPr
c-Hexyl
A(CH2)2O(CH2)2A
A(CH2)2O(CH2)2A
A(CH2)2O(CH2)2A
8g
8h
a Isolated as free base.
EXPERIMENTAL
Melting points (uncorrected) were determined on a Mettler
FP 62 apparatus. Elemental analysis were carried out with a
Heraeus CHN-O-Rapid instrument. HRMS-FAB analysis were
performed on a Micromass VG 70-250S spectrometer. IR spec-
tra were recorded on a Varian 800 FT-IR. 1H-NMR (400
MHz) and 13C-NMR (100 MHz) spectra were recorded on a
Bruker AMX 400 spectrometer using tetramethylsilane as an
internal standard and [D6]DMSO as solvent. X-ray crystal
analysis was performed on a Bruker Smart APEX CCD dif-
fractometer with Mo Ka-radiation at 100 K.
1720–1750 cmꢁ1 in the IR-spectrum. Instead of its
hydrochloride, compound 6h was isolated as free base.
For this purpose, the alkoxyacylation was realized in the
presence of triethylamine (see Experimental Section).
After purification via column chromatography and sub-
sequent crystallization from 1-propanol, 6h was obtained
in pure crystalline state, suitable for X-ray analysis. The
X-ray crystal structure of 6h proved the desired N5-acy-
Figure 2. X-ray crystal structure of compound 6h.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

324
F. K. Hansen and D. Geffken
Vol 49
HRMS-FAB: m/z [M þ H]þ calcd. for C10H9N5O2: 232.0835;
found: 232.0835.
General procedure for the preparation of N2-substituted
5-nitropyrimidine-2,4-diamines (4a–g). The appropriate pri-
mary or secondary amine (20 mmol) was added to a suspen-
sion of 2-chloro-5-nitropyrimidin-4-amine (1.75 g, 10 mmol)
in dry ethanol (40 mL). The mixture was refluxed for 2 h. The
reaction was allowed to cool to room temperature; the sepa-
rated solid was collected and recrystallized from methanol.
N2-(4-Fluorobenzyl)-5-nitropyrimidine-2,4-diamine (4a). This
compound was obtained as yellow crystals in 81% yield, mp
195ꢀC. mmax (KBr)/cmꢁ1 3469, 3282, 1560. dH (400 MHz,
[D6]DMSO): 4.49 (1.5H, d, J ¼ 6.4 Hz, ArCH2), 4.55 (0.5H,
d, J ¼ 6.4 Hz, ArCH2), 7.09–7.42 (4H, m, ArH), 7.91–8.25
(2H, m, NH2), 8.37 (0.25H, t, J ¼ 6.9 Hz, NH), 8.62 (0.75H,
t, J ¼ 6.2 Hz, NH), 8.86 (0.75H, s, ArH), 8.91 (0.25H, s,
ArH); due to existence of rotamers some signals appear twice.
N2-Benzyl-5-nitropyrimidine-2,4-diamine (4f). This com-
pound was obtained as yellow crystals in 84% yield, mp
194ꢀC. mmax (KBr)/cmꢁ1 3469, 3354, 1620, 1543. dH (400
MHz, [D6]DMSO): 4.54 (1.5H, d, J ¼ 6.6 Hz, ArCH2), 4.59
(0.5H, d, J ¼ 6.6 Hz, ArCH2), 7.19–7.38 (5H, m, ArH), 7.91–
8.24 (2H, complex m, NH2), 8.37 (0.25H, t, J ¼ 6.3 Hz, NH),
8.62 (0.75H, t, J ¼ 6.2 Hz, NH), 8.87 (0.75H, s, ArH), 8.91
(0.25H, s, ArH); due to existence of rotamers some signals
appear twice. dC (100 MHz, [D6]DMSO): 44.0, 44.1, 119.4,
120.4, 126.7, 126.8, 126.9, 127.3, 128.2, 139.0, 139.5, 157.0,
157.4, 157.6, 157.9, 161.9, 162.0; due to existence of rotamers
some signals appear twice. HRMS-FAB: m/z [M þ H]þ calcd.
for C11H11N5O2: 246.0991; found: 246.0995.
N2-Benzyl-N2-methyl-5-nitropyrimidine-2,4-diamine (4g). This
compound was obtained as yellow powder in 70% yield, mp
84ꢀC. mmax (KBr)/cmꢁ1 3433, 3280. dH (400 MHz,
[D6]DMSO): 3.10 (1.5H, s, CH3), 3.16 (1.5H, s, CH3), 4.89
(1H, s, ArCH2), 4.95 (1H, s, ArCH2), 7.18–7.42 (5H, m, ArH),
7.97–8.32 (2H, m, NH2), 8.94 (0.5H, s, ArH), 8.96 (0.5H, s,
ArH); due to existence of rotamers some signals appear twice.
dC (100 MHz, [D6]DMSO): 34.8, 35.1, 51.7, 51.8, 119.6,
119.7, 127.1, 127.2, 127.5, 128.5, 128.6, 128.8, 129.7, 137.1,
137.4, 156.8, 156.9, 157.3, 157.5, 161.0, 161.1; due to exis-
tence of rotamers some signals appear twice. HRMS-FAB: m/z
[M þ H]þ calcd. for C12H13N5O2: 260.1148; found: 260.1150.
General procedure for the preparation of N2-substituted
5-alkoxycarbonylamino-2,4-diaminopyrimidines (6a–g). A
suspension of the respective N2-substituted 5-nitropyrimidine-
2,4-diamine 4 (3 mmol) in dry dioxane (30 mL) was hydro-
genated using a catalytic amount of 10% Pd/C (20 h/2 bar).
Afterward, the suspension was filtered through a SPE tube RP-
18 purchased from Supelco (Sigma-Aldrich, Munich, Ger-
many) to remove the catalyst. A solution of the appropriate
alkyl chloroformate (3.3 mmol) in dry dioxane (3 mL) was
added to the filtrate dropwise over 5 min at room temperature.
The reaction mixture was stirred for 30 min; the precipitate
was collected and washed with diethyl ether (2 ꢂ 10 mL).
Recrystallization from methanol/diethyl ether provided analyti-
cally pure products.
