Preparation of pyrimidine derivatives as potential medicinal agents by the reaction of 2-amino-4-chloro-6-methylpyrimidine with primary and secondary amines

Article abstract of DOI:10.1002/jhet.5570420707

Thirteen derivatives of pyrimidine were prepared as potential medicinal agents by the reaction of 2-amino-4-chloro-6-methylpyrimidine with primary and secondary amines in the absence of a solvent. Six of the derivatives are piperazinylpyrimidines. The com

Full text of DOI:10.1002/jhet.5570420707

Preparation of Pyrimidine Derivatives as Potential Medicinal Agents
by the Reaction of 2-Amino-4-chloro-6-methylpyrimidine
with Primary and Secondary Amines
Nov-Dec 2005
1289
Irwin Becker
Department of Chemistry, Villanova University, Villanova, PA l9085
Received February 14, 2005
Thirteen derivatives of pyrimidine were prepared as potential medicinal agents by the reaction of 2-
amino-4-chloro-6-methylpyrimidine with primary and secondary amines in the absence of a solvent. Six of
the derivatives are piperazinylpyrimidines. The compounds prepared in this work may prove to be effica-
cious in the treatment of inflammation, hypertension, anxiety, depression, or cancer.
J. Heterocyclic Chem., 42, 1289 (2005).
Several biologically active agents are given in Chart 1.
It may act by reducing serotonin in the brain. Gleevec, a
useful anticancer agent, inhibits the progress of chronic
myeloid leukemia. The Bristol-Myers Squibb compound
BMS-354825 overcomes resistance of Gleevec-resistant
mutants in tissue culture and in mice [5]. BMS-354825
currently is undergoing Phase I clinical trials [5].
Six of the compounds prepared in this work (see Table 1,
compounds 2 through 7) are 1,4-disubstituted piperazines
in which one of the nitrogen atoms of piperazine is bonded
directly to carbon-4 (or carbon-6) of the pyrimidine ring.
These six piperazinylpyrimidines have structural features
similar to those present in the biologically active com-
pounds given in Chart 1.
The 1,4-disubstituted piperazines A and B have exhibited
antiinflammatory, adrenolytic, and central nervous system
depressant activity [1]. The piperazinylpyrimidine C has
displayed excellent long lasting efficacy as an antihyper-
tensive agent [2]. The corresponding 4-pyrimidinyl iso-
mer, interestingly enough, was much less effective than C.
Mezilamine, a dopamine antagonist, apparently has not
been evaluated as an antidepressant in humans [3].
Buspirone is used for the treatment of general anxiety dis-
orders and depression [4]. Its mode of action is not known.

1290
I. Becker
Vol. 42
6-methylpyrimidine [9]. This 4-hydroxy compound was con-
verted to the corresponding 4-chloro compound by refluxing the
4-hydroxy compound with an excess of phosphorus oxychloride
[10,11]. Amines were purchased from Sigma Aldrich except as
noted.
The compounds prepared in this work may prove to be
efficacious in the treatment of inflammation, hypertension,
anxiety, depression, or cancer. None of the compounds,
however, have yet been tested for biological activity.
In this work we prepared thirteen derivatives of pyrimi-
dine (see Table 1) by the reaction of 2-amino-4-chloro-6-
methylpyrimidine (1) with primary and secondary amines
in the absence of a solvent. In each reaction the nitrogen
atom of the entering amine moiety became bonded directly
to carbon-4 (or carbon-6) of the pyrimidine ring. The
The general preparative procedure involved heating 2-amino-
4-chloro-6-methylpyrimidine (1) with the amine on the steam
bath for 1-3.5 h. No solvent was used. The mole ratio of amine
to chloropyrimidine was 3:1. After heating the reactants, water
was added. Solids were broken up and mixed with the water.