2
dC (100 MHz, [D6]DMSO): 43.4, 43.5, 115.0 (d, JCAF ¼ 21.4
3
3
Hz), 119.5, 120.5, 129.0 (d, JCAF ¼ 8.4 Hz), 129.5 (d, JCAF
4
4
¼ 7.6 Hz), 135.2 (d, JCAF ¼ 3.1 Hz), 135.8 (d, JCAF ¼ 3.1
1
Hz), 157.1, 157.4, 157.7, 157.9, 161.2 (d, JCAF ¼ 241.9 Hz),
1
161.3 (d, JCAF ¼242.6 Hz), 161.8, 162.0; due to existence of
rotamers some signals appear twice. HRMS-FAB: m/z [M þ
H]þ calcd. for C11H10FN5O2: 264.0897; found: 264.0893.
2-Morpholin-4-yl-5-nitropyrimidin-4-amine (4b). This com-
pound was obtained as orange crystals in 84% yield, mp
215ꢀC (lit. [23], 214ꢀC). mmax (KBr)/cmꢁ1 3469, 3280, 1560.
dH (400 MHz, [D6]DMSO): 3.58–3.95 (8H, m, CH2), 8.03 þ
8.19 (2H, 2s, NH2), 8.91 (1H, s, ArH). dC (100 MHz,
[D6]DMSO): 44.1, 65.9, 119.5, 156.9, 157.3, 160.0. HRMS-
FAB: m/z [M þ H]þ calcd. for C8H11N5O3: 226.0940; found:
226.0942.
N2-(4-Methylbenzyl)-5-nitropyrimidine-2,4-diamine (4c). This
compound was obtained as yellow crystals in 93% yield, mp
221ꢀC. mmax (KBr)/cmꢁ1 3471, 3352, 1618, 1543. dH (400
MHz, [D6]DMSO): 2.27 (3H, s, CH3), 4.48 (1.5H, d, J ¼ 6.4
Hz, ArCH2), 4.53 (0.5H, d, J ¼ 6.6 Hz, ArCH2), 7.06–7.26
(4H, m, ArH), 7.91–8.24 (2H, m, NH2), 8.35 (0.25H, t, J ¼
6.5 Hz, NH), 8.60 (0.75H, t, J ¼ 6.2 Hz, NH), 8.86 (0.75H, s,
ArH), 8.91 (0.25H, s, ArH); due to existence of rotamers some
signals appear twice. dC (100 MHz, [D6]DMSO): 20.6, 43.7,
43.9, 119.3, 120.3, 126.9, 127.4, 128.7, 135.7, 135.8, 135.9,
136.5, 157.0, 157.3, 157.6, 157.8, 161.8, 161.9; due to exis-
tence of rotamers some signals appear twice. HRMS-FAB: m/z
[M þ H]þ calcd. for C12H13N5O2: 260.1148; found: 260.1148.
5-Nitro-N2-(2-phenylethyl)pyrimidine-2,4-diamine (4d). This
compound was obtained as yellow powder in 80% yield, mp
176ꢀC. mmax (KBr)/cmꢁ1 3485, 3356, 1542. dH (400 MHz,
[D6]DMSO): 2.79–2.91 (2H, m, CH2CH2Ph), 3.46–3.63 (2H,
m, CH2CH2Ph), 7.14–7.38 (5H, m, ArH), 7.81–8.32 (3H, com-
plex m, NH, and NH2), 8.84 (0.75H, s, ArH), 8.92 (0.25H, s,
ArH); due to existence of rotamers some signals appear twice.
dC (100 MHz, [D6]DMSO): 34.5, 35.2, 42.3, 42.6, 119.2,
120.2, 126.0, 128.2, 128.6, 128.6, 139.2, 139.2, 156.9, 157.4,
157.4, 157.8, 161.6, 161.8; due to existence of rotamers some
signals appear twice. HRMS-FAB: m/z [M þ H]þ calcd. for
C12H13N5O2: 260.1148; found: 260.1150.
Ethyl
{4-amino-2-[(4-fluorobenzyl)amino]pyrimidin-5-yl}
carbamate hydrochloride (6a). This compound was obtained
as colorless solid in 59% yield, mp 140ꢀC. mmax (KBr)/cmꢁ1
3349, 3192, 3104, 1744. dH (400 MHz, [D6]DMSO): 1.36
(3H, t, J ¼ 7.1 Hz, CH2CH3), 4.43 (2H, q, J ¼ 7.0 Hz,
CH2CH3), 4.65 (2H, d, J ¼ 5.9 Hz, ArCH2), 5.15 (2H, s,
NH2), 7.11–7.53 (4H, m, ArH), 7.56 (1H, s, ArH), 8.91 (1H, s,
NH), 9.28 (1H, s, NH), 9.45 (1H, t, J ¼ 6.0 Hz, NH). dC (100
2
MHz, [D6]DMSO): 13.6, 44.0, 65.8, 114.9 (d, JCAF ¼ 21.3
3
4
Hz), 115.1, 121.6, 130.1 (d, JCAF ¼ 8.1 Hz), 134.1 (d, JCAF
1
¼ 2.9 Hz), 149.0, 150.4, 158.0, 161.3 (d, JCAF ¼ 242.8 Hz).
Calc. for C14H17ClFN5O2: C, 49.20; H, 5.01; N, 20.49. Found:
C, 49.13; H, 5.31; N, 20.44.
Propyl {4-amino-2-[(4-fluorobenzyl)amino]pyrimidin-5-yl}car-
bamate hydrochloride (6b). This compound was obtained as
colorless solid in 53% yield, mp 135ꢀC. mmax (KBr)/cmꢁ1
3319, 3168, 3035, 1748. dH (400 MHz, [D6]DMSO): 0.99
5-Nitro-N2-phenylpyrimidine-2,4-diamine (4e). This com-
pound was obtained as yellow powder in 92% yield, mp
239ꢀC. mmax (KBr)/cmꢁ1 3467, 3344, 1560. dH (400 MHz,
[D6]DMSO): 7.00–8.02 (5H, m, ArH), 8.21 þ 8.53 (2H, 2s,
NH2), 8.99 (1H, s, ArH), 10.22 (1H, s, NH). dC (100 MHz,
[D6]DMSO): 120.1, 123.0, 128.5, 139.1, 157.1, 157.2, 159.7.
(3H, t,
J
¼ 7.4 Hz, CH2CH2CH3), 1.71–1.80 (2H, m,
CH2CH2CH3), 4.34 (2H, t, J ¼ 6.4 Hz, CH2CH2CH3), 4.65
(2H, d, J ¼ 5.8 Hz, ArCH2), 5.27 (2H, s, NH2), 7.11–7.52
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Efficient Synthesis of Flupirtine Analogues Derived from Pyrimidine
325
(4H, m, ArH), 7.56 (1H, s, ArH), 9.07 (1H, s, NH), 9.30 (1H,
2-Methylpropyl {4-amino-2-[(4-methylbenzyl)amino]pyrimi-
din-5-yl}carbamate hydrochloride (6g). This compound was
obtained as colorless solid in 49% yield, mp 150ꢀC. mmax
(KBr)/cmꢁ1 3286, 3179, 3061, 1745. dH (400 MHz,
[D6]DMSO): 0.99 (6H, d, J ¼ 6.3 Hz, CH2CH(CH3)2), 1.98–
2.14 (1H, m, CH2CH(CH3)2), 2.28 (3H, s, CH3), 4.16 (2H, d,
J ¼ 6.0 Hz, CH2CH(CH3)2), 4.63 (2H, d, J ¼ 4.4 Hz, ArCH2),
5.42 (2H, s, NH2), 7.05–7.41 (4H, m, ArH), 7.55 (1H, s, ArH),
9.24 (1H, s, NH), 9.31 (1H, s, NH), 9.36 (1H, t, J ¼ 5.7 Hz,
NH). dC (100 MHz, [D6]DMSO): 18.6, 20.6, 27.0, 44.5, 74.9,
114.8, 121.7, 127.8, 128.8, 134.7, 136.3, 149.1, 150.6, 158.0.
Calc. for C17H24ClN5O2: C, 55.81; H, 6.61; N, 19.14. Found:
C, 55.42; H, 6.68; N, 19.17.
Ethyl (4-amino-2-morpholin-4-ylpyrimidin-5-yl)carbamate
(6h). A suspension of 2-morpholin-4-yl-5-nitropyrimidin-4-
amine 4b (0.676 g, 3 mmol) in dry dioxane (30 mL) was
hydrogenated using a catalytic amount of 10% Pd/C (20 h/2
bar). Afterward, the suspension was filtered through a SPE
tube RP-18 purchased from Supelco (Sigma-Aldrich, Munich,
Germany) to remove the catalyst. To the filtrate was added
triethylamine (0.4 g, 4 mmol). Next, a solution of ethyl chloro-
formate (0.358 g, 3.3 mmol) in dry dioxane (3 mL) was added
dropwise over 5 min at room temperature. The reaction mix-
ture was stirred for 30 min, and the triethylammonium chloride
was separated by filtration and washed with THF. The com-
bined organic layers were evaporated, and the crude product
was purified by column chromatography using ethyl acetate/n-
hexane (2:1) as eluent. The residue was recrystallized from
dichloromethane/n-hexane. Crystals for X-ray analysis were
obtained from 1-propanol.
s, NH), 9.44 (1H, t, J ¼ 5.9 Hz, NH). dC (100 MHz,
2
[D6]DMSO): 10.1, 21.1, 44.0, 70.9, 114.9, 114.9 (d, JCAF
¼
¼
3
4
21.4 Hz), 121.1, 130.1 (d, JCAF ¼ 8.4 Hz), 134.1 (d, JCAF
1
3.1 Hz), 149.0, 150.8, 158.0, 161.3 (d, JCAF ¼ 241.9 Hz).
Calc. for C15H19ClFN5O2: C, 50.64; H, 5.38; N, 19.68. Found:
C, 50.24; H, 5.50; N, 19.67.
Butyl {4-amino-2-[(4-fluorobenzyl)amino]pyrimidin-5-yl}car-
bamate hydrochloride (6c). This compound was obtained as
colorless solid in 64% yield, mp 164ꢀC. mmax (KBr)/cmꢁ1
3297, 3185, 3067, 1741. dH (400 MHz, [D6]DMSO): 0.93
(3H, t, J ¼ 7.4 Hz, CH2CH2CH2CH3), 1.37–1.49 (2H, m,
CH2CH2CH2CH3), 1.65–1.77 (2H, m, CH2CH2CH2CH3), 4.38
(2H, t, J ¼ 6.4 Hz, CH2CH2CH2CH3), 4.65 (2H, d, J ¼ 5.9
Hz, ArCH2), 5.37 (2H, s, NH2), 7.12–7.53 (4H, m, ArH), 7.54
(1H, s, ArH), 9.23 (1H, s, NH), 9.33 (1H, s, NH), 9.43 (1H, t,
J ¼ 5.9 Hz, NH). dC (100 MHz, [D6]DMSO): 13.5, 18.4,
2
29.7, 44.0, 69.2, 114.9 (d, JCAF ¼ 21.1 Hz), 114.9, 121.7,
3
4
130.1 (d, JCAF ¼ 8.3 Hz), 134.2 (d, JCAF ¼ 2.8 Hz), 149.1,
1
150.5, 158.0, 161.4 (d, JCAF
C16H21ClFN5O2: C, 51.96; H, 5.72; N, 18.94. Found: C,
51.82; H, 5.78; N, 19.07.
¼
242.9 Hz). Calc. for
2-Methylpropyl {4-amino-2-[(4-fluorobenzyl)amino]pyrimi-
din-5-yl}carbamate hydrochloride (6d). This compound was
obtained as colorless solid in 47% yield, mp 149ꢀC. mmax
(KBr)/cmꢁ1 3295, 3183, 3063, 1742. dH (400 MHz,
[D6]DMSO): 0.99 (6H, d, J ¼ 6.8 Hz, CH2CH(CH3)2), 1.99–
2.15 (1H, m, CH2CH(CH3)2), 4.17 (2H, d, J ¼ 6.5 Hz,
CH2CH(CH3)2), 4.65 (2H, d, J ¼ 5.5 Hz, ArCH2), 5.47 (2H, s,
NH2), 7.10–7.55 (4H, m, ArH), 7.56 (1H, s, ArH), 9.33 (1H, s,
NH), 9.36 (1H, s, NH), 9.44 (1H, t, J ¼ 5.5 Hz, NH). dC (100
MHz, [D6]DMSO): 18.6, 27.0, 44.0, 74.9, 114.7, 114.9 (d,
Colorless solid, yield 35%, mp 161ꢀC. mmax (KBr)/cmꢁ1
3487, 3296, 3202, 1716. dH (400 MHz, [D6]DMSO): 1.21 (3H,
br. s, CH2CH3), 3.49–3.68 (8H, m, CH2), 4.05 (2H, q, J ¼ 6.7
Hz, CH2CH3), 6.34 (2H, s, NH2), 7.72 (1H, s, ArH), 8.26 (1H,
s, NH). dC (100 MHz, [D6]DMSO): 14.4, 44.1, 60.1, 66.0,
107.5, 152.6, 155.1, 159.3, 159.5. Calc. for C11H17N5O3: C,
49.43; H, 6.41; N, 26.20. Found: C, 49.37; H, 6.55; N, 25.87.