Solids were collected by vacuum filtration, washed with water,
and dried. The product so obtained was analyzed or, more typi-
cally, was recrystallized from the solvent pair of 95% ethanol and
water and then analyzed. Compounds were dried by heating
them in the air oven or by letting them stand in the desiccator
over Drierite at room temperature in the dark or by both methods.
Melting points were determined on a Thomas-Hoover Unimelt
apparatus. CHN analyses were determined by Schwarzkopf
th
Microanalytical Laboratory Inc, 56-19 37 Avenue, Woodside,
1
NY 11377. Three of the H nmr spectra were determined by
Professor Walter Boyko, Director of NMR Services at Villanova
1
University. The other H nmr spectra were determined by
Spectral Data Services Inc, 818 Pioneer Street, Champaign, IL
61820.
4-(4-Ethylpiperazin-1-yl)-6-methylpyrimidin-2-amine (2).
A mixture of 1.00 g (0.00694 mol) of 2-amino-4-chloro-6-
methylpyrimidine (mp 176.5-181°) and 2.64 mL of 98% pure 1-
ethylpiperazine (d 0.899), equivalent to 2.37 g (0.0208 mol) of
100% pure amine, was heated on the steam bath for 3.5 h. The
mixture of dark red brown clear liquid and a small button of solid
was let stand for nearly 7 days during which time the contents
formed a mixture of white, tan, and brown solids. The solids
were broken up and mixed well with 3x5 mL of water whereupon
virtually all of the solid dissolved. Even so, the mixture was
passed through a Hirsch funnel. The mini amount of solid that
was collected on the funnel was washed with 5 mL water where-
upon virtually all of this solid dissolved. The combined clear
dark orange filtrate (20 mL) was let stand for nearly 4 days dur-
ing which time fine white crystals separated. The dark orange
liquid (Liquid A) above these crystals was decanted from the
crystals into an evaporating dish. The damp crystals were col-
lected, using 6x1 mL water to complete the transfer, washed with
2x2 mL water, sucked with the vacuum for 23 min, and dried at
62-63° for 3 h, white crystals, 0.204 g (13.3%), mp 112.5-117°,
negative Beilstein test (no Cl). Prior to analysis this sample was
preparation of three of the compounds is illustrated in
Scheme 1. In each reaction the 4-chlorine atom in the
pyrimidine ring underwent nucleophilic substitution by a
primary or secondary amine. Nucleophilic substitution of
an active chlorine atom in the 2-, 4-, or 6-position of the
pyrimidine ring by a primary or secondary amine is well-
documented [7]. The kinetics and mechanism of this type
of reaction have been studied in detail [8].
1
let stand over Drierite for 68 h. H nmr (CDCl ): δ 1.12 (t, 3H,
3
CH , ethyl), 2.21 (s, 3H, 6-CH , pyrimidine), 2.43 (q, 2H, CH ,
3
3
2
ethyl), 2.47 (ct, 4H, piperazine closest to ethyl), 3.60 (ct, 4H,
piperazine closest to pyrimidine), 4.71 (bs, 2H, 2-NH , pyrimi-
2
dine), 5.83 (s, 1H, 5-H, pyrimidine).
Anal. Calcd. for C H N : C, 59.70; H, 8.65; N, 31.65.
11 19
5
Found: C, 60.10; H, 8.89; N, 31.66.
Liquid A was concentrated on the steam bath to 6 mL. The
dark orange concentrate was cooled in ice for 84 min, let stand
for nearly 7 days, and seeded with the first crop of white crystals
described above. The mixture was vigorously stirred whereupon
solid separated. This mixture was cooled in ice for 30 min. The
solid was collected, using 2x1 mL and 1.5 mL water to complete
the transfer, washed with 5 mL and 3 mL water, sucked with the
vacuum for 23 min, and dried at 62° for 2 h, pure white solid,
EXPERIMENTAL
The requisite 2-amino-4-chloro-6-methylpyrimidine (1) was
prepared in two steps. Condensation of guanidine carbonate with
ethyl acetoacetate in refluxing ethanol gave 2-amino-4-hydroxy-

Nov-Dec 2005
Preparation of Pyrimidine Derivatives as Potential Medicinal Agents
1291
0.337 g (22.0%), mp 112-113.5° after softening at 111-112°, neg-
ative Beilstein test (no Cl). For analysis this sample was let stand
over Drierite for 67 h.
After Solid F was collected, a pale yellow oil remained in the
crystallization beaker. This oil solidified upon standing, forming
a crusty pale yellow solid (Solid G), 0.179 g (9.1%), mp 140-
Anal. Calcd. for C H N : C, 59.70; H, 8.65; N, 31.65.
Found: C, 59.89; H, 8.61; N, 31.64.
142°. Solid G was dried at 69° for 1 h and then analyzed.
11 19
5
1
Anal. Calcd. for C
H
N · / H O: C, 66.75; H, 7.53; N,
16 21
5
4 2
24.33. Found: C, 66.50; H, 7.45; N, 24.07.
4-(4-Benzylpiperazin-1-yl)-6-methylpyrimidin-2-amine (3).
4-[4-(2-Fluorophenyl)piperazin-1-yl]-6-methylpyrimidin-2-
amine (4).
A mixture of 1.00 g (0.00694 mol) of 2-amino-4-chloro-6-
methylpyrimidine (mp 176.5-181°) and 3.62 mL of 98% pure 1-
benzylpiperazine (Avocado Chemical Co., d 1.01), equivalent to
3.59 g (0.0204 mol) of 100% pure amine, was heated on the
steam bath for 1 h and let stand overnight. To the mixture of
orange mush and hard dark orange glass, 3.5 mL water were
added. The mixture was heated briefly on the steam bath. The
glass was broken up as much as possible. The solid was col-
lected. This procedure was repeated with 3 mL and 2x3.5 mL
water. The combined solid was washed with 2x6.5 mL water and
sucked with the vacuum for 28 min, off white solid (Solid A),
melted completely by 140°, negative Beilstein test (no Cl). This
solid was let stand over Drierite for 3 days, 0.923 g (47.1%).
Solid A was recrystallized (charcoal) from the solvent pair of
95% ethanol and water, letting the final mixture stand for 3 days.
The solid was collected, using 3x2.5 mL water to complete the
transfer, washed with 2x3 mL water, and sucked with the vacuum
for 138 min, off white solid (Solid B), 0.611 g (31.2%). After
standing over Drierite overnight, Solid B had mp 138-141°.
Solid B was recrystallized from the solvent pair of 95%
ethanol (4 mL) and water, letting the final mixture cool in ice for
38 min. The solid was collected, using 4x3 mL water to complete
the transfer, washed with 2x7 mL water, sucked with the vaccum
for 18 min, dried at 73-78° for 2 h, and let stand over Drierite for
45 h, off white solid (Solid C), 0.357 g (18.2%), mp 138-141°.
A mixture of 1.00 g (0.00694 mol) of 2-amino-4-chloro-6-
methylpyrimidine (mp 176.5-178.5°) and 3.39 mL of 97% pure
1-(2-fluorophenyl)piperazine (d 1.14), equivalent to 3.74 g
(0.0208 mol) of 100% pure amine, was heated on the steam bath
for 1.5 h. The mixture was cooled in ice for 12 min. The mix-
ture, consisting of semisolid and hard pale yellow glass, was
treated with 3 mL and 5x5 mL water, with brief heating on the
steam bath. The glass was scraped to dislodge solid. Solid was
collected after each treatment with water. The combined solid
was washed with 2x10 mL water, sucked with the vacuum for 10
min, and let stand over Drierite for 47 h, white solid (Solid A),
1.40 g (70.4%), mp 143-147° after softening and shrinking, neg-
ative Beilstein test (no Cl). Solid A was dried at 66-75° for 82
min, 1.37 g (68.8%).