General procedure for the preparation of N2-substituted
5-acylamino-2,4-diaminopyrimidines (7a–l).. A suspension
of the respective N2-substituted 5-nitropyrimidine-2,4-diamine
4 (3 mmol) in dry dioxane (30 mL) was hydrogenated using a
catalytic amount of 10% Pd/C (20 h/2 bar). Afterward, the sus-
pension was filtered through a SPE tube RP-18 purchased
from Supelco (Sigma-Aldrich, Munich, Germany) to remove
the catalyst. A solution of the appropriate acid chloride (3.3
mmol) in dry dioxane (3 mL) was added to the filtrate drop-
wise over 5 min at room temperature. The reaction mixture
was stirred for 30 min; the precipitate was collected and
washed with diethyl ether (2 ꢂ 10 mL). Recrystallization from
methanol/diethyl ether provided analytically pure products.
N-{4-Amino-2-[(4-fluorobenzyl)amino]pyrimidin-5-yl}aceta-
mide hydrochloride (7a). This compound was obtained as col-
orless solid in 64% yield, mp 239ꢀC. mmax (KBr)/cmꢁ1 3294,
3174, 1654. dH (400 MHz, [D6]DMSO): 2.05 (3H, s, CH3),
4.53 (2H, d, J ¼ 5.9 Hz, ArCH2), 7.10–7.49 (4H, m, ArH),
8.00 (1H, s, ArH), 8.38 (1H, s, NH), 8.57 (2H, s, NH2), 9.65
(1H, s, NH), 12.39 (1H, s, NH). dC (100 MHz, [D6]DMSO):
3
2JCAF ¼ 22.0 Hz), 121.7, 130.1 (d, JCAF ¼ 8.3 Hz), 134.1 (d,
1
4JCAF ¼ 2.8 Hz), 149.1, 150.5, 158.0, 161.3 (d, JCAF ¼ 242.9
Hz). Calc. for C16H21ClFN5O2: C, 51.96; H, 5.72; N, 18.94.
Found: C, 51.88; H, 5.90; N, 19.07.
Ethyl {4-amino-2-[(4-methylbenzyl)amino]-pyrimidin-5-yl}car-
bamate hydrochloride (6e). This compound was obtained as
colorless solid in 51% yield, mp 137ꢀC. mmax (KBr)/cmꢁ1
3348, 3170, 3026, 1738. dH (400 MHz, [D6]DMSO): 1.36
(3H, t, J ¼ 7.1 Hz, CH2CH3), 2.28 (3H, s, CH3), 4.42 (2H, q,
J ¼ 7.1 Hz, CH2CH3), 4.63 (2H, d, J ¼ 5.9 Hz, ArCH2), 5.27
(2H, s, NH2), 7.05–7.39 (4H, m, ArH), 7.56 (1H, s, ArH), 9.07
(1H, s, NH), 9.27 (1H, s, NH), 9.36 (1H, t, J ¼ 5.6 Hz, NH).
dC (100 MHz, [D6]DMSO): 13.7, 20.7, 44.5, 65.8, 115.0,
121.6, 127.8, 128.8, 134.8, 136.3, 149.1, 150.5, 158.2. Calc.
for C15H20ClN5O2: C, 53.33; H, 5.97; N, 20.73. Found: C,
53.20; H, 6.05; N, 20.60.
Propyl
{4-amino-2-[(4-methylbenzyl)amino]-pyrimidin-5-
yl}carbamate hydrochloride (6f). This compound was obtained
as colorless solid in 41% yield, mp 139ꢀC. mmax (KBr)/cmꢁ1
3283, 3176, 3069, 1744. dH (400 MHz, [D6]DMSO): 0.98
(3H, t,
J
¼ 7.4 Hz, CH2CH2CH3), 1.66–1.83 (2H, m,
CH2CH2CH3), 2.28 (3H, s, CH3), 4.33 (2H, t, J ¼ 6.5 Hz,
CH2CH2CH3), 4.63 (2H, d, J ¼ 5.8 Hz, ArCH2), 5.36 (2H, s,
NH2), 7.10–7.37 (4H, m, ArH), 7.56 (1H, s, ArH), 9.18 (1H, s,
NH), 9.29 (1H, s, NH), 9.35 (1H, t, J ¼ 5.9 Hz, NH). dC (100
MHz, [D6]DMSO): 10.1, 20.6, 21.1, 44.5, 71.0, 115.0, 121.5,
127.7, 128.8, 134.7, 136.3, 149.1, 150.6, 158.0. Calc. for
C16H22ClN5O2: C, 54.62; H, 6.30; N, 19.90. Found: C, 54.28;
H, 6.43; N, 19.92.
2
3
23.0, 43.0, 109.1, 115.1 (d, JCAF ¼ 21.4 Hz), 129.4 (d, JCAF
1
¼ 8.4 Hz), 134.2, 136.4, 151.7, 160.9, 161.3 (d, JCAF
¼
242.6 Hz), 169.6. Calc. for C13H15ClFN5O: C, 50.09; H, 4.85;
N, 22.46. Found: C, 50.00; H, 5.04; N, 22.43.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

326
F. K. Hansen and D. Geffken
Vol 49
1
134.2, 137.3, 139.2, 152.2, 161.3 (d, JCAF ¼ 242.6 Hz),
162.0, 166.6. Calc. for C19H19ClFN5O: C, 58.84; H, 4.94; N,
18.06. Found: C, 58.70; H, 5.03; N, 18.19.
N-{4-Amino-2-[(4-fluorobenzyl)amino]pyrimidin-5-yl}propa-
namide hydrochloride (7b). This compound was obtained as
colorless solid in 69% yield, mp 242ꢀC. mmax (KBr)/cmꢁ1
3293, 3171, 1676. dH (400 MHz, [D6]DMSO): 1.05 (3H, t, J
¼ 7.5 Hz, CH2CH3), 2.38 (2H, q, J ¼ 7.5 Hz, CH2CH3), 4.53
(2H, d, J ¼ 5.9 Hz, ArCH2), 7.14–7.46 (4H, m, ArH), 8.00
(1H, s, ArH), 8.33 (1H, s, NH), 8.53 (2H, s, NH2), 9.51 (1H,
s, NH), 12.33 (1H, s, NH). dC (100 MHz, [D6]DMSO): 9.2,
N-[4-Amino-2-(benzylamino)pyrimidin-5-yl]acetamide hydro-
chloride (7g). This compound was obtained as colorless solid
in 59% yield, mp 235ꢀC. mmax (KBr)/cmꢁ1 3388, 3155, 1697.