The combined filtrate from Solid A, consisting of pale yellow
liquid and white solid, was mixed with 10 mL water. The mix-
ture was let stand for 47 h. The solid was collected, using 2x3
mL water to complete the transfer, washed with 2x7 mL water,
sucked with the vacuum for 15 min, and dried at 66-68° for 22
min, off white solid (Solid B), 0.344 g (17.2%), mp 144-148°
after some softening, negative Beilstein test (no Cl).
Solid A was recrystallized from the solvent pair of 95%
ethanol and water, letting the final mixture cool in ice for 41 min.
The solid was collected, using 2x4 mL water to complete the
transfer, washed with 2x7 mL water, sucked with the vacuum for
12 min, let stand over Drierite for 70 h, and dried at 65-70° for 1
h, off white solid (Solid C), blunt end transparent needles (x100),
1
H nmr (CDCl ): δ 2.20 (s, 3H, 4-CH , pyrimidine), 2.44 (ct, 4H,
3
3
piperazine, closest to benzyl group), 3.52 (s, 2H, benzyl CH ),
2
3.58 (ct, 4H, piperazine, closest to pyrimidine ring), 4.77 (bs, 2H,
2-NH , pyrimidine), 5.80 (s, 1H, 5-H, pyrimidine), 7.25-7.40 (m,
2
1
5H, benzene).
1.02 g (51.3%), mp 146-148.5°. H nmr (CDCl ): δ 2.23 (s, 3H,
3
Anal. Calcd. for C
H N : C, 67.82; H, 7.47; N, 24.71.
6-CH , pyrimidine), 3.10 (ct, 4H, piperazine, closest to benzene),
16 21 5
3
Found: C, 67.34; H, 7.43; N, 24.70.
3.73 (ct, 4H, piperazine, closest to pyrimidine), 4.73 (bs, 2H, 2-
The combined filtrate from Solid A, consisting of pale yellow
liquid and white solid, was let stand for 3 days. The solid was
collected, using 2x1.5 mL water to complete the transfer, washed
with 2x10 mL water, and sucked with the vacuum for 20 min,
pale yellow solid (Solid D), 0.661 g (33.7%), mp 138-142°, neg-
ative Beilstein test (no Cl).
Solid D was recrystallized from the solvent pair of 95%
ethanol and water, letting the final mixture stand for 15 min and
cool in ice for 20 min. The solid was collected, using 2x3 mL
water to complete the transfer, washed with 2x7 mL water, and
sucked with the vaccum for 25 min, pale yellow solid (Solid E),
0.452 g (23.1%), mp 140-143°. Solid E was more yellowish than
Solid D.
NH , pyrimidine), 5.90 (s, 1H, 5-H, pyrimidine), 6.90-7.10 (m,
4H, benzene).
2
Anal. Calcd. for C
H N F: C, 62.70; H, 6.31; N, 24.37.
15 18 5
Found: C, 62.82; H, 6.12; N, 24.38.
Solid B was recrystallized from the solvent pair of 95%
ethanol and water, letting the final mixture cool in ice for 2.5 h.
The solid was collected, using 3x2 mL water to complete the
transfer, washed with 2x3 mL water, sucked with the vacuum for
10 min, let stand over Drierite for 44 h, and dried at 64-67° for
1.5 h, cream colored solid (Solid D), 0.237 g (11.9%), mp 145-
147.5°.
Anal. Calcd. for C
H N F: C, 62.70; H, 6.31; N, 24.37.
15 18 5
Found: C, 62.89; H, 6.22; N, 24.23.
Solid E was recrystallized from the solvent pair of 95% ethanol
and water, letting the final mixture cool in ice for 36 min. The
solid was collected, using 2x3 mL water to complete the transfer,
washed with 2 mL and 3.5 mL water, and sucked with the vacuum
for 15 min, off white solid (Solid F), 32 mg (1.6%). Solid F was
let stand over Drierite for 22 h, dried at 70-71° for 162 min, and let
stand over Drierite for 19 h more, mp 139.5-142°.
4-[4-(4-Fluorophenyl)piperazin-1-yl]-6-methylpyrimidin-2-
amine (5).
A mixture of 1.00 g (0.00694 mol) of 2-amino-4-chloro-6-
methylpyrimidine (mp 178-181°) and 3.82 g of 98% pure 1-(4-
fluorophenyl)piperazine (white solid, mp 30-33°, forming a col-
orless liquid upon warming on the steam bath), equivalent to 3.74
g (0.0208 mol) of 100% pure amine, was heated on the steam
bath for 2 h. To the mixture of yellow brown semisolid and hard
Anal. Calcd. for C
H N : C, 67.82; H, 7.47; N, 24.71.
16 21 5
Found: C, 68.15; H, 7.65; N, 24.78.

1292
I. Becker
Vol. 42
white solid, 4x3 mL water was added with brief heating each
time. The solid was broken up and collected along the way. The
combined solid, still in the funnel, was dried at 62-63° for 19 h,
yellowish hard solid (Solid A), 1.41 g, mp 189-192° after darken-
ing, sintering, and shrinking, weak positive Beilstein test (some
Cl present).
lected, using 2x2.5 mL water to complete the transfer, washed with
2x3 mL water, sucked with the vacuum for 8 min, and dried at 63-
64° for 2 h, pale yellow solid (Solid A), 0.328 g (17.5%). Solid A
was let stand over Drierite for 211 h, mp 173-174.5° after softening
1
at 171.5-173°, negative Beilstein test (no Cl). H nmr (CDCl ): δ
3
2.23 (s, 3H, 4-CH , pyrimidine), 3.61-3.64 and 3.71-3.73 (each ct,
3
Solid A was recrystallized from the solvent pair of 95%
ethanol (6 mL) and water (6 mL). Much solid did not dissolve in
the boiling 95% ethanol. This insoluble solid was discarded. The
final mixture was let stand for 28 min and cooled in ice for 37
min. The solid was collected, using 2.5 mL and 1.5 mL water to
complete the transfer, washed with 2x2 mL water, sucked with
the vacuum for 11 min, and dried a 62° for 2 h, pale yellow crys-
talline solid (Solid B), 67 mg (3.4%), mp 192-194.5° after soften-
ing and darkening at 189.5-192°, negative Beilstein test (no Cl).
Just before analysis Solid B was let stand over Drierite for 18.5 h.
8H, piperazine), 4.86 (bs, 2H, 2-NH , pyrimidine), 5.86 (s, 1H, 5-
2
H, pyrimidine), 6.64-6.66 (cm, 2H, 2x β-H, pyridine), 7.48-7.52
(td, 1H, γ-H, pyridine), 8.20-8.22 (dd, 1H, α-H, pyridine).
Anal. Calcd. for C
H N : C, 62.20; H, 6.71; N, 31.09.
14 18 6
Found: C, 62.34; H, 6.82; N, 31.02.
The combined filtrate from Solid A was let stand for 9 days.
The solid was collected, using 2x1 mL water to complete the
transfer, washed with 1.5 mL water, sucked with the vacuum for
15 min, dried at 62° for 1 h, and let stand over Drierite for 67.5 h,
pale yellow solid, 37 mg (2.0%), mp 168-172.5° after softening
at 167-168°.
Anal. Calcd. for C
H N F: C, 62.70; H, 6.31; N, 24.37.
15 18 5
Found: C, 62.47; H, 6.43; N, 24.24.
4-Methyl-6-(4-pyrimidin-2-ylpiperazin-1-yl)pyrimidin-2-amine
(7).
The combined filtrate from Solid A, consisting of pale orange
liquid and fine white solid, was let stand for 24 h. The solid was
collected, using 2 mL and 1 mL water to complete the transfer,
washed with 2x3 mL water, sucked with the vacuum for 10 min,
and dried at 62-63° for 21 h, cream colored solid (Solid C), 157
mg (7.9%), mp 189-193.5° after shrinking and darkening, nega-
tive Beilstein test (no Cl).