dH (400 MHz, [D6]DMSO): 2.06 (3H, s, CH3), 4.56 (2H, d, J
¼ 6.0 Hz, ArCH2), 7.24–7.40 (5H, m, ArH), 8.03 (1H, s,
ArH), 8.42 (1H, s, NH), 8.49–8.68 (2H, m, NH2), 9.71 (1H, s,
NH), 12.43 (1H, s, NH). dC (100 MHz, [D6]DMSO): 23.1,
43.8, 109.2, 127.2, 127.3, 128.4, 136.3, 138.1, 151.9, 160.9,
169.7. Calc. for C13H16ClN5O: C, 53.15; H, 5.49; N, 23.84.
Found: C, 52.88; H, 5.44; N, 23.93.
2
3
28.5, 43.0, 109.2, 115.1 (d, JCAF ¼ 21.3 Hz), 129.5 (d, JCAF
1
¼ 8.1 Hz), 134.3, 136.1, 151.6, 160.8, 161.3 (d, JCAF
¼
242.8 Hz), 173.3. Calc. for C14H17ClFN5O: C, 51.62; H, 5.26;
N, 21.50. Found: C, 51.53; H, 5.42; N, 21.49.
N-{4-Amino-2-[(4-fluorobenzyl)amino]pyrimidin-5-yl}penta-
namide hydrochloride (7c). This compound was obtained as
colorless solid in 70% yield, mp 215ꢀC. mmax (KBr)/cmꢁ1
3312, 3150, 1671. dH (400 MHz, [D6]DMSO): 0.89 (3H, t,
N-{4-Amino-2-[benzyl(methyl)amino]pyrimidin-5-yl}propa-
namide hydrochloride (7h). This compound was obtained as
colorless solid in 62% yield, mp 230ꢀC. mmax (KBr)/cmꢁ1
3346, 3266, 3185, 1685. dH (400 MHz, [D6]DMSO): 1.06
(3H, t, J ¼ 7.6 Hz, CH2CH3), 2.40 (2H, q, J ¼ 7.4 Hz,
CH2CH3), 3.10 (3H, s, CH3), 4.84 (2H, s, ArCH2), 7.26–7.46
(5H, m, ArH), 8.00 (1H, s, ArH), 8.34 þ 8.50 (2H, 2s, NH2),
9.55 (1H, s, NH), 12.42 (1H, s, NH). dC (100 MHz,
[D6]DMSO): 9.2, 28.6, 35.5, 52.1, 109.8, 127.3, 127.4, 128.5,
134.9, 136.2, 150.9, 159.8, 173.2. Calc. for C15H20ClN5O: C,
55.99; H, 6.26; N, 21.76. Found: C, 55.76; H, 21.70; N, 6.36.
N-{4-Amino-2-[(4-methylbenzyl)amino]pyrimidin-5-yl}aceta-
mide hydrochloride (7i). This compound was obtained as col-
orless solid in 61% yield, mp 238ꢀC. mmax (KBr)/cmꢁ1 3399,
3142, 1695. dH (400 MHz, [D6]DMSO): 2.05 (3H, s, CH3),
2.28 (3H, s, CH3), 4.50 (2H, d, J ¼ 6.1 Hz, ArCH2), 7.12–
7.28 (4H, m, ArH), 7.99 (1H, s, ArH), 8.36 (1H, s, NH), 8.54
(2H, s, NH2), 9.65 (1H, s, NH), 12.32 (1H, s, NH). dC (100
MHz, [D6]DMSO): 20.6, 23.0, 43.5, 109.1, 127.3, 128.9,
134.9, 136.3, 151.8, 161.0, 169.6. Calc. for C14H18ClN5O: C,
54.63; H, 5.89; N, 22.75. Found: C, 54.34; H, 6.03; N, 22.67.
N-{4-Amino-2-[(4-methylbenzyl)amino]pyrimidin-5-yl}propa-
namide hydrochloride (7j). This compound was obtained as
colorless solid in 63% yield, mp 241ꢀC. mmax (KBr)/cmꢁ1
3394, 3261, 3129, 1694. dH (400 MHz, [D6]DMSO): 1.04
(3H, t, J ¼ 7.6 Hz, CH2CH3), 2.28 (3H, s, CH3), 2.38 (2H, q,
J ¼ 7.5 Hz, CH2CH3), 4.50 (2H, d, J ¼ 5.9 Hz, ArCH2),
7.12–7.28 (4H, m, ArH), 7.99 (1H, s, ArH), 8.31 (1H, s, NH),
8.49 (2H, s, NH2), 9.50 (1H, s, NH), 12.26 (1H, s, NH). dC
(100 MHz, [D6]DMSO): 9.2, 20.6, 28.5, 43.5, 109.2, 127.3,
128.9, 135.0, 136.0, 136.3, 151.7, 160.8, 173.2. Calc. for
C15H20ClN5O: C, 55.99; H, 6.26; N, 21.76. Found: C, 55.72;
H, 6.42; N, 21.72.