Solid C was recrystallized from the solvent pair of 95% ethanol
(5 mL) and enough hot water to reach the cloud point. The final
mixture was let stand for 3 min and cooled in ice for 22 min. The
solid was collected, using 3x1 mL water to complete the transfer,
washed with 3x2 mL water, sucked with the vacuum for 15 min,
and dried at 60-76° for 2 h, pale yellow crystalline solid, 49 mg
A mixture of 1.00 g (0.00694 mol) of 2-amino-4-chloro-6-
methylpyrimidine (mp 176.5-178.5°) and 3.68 g of 98% pure 1-
(2-pyrimidinyl)piperazine (Acros Fisher), equivalent to 3.61 g
(0.0220 mol) of 100% pure amine, was heated on the steam bath
for 185 min. To the cool hard mixture of white, tan, and brown
solids, 3 mL water were added. The solids were broken up and
collected, using 2 mL and 4 mL water to complete the transfer.
The solids were transferred to a porcelain dish, pulverized,
returned to a clean funnel, washed with 2x6 mL water, sucked
with the vacuum for 10 min, let stand over Drierite for 164.5 h,
and dried at 65-66° for 1 h, 1.59 g, mp 184-188.5° after softening
at 177-184°, strong positive Beilstein test (Cl present).
1
(2.5%), mp 194-196° after softening at 191-194°. H nmr
This solid was recrystallized from the solvent pair of 95%
ethanol (9 mL) and water. The solid that did not dissolve in the
boiling 95% ethanol was discarded. The final mixture was let
stand for 18 min and cooled in ice for 80 min. The solid was col-
lected, using 4x3 mL water to complete the transfer, washed with
2x6 mL water, sucked with the vacuum for 17 min (pasty solid),
and dried at 67-68° for 75 min, crusty cream colored solid, 0.412 g
(21.9%), mp 187.5-188.5° after softening at 186-187.5°, negative
Beilstein test (no Cl).
(CDCl ): δ 2.24 (s, 3H, 6-CH , pyrimidine), 3.12-3.15 (ct, 4H,
3
3
piperazine), 3.72-3.75 (ct, 4H, piperazine), 4.69 (bs, 2H, 2-NH ,
2
pyrimidine), 5.88 (s, 1H, 5-H, pyrimidine), 6.89-6.92 (cm, 2H
meta to F, phenyl), 6.92-7.01 (cm, 2H ortho to F, phenyl).
Anal. Calcd. for C
H N F: C, 62.70; H, 6.31; N, 24.37.
15 18 5
Found: C, 62.88; H, 6.26; N, 24.35.
4-Methyl-6-(4-pyridin-2-ylpiperazin-1-yl)pyrimidin-2-amine
(6).
This product was recrystallized from the solvent pair of 95%
ethanol (5 mL) and water (7 mL), letting the final mixture cool in
ice for 43 min. The solid was collected, using 2x1 mL water to
complete the transfer, washed with 2 mL and 3 mL water, sucked
with the vacuum for 30 min (pasty solid), dried at 67-68° for 2 h,
let stand over Drierite for 91 h, and dried at 67° for 161 min, cream
A mixture of 1.00 g (0.00694 mol) of 2-amino-4-chloro-6-
methylpyrimidine (mp 178-181°) and 3.16 mL of 98% pure 1-(2-
pyridinyl)piperazine (d 1.072), equivalent to 3.39 g (0.0208 mol)
of 100% pure amine, was heated on the steam bath for 2.5 h. The
mixture of tan, yellow, white, and brown solids was let stand for
70 h. This mixture, containing hard solid, was mixed well with 7
mL of water. Solid was collected. The remaining solid was
mixed with five small portions of water (13 mL total), collecting
solid after each treatment with water. A small amount of solid
could not be dislodged from the flask. The combined solid was
washed with 6 mL water, sucked with the vacuum for 13 min,
and dried at 62-63° for 1 h, cream colored solid, 1.31 g (70.1%).
This product was let stand over Drierite for 46 h, mp 161-172°
after softening and shrinking, negative Beilstein test (no Cl).
This product was recrystallized from the solvent pair of 95%
ethanol (7 mL) and water. The filter paper was rinsed with addi-
tional hot 95% ethanol to dissolve solid. Yet, substantial solid set-
tled out on the filter paper. This solid was discarded. The final
mixture was let stand for 16 min, cooled in ice for 64 min, stirred
rapidly, and cooled in ice for 12 min more. The solid was col-
1
colored solid, mp 188-189° after softening at 187-188°. H nmr
(CDCl ): δ 2.23 (s, 3H, 4-CH , trisubstituted pyrimidine), 3.68 (ct,
3
3
4H, piperazine), 3.89 (ct, 4H, piperazine), 4.82 (bs, 2H, 2-NH ,
2
trisubstituted pyrimidine), 5.87 (s, 1H, 5-H, trisubstituted pyrimi-
dine), 6.54 (t, 1H, 5-H, monosubstituted pyrimidine), 8.34 (d, 2H,
4-H & 6-H, monosubstituted pyrimidine).
Anal. Calcd. for C
H N : C, 57.55; H, 6.32; N, 36.14.
13 17 7
Found: C, 57.68; H, 6.51; N, 35.99.
4-(4-Benzylpiperidin-1-yl)-6-methylpyrimidin-2-amine (8).
A mixture of 1.00 g (0.00694 mol) of 2-amino-4-chloro-6-
methylpyrimidine (mp 176.5-178.5°) and 3.74 mL of 99% pure
4-benzylpiperidine (d 0.985), equivalent to 3.64 g (0.0208 mol)
of 100% pure amine, was heated on the steam bath for 1.5 h. The

Nov-Dec 2005
Preparation of Pyrimidine Derivatives as Potential Medicinal Agents
1293
resulting mixture, consisting of yellow semisolid and hard orange
red material, was mixed well with six small portions of water.
Each time the hard solid was partially broken up and the liberated
solid was collected. The combined solid was sucked with the
vacuum for 20 min and let stand over Drierite for 68 h, mixture of
yellow and orange solids (Solid A), 0.344 g, mp 104-117°, strong
positive Beilstein test (Cl present).
The filtrate from Solid A, consisting of yellow oil and cloudy
pale yellow liquid, was let stand for 69 h. The solid was col-
lected, using 3x3.5 mL water to complete the transfer, washed
with 7 mL and 9 mL water, sucked with the vacuum for 13 min,
and dried at 53-56° for 88 min, 0.910 g, mp 98-115°. This solid
was let stand over Drierite for 10 days, yellow solid (Solid B),
0.825 g, negative Beilstein test (no Cl).
min and cool in ice for 23 min. The crusty off white solid was
collected, using 3x2 mL water to complete the transfer, washed
with 2x2 mL water, sucked with the vacuum for 15 min (0.10 g,
7.0%), and let stand over Drierite for 14 min, mp 107-109°. For
analysis the solid was let stand over Drierite for 23 h and dried at
1
57-65° for 97 min. H nmr (CDCl ): δ 1.50-1.59 (cm, 4H, 4x γ-
3
H, hexamethyleneimine), 1.75 (bs, 4H, 4x β-H, hexamethyl-
eneimine), 2.20 (s, 3H, 6-CH , pyrimidine), 3.57 (bs, 4H, 4x α-
3
H, hexamethyleneimine), 4.70 (bs, 2H, 2-NH , pyrimidine), 5.73
2
(s, 1H, 5-H, pyrimidine).
Anal. Calcd. for C H N : C, 64.05; H, 8.80; N, 27.16.