N-[4-Amino-2-(phenylamino)pyrimidin-5-yl]propanamide
hydrochloride (7k). This compound was obtained as colorless
solid in 57% yield, mp 257ꢀC. mmax (KBr)/cmꢁ1 3314, 3162,
1676. dH (400 MHz, [D6]DMSO): 1.07 (3H, t, J ¼ 7.5 Hz,
CH2CH3), 2.43 (2H, q, J ¼ 7.4 Hz, CH2CH3), 7.10–7.69 (5H,
m, ArH), 8.22 (1H, s, ArH), 8.68 (2H, s, NH2), 9.73 (1H, s,
NH), 10.57 (1H, s, NH), 12.21 (1H, s, NH). dC (100 MHz,
[D6]DMSO): 9.3, 28.6, 110.2, 121.4, 124.3, 129.0, 136.2,
137.3, 149.6, 160.5, 173.3. Calc. for C13H16ClN5O: C, 53.15;
H, 5.49; N, 23.84. Found: C, 53.28; H, 5.65; N, 24.13.
N-{4-Amino-2-[(2-phenylethyl)amino]pyrimidin-5-yl}propana-
mide hydrochloride (7l). This compound was obtained as col-
orless solid in 63% yield, mp 249ꢀC. mmax (KBr)/cmꢁ1 3387,
3314, 3118, 1696. dH (400 MHz, [D6]DMSO): 1.05 (3H, t, J
¼ 7.5 Hz, CH2CH3), 2.40 (2H, q, J ¼ 7.6 Hz, CH2CH3), 2.85
J
¼
7.3 Hz CH2CH2CH2CH3), 1.26–1.37 (2H, m,
CH2CH2CH2CH3), 1.49–1.60 (2H, m, CH2CH2CH2CH3), 2.40
(2H, t, J ¼ 7.6 Hz, CH2CH2CH2CH3), 4.53 (2H, d, J ¼ 6.1
Hz, ArCH2), 7.12–7.49 (4H, m, ArH), 8.07 (1H, s, ArH), 8.46
(1H, s, NH), 8.57 (2H, s, NH2), 9.68 (1H, s, NH), 12.44 (1H,
s, NH). dC (100 MHz, [D6]DMSO): 13.7, 21.7, 26.9, 35.1,
2
3
43.0, 109.3, 115.1 (d, JCAF ¼ 21.4 Hz), 129.5 (d, JCAF
¼
1
7.6 Hz), 134.3, 135.7, 151.5, 160.6, 161.3 (d, JCAF ¼ 242.6
Hz), 172.5. Calc. for C16H21ClFN5O: C, 54.31; H, 5.98; N,
19.79. Found: C, 54.00; H, 6.27; N, 20.10.
N-{4-Amino-2-[(4-fluorobenzyl)amino]pyrimidin-5-yl}-2-cyclo-
pentylacetamide hydrochloride (7d). This compound was
obtained as colorless solid in 80% yield, mp 228ꢀC. mmax
(KBr)/cmꢁ1 3296, 3188, 3122, 1684. dH (400 MHz,
[D6]DMSO): 1.07–1.79 (8H, m, CH2), 2.12–2.28 (1H, m, CH),
2.40 (2H, d, J ¼ 7.4 Hz, CH2), 4.53 (2H, d, J ¼ 5.9 Hz,
ArCH2), 7.12–7.48 (4H, m, ArH), 8.09 (1H, s, ArH), 8.45–
8.53 (3H, m, NH and NH2), 9.67 (1H, s, NH), 12.40 (1H, s,
NH). dC (100 MHz, [D6]DMSO): 24.4, 31.8, 36.3, 41.4, 43.0,
2
3
109.3, 115.1 (d, JCAF ¼ 20.6 Hz), 129.5 (d, JCAF ¼ 7.6 Hz),
1
134.3, 135.5, 151.5, 160.5, 161.3 (d, JCAF ¼ 242.6 Hz),
172.1. Calc. for C18H23ClFN5O: C, 56.91; H, 6.10; N, 18.44.
Found: C, 56.88; H, 6.28; N, 18.29.
N-{4-Amino-2-[(4-fluorobenzyl)amino]pyrimidin-5-yl}-3-meth
oxybenzamide hydrochloride (7e). This compound was
obtained as colorless solid in 58% yield, mp 262ꢀC. mmax
(KBr)/cmꢁ1 3355, 3288, 3156, 1668. dH (400 MHz,
[D6]DMSO): 3.84 (3H, s, CH3), 4.56 (2H, d, J ¼ 5.9 Hz,
ArCH2), 7.13–7.62 (8H, m, ArH), 7.96 (1H, s, ArH), 8.24 þ
8.57 (2H, 2s, NH2), 8.71 (1H, s, NH), 9.88 (1H, s, NH), 12.65
(1H, s, NH). dC (100 MHz, [D6]DMSO): 43.2, 55.4, 108.6,
2
113.3, 115.1 (d, JCAF ¼ 21.3 Hz), 117.6, 120.4, 129.3, 129.6
3
(d, JCAF ¼ 8.1 Hz), 134.3, 134.9, 139.3, 152.3, 159.0, 161.4
(d, 1JCAF
¼
242.8 Hz), 162.0, 166.3. Calc. for
C19H19ClFN5O2: C, 56.51; H, 4.74; N, 17.34. Found: C,
56.38; H, 4.77; N, 17.29.
N-{4-amino-2-[(4-fluorobenzyl)amino]pyrimidin-5-yl}-3-meth-
ylbenzamide hydrochloride (7f). This compound was obtained
as colorless solid in 59% yield, mp 266ꢀC. mmax (KBr)/cmꢁ1
3262, 1686. dH (400 MHz, [D6]DMSO): 2.39 (3H, s, CH3),
4.56 (2H, d, J ¼ 6.1 Hz, ArCH2), 7.13–7.90 (8H, m, ArH),
7.95 (1H, s, ArH), 8.21 þ 8.55 (2H, 2s, NH2), 8.68 (1H, s,
NH), 9.79 (1H, s, NH), 12.61 (1H, s, NH). dC (100 MHz,
2
[D6]DMSO): 20.8, 43.1, 108.6, 115.1 (d, JCAF ¼ 21.4 Hz),
3
125.2, 128.0, 128.5, 129.5 (d, JCAF ¼ 8.4 Hz), 132.3, 133.4,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