11 18
4
Found: C, 64.20; H, 9.09; N, 27.09.
4-Azocan-1-yl-6-methylpyrimidin-2-amine (10).
A mixture of 1.00 g (0.00694 mol) of 2-amino-4-chloro-6-
methylpyrimidine (mp 176.5-178.5°) and 2.62 mL of 98% pure
heptamethyleneimine (d 0.896), equivalent to 2.35 g (0.0208
mol) of 100% pure amine, was heated on the steam bath for 4 h
and let stand for 46 h. Water (2 mL) was added and hard solids
were broken up. The solid was collected, using 5x2 mL water to
complete the transfer. Large pieces of solid in the funnel were
pulverized in an agate mortar and returned to the funnel. The
solid in the funnel was washed with 2 mL water, sucked with the
vacuum for 12 min, and dried at 61-65° for 35 min, essentially
cream colored solid, 0.265 g, positive Beilstein test (Cl present).
The combined filtrate from this solid, consisting of cloudy
white and golden liquids, was let stand for 9 days, giving a mix-
ture of yellow gum, yellow crystals, and colorless liquid. The
colorless liquid was decanted off and discarded. The mixture of
gum and crystals was let stand for 70 h. This mixture was mixed
well with 10 mL water. The solid in this mixture was collected,
using 2x5 mL water to complete the transfer, washed with 2x5
mL water, sucked with the vacuum for 15 min, let stand over
Drierite for 70.5 h, and dried at 62-63° for 85 min, pale yellow
solid, 0.627 g (41.0%), mp 106-110° after slight softening, nega-
tive Beilstein test (no Cl).
This product was recrystallized from the solvent pair of 95%
ethanol and water, letting the final mixture stand for 17 days, dur-
ing which time the yellow oil in the mixture did not solidify. The
mixture then was cooled briefly in ice, vigorously stirred, and
seeded with solid that formed on the stirring rod. The yellow oil
was transformed into solid. The mixture was cooled in ice for 10
min. The solid was collected, using 3x1 mL water to complete
the transfer, washed with 2 mL and 3 mL water, sucked with the
vacuum for 12 min, dried at 63° for 103 min, and let stand over
Drierite for 45 h, pale yellow solid, 0.308 g (20.1%), mp 102-
Solid B was recrystallized from the solvent pair of 95%
ethanol and water, letting the final mixture cool in ice for 1.5 h.
The solid was collected, using 4x2 mL water to complete the
transfer, washed with 2x2 mL water, sucked with the vacuum for
10 min, dried at 58-62° for 1 h, let stand over Drierite for 69 h,
and dried at 62° for 2.5 h more, pale yellow solid, 0.489 g
1
(24.6%), mp 138-142.5°. H nmr (CDCl ): δ 1.20 (m, 2H, 2x β-
3
H, piperidine), 1.69 (bd, , 2H, 2x β-H, piperidine), 1.78 (m, lone
H, piperidine), 2.20 (s, 3H, 6-CH , pyrimidine), 2.55 (d, 2H, ben-
3
zyl CH ), 2.74 (m, 2H, 2x α-H, piperidine), 4.32 (bd, 2H, 2x α-
2
H, piperidine), 4.63 (bs, 2H, 2-NH , pyrimidine), 5.82 (s, 1H, 5-
2
H, pyrimidine), 7.13-7.31 (m, 5H, phenyl).
Anal. Calcd. for C
H N : C, 72.31; H, 7.82; N, 19.84.
17 22 4
Found: C, 72.44; H, 8.05; N, 19.81.
4-Azepan-1-yl-6-methylpyrimidin-2-amine (9).
A mixture of 1.00 g (0.00694 mol) of 2-amino-4-chloro-6-
methylpyrimidine (mp 176.5-178.5°) and 2.34 mL of 99% pure
hexamethyleneimine (d 0.880), equivalent to 2.04 g (0.0206 mol)
of 100% pure amine, was heated on the steam