March 2012
Efficient Synthesis of Flupirtine Analogues Derived from Pyrimidine
327
(2H, t,
J
¼
7.5 Hz, CH2CH2Ph), 3.49–3.59 (2H, m,
1610. dH (400 MHz, [D6]DMSO): 4.41 (2H, d, J ¼ 6.4 Hz,
ArCH2), 6.24 (2H, s, NH2), 6.83–7.49 (11H, complex m, ArH
and 2 NH), 7.61 (1H, s, ArH), 8.56 (1H, s, NH). dC (100
CH2CH2Ph), 7.19–7.35 (5H, m, ArH), 8.02 (1H, s, ArH), 8.40
(1H, s, NH), 8.54 þ 8.12 (2H, 2s, NH2), 9.63 (1H, s, NH),
12.24 (1H, s, NH). dC (100 MHz, [D6]DMSO): 9.2, 28.5,
34.5, 42.0, 109.1, 126.2, 128.3, 128.7, 136.0, 138.7, 151.5,
160.7, 173.2. Calc. for C15H20ClN5O: C, 55.99; H, 6.26; N,
21.76. Found: C, 55.66; H, 6.45; N, 21.73.
General procedure for the preparation of N2-substituted
2,4-diamino-5-ureidopyrimidines (8a–h). A suspension of the
respective N2-substituted 5-nitropyrimidine-2,4-diamine 4 (3
mmol) in dry THF (30 mL) was hydrogenated using a catalytic
amount of 10% Pd/C (15 h/2 bar). Afterward, the suspension
was filtered through a SPE tube RP-18 purchased from
Supelco (Sigma-Aldrich, Munich, Germany) to remove the cat-
alyst. A solution of the appropriate isocyanate (3.3 mmol) in
dry THF (3 mL) was added to the filtrate dropwise over 5 min
at room temperature. The reaction mixture was stirred for 1 h
and subsequently stored in a freezer for 5 h. The precipitate
was collected and recrystallized from methanol to afford com-
pounds 8a–h as solid products.
2
MHz, [D6]DMSO): 43.3, 107.3, 114.7 (d, JCAF ¼ 21.1 Hz),
3
117.9, 121.3, 128.6, 128.9 (d, JCAF ¼ 7.3 Hz), 137.4 (d,
4JCAF ¼ 2.8 Hz), 140.2, 154.1, 154.2, 160.3, 160.8, 160.9 (d,
1JCAF ¼ 241.9 Hz). Calc. for C18H17FN6O: C, 61.36; H, 4.86;
N, 23.85. Found: C, 61.40; H, 5.22; N, 23.96.
1-{4-Amino-2-[(4-fluorobenzyl)amino]pyrimidin-5-yl}-3-(3-
chlorophenyl)urea (8e). This compound was obtained as col-
orless solid in 54% yield, mp 183ꢀC. mmax (KBr)/cmꢁ1 3296,
1654, 1596. dH (400 MHz, [D6]DMSO): 4.41 (2H, d, J ¼ 6.1
Hz, ArCH2), 6.26 (2H, s, NH2), 6.86–7.42 (9H, complex m,
ArH and 2 NH), 7.60 (1H, s, ArH), 7.68 (1H, s, ArH), 8.80
(1H, s, NH). dC (100 MHz, [D6]DMSO): 43.2, 106.8, 114.6
2
(d, JCAF ¼ 20.6 Hz), 116.3, 117.3, 120.8, 130.1, 128.8 (d,
4
3JCAF ¼ 8.4 Hz), 132.9, 137.3 (d, JCAF ¼ 3.1 Hz), 141.8,
1
154.0, 154.2, 160.3, 160.8, 160.8 (d, JCAF ¼ 241.1 Hz). Calc.
for C18H16ClFN6O: C, 55.89; H, 4.17; N, 21.73. Found: C,
55.49; H, 4.30; N, 21.41.
1-(4-Amino-2-morpholin-4-ylpyrimidin-5-yl)-3-ethylurea (8f).
This compound was obtained as colorless solid in 72% yield,
mp >300ꢀC. mmax (KBr)/cmꢁ1 3469, 3319, 2971, 2857, 1629.
dH (400 MHz, [D6]DMSO): 1.01 (3H, t, J ¼ 7.1 Hz,
CH2CH3), 2.98–3.13 (2H, m, CH2CH3), 3.47–3.73 (8H, m,
CH2), 5.96 (1H, t, J ¼ 5.3 Hz, NH), 6.19 (2H, s, NH2), 7.12
(1H, s, NH), 7.66 (1H, s, ArH). dC (100 MHz, [D6]DMSO):
15.4, 34.2, 44.2, 66.0, 108.5, 152.8, 156.6, 159.1, 160.1. Calc.
for C11H18N6O2: C, 49.61; H, 6.81; N, 31.56. Found: C,
49.56; H, 6.92; N, 31.67.
1-(4-Amino-2-morpholin-4-ylpyrimidin-5-yl)-3-propylurea (8g).
This compound was obtained as colorless solid in 71% yield,
mp >300ꢀC. mmax (KBr)/cmꢁ1 3448, 3302, 2965, 2863, 1631.
dH (400 MHz, [D6]DMSO): 0.84 (3H, t, J ¼ 7.4 Hz,
CH2CH2CH3), 1.32–1.48 (2H, m, CH2CH2CH3), 2.93–3.05 (2H,
m, CH2CH2CH3), 3.46–3.72 (8H, m, CH2), 5.99 (1H, t, J ¼ 5.6
Hz, NH), 6.19 (2H, s, NH2), 7.11 (1H, s, NH), 7.66 (1H, s,
ArH). dC (100 MHz, [D6]DMSO): 11.4, 23.1, 41.3, 44.3, 66.1,
108.7, 152.8, 156.8, 159.2, 160.2. Calc. for C12H20N6O2: C,
51.42; H, 7.19; N, 29.98. Found: C, 51.42; H, 7.28; N, 29.85.
1-(4-Amino-2-morpholin-4-ylpyrimidin-5-yl)-3-cyclohexylurea
(8h). This compound was obtained as colorless solid in 69%
yield, mp >300ꢀC. mmax (KBr)/cmꢁ1 3447, 3345, 3277, 2948,
2924, 2853, 1605. dH (400 MHz, [D6]DMSO): 1.04–1.88
(10H, m, CH2), 3.32–3.47 (1H, m, CH), 3.48–3.71 (8H, m,
CH2), 5.87 (1H, d, J ¼ 7.9 Hz, NH), 6.16 (2H, s, NH2), 7.06
(1H, s, NH), 7.68 (1H, s, ArH). dC (100 MHz, [D6]DMSO):
24.6, 25.3, 33.1, 44.3, 48.1, 66.1, 108.8, 152.3, 155.9, 159.1,
160.0. Calc. for C15H24N6O2: C, 56.23; H, 7.55; N, 26.23.
Found: C, 56.04; H, 7.67; N, 25.95.
1-{4-Amino-2-[(4-fluorobenzyl)amino]pyrimidin-5-yl}-3-eth-
ylurea (8a). This compound was obtained as colorless solid in
56% yield, mp 202ꢀC. mmax (KBr)/cmꢁ1 3342, 2923, 2854, 1637,
1603. dH (400 MHz, [D6]DMSO): 1.01 (3H, t, J ¼ 7.3 Hz,
CH2CH3), 2.94–3.18 (2H, m, CH2CH3), 4.39 (2H, d, J ¼ 6.4 Hz,
ArCH2), 5.95 (1H, t, J ¼ 5.5 Hz, NH), 6.07 (2H, s, NH2), 6.88
(1H, t, J ¼ 6.4 Hz, NH), 7.04 (1H, s, NH), 7.06–7.37 (4H, m,
ArH), 7.55 (1H, s, ArH). dC (100 MHz, [D6]DMSO): 15.5, 34.3,
2
3
43.4, 108.3, 114.7 (d, JCAF ¼ 21.4 Hz), 128.9 (d, JCAF ¼ 7.6
4
Hz), 137.4 (d, JCAF ¼ 3.1 Hz), 153.4, 156.8, 160.0, 160.6,
1
160.9 (d, JCAF ¼ 241.1 Hz). Calc. for C14H17FN6O: C, 55.25;
H, 5.63; N, 27.61. Found: C, 55.00; H, 5.80; N, 27.34.
1-{4-Amino-2-[(4-fluorobenzyl)amino]pyrimidin-5-yl}-3-pro-
pylurea (8b). This compound was obtained as colorless solid in
59% yield, mp 201ꢀC. mmax (KBr)/cmꢁ1 3448, 3344, 3232,
2964, 1637, 1604. dH (400 MHz, [D6]DMSO): 0.84 (3H, t, J ¼
7.4 Hz, CH2CH2CH3), 1.34–1.47 (2H, m, CH2CH2CH3), 2.92–
3.03 (2H, m, CH2CH2CH3), 4.39 (2H, d, J ¼ 6.4 Hz, ArCH2),
5.98 (1H, t, J ¼ 5.6 Hz, NH), 6.05 (2H, s, NH2), 6.88 (1H, t,
J ¼ 6.0 Hz, NH), 7.03 (1H, s, NH), 7.06–7.37 (4H, m, ArH),
7.55 (1H, s, ArH). dC (100 MHz, [D6]DMSO): 11.2, 23.0, 41.2,
2
3
43.3, 108.3, 114.6 (d, JCAF ¼ 21.3 Hz), 128.8 (d, JCAF ¼ 8.1
4
Hz), 137.3 (d, JCAF ¼ 2.9 Hz), 153.2, 156.8, 159.9, 160.4,
1
160.8 (d, JCAF ¼ 241.4 Hz). Calc. for C15H19FN6O: C, 56.59;
H, 6.02; N, 26.40. Found: C, 56.35; H, 6.04; N, 26.41.
1-{4-Amino-2-[(4-fluorobenzyl)amino]pyrimidin-5-yl}-3-cyclo-
hexylurea (8c). This compound was obtained as colorless solid
in 75% yield, mp 210ꢀC. mmax (KBr)/cmꢁ1 3341, 3288, 2927,
2856, 1635, 1604. dH (400 MHz, [D6]DMSO): 1.06–1.86
(10H, m, CH2), 3.32–3.47 (1H, m, CH), 4.39 (2H, d, J ¼ 6.4
Hz, ArCH2), 5.86 (1H, d, J ¼ 7.6 Hz, NH), 6.03 (2H, s, NH2),
6.86 (1H, t, J ¼ 6.1 Hz, NH), 6.97 (1H, s, NH), 7.04–7.36
(4H, m, ArH), 7.55 (1H, s, ArH). dC (100 MHz, [D6]DMSO):
Acknowledgment. The authors thank Miss Isabelle Nevoigt for
performing the X-ray analysis. They also thank Schwarz Pharma
Germany GmbH, for generous financial support.
2
24.5, 25.3, 33.1, 43.3, 48.1, 108.4, 114.7 (d, JCAF ¼ 21.4
3
4
Hz), 128.8 (d, JCAF ¼ 7.6 Hz), 137.4 (d, JCAF ¼ 3.1 Hz),
1
153.0, 156.0, 159.8, 160.3, 160.9 (d, JCAF ¼ 241.1 Hz). Calc.
REFERENCES AND NOTES
for C18H23FN6O: C, 60.32; H, 6.47; N, 23.45. Found: C,
60.04; H, 6.52; N, 23.45.
[1] Porter, R. J.; Nohria, V.; Rundfeldt, C. Neurotherapeutics
2007, 4, 149.
1-{4-Amino-2-[(4-fluorobenzyl)amino]pyrimidin-5-yl}-3-phe-
nylurea (8d). This compound was obtained as colorless solid
in 52% yield, mp 198ꢀC. mmax (KBr)/cmꢁ1 3345, 3291, 1646,
[2] Blackburn-Munro, G.; Dalby-Brown, W.; Mirza, N. R.;
Mikkelsen, J. D.; Blackburn-Munro, R. E. CNS Drug Rev 2005, 11, 1.
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[20] Crystallographic data for compound 6h have been deposited
with the Cambridge Crystallographic Data Centre as supplementary
publication number CCDC 751329. These data can be obtained free of
charge from the Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/ cif. Selected crystal data for com-
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C. G. J Neural Transm 1999, 106, 857.
pound 6h: C11H17N5O3, Mr ¼ 267.30, orthorhombic, Pbca, a ¼
3
˚
˚
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12.9475 (10), b ¼ 7.4897 (6), c ¼ 27.029 (2) A; V ¼ 2621.1 (4) A , T
¼ 153 K, Z ¼ 8, Dx ¼ 1.334 Mg mꢁ3, l ¼ 0.10 mmꢁ1, k (Mo Ka) ¼
˚
0.71073 A, F(000) ¼ 1104, 2950 independent reflections (Rint
¼
0.045), 2622 reflections with I > 2r(I); refinement method, full-matrix
least-squares refinement on F2; R[F2 > 2r(F2)] ¼ 0.051, wR(F2) ¼
0.114, S ¼ 1.21.
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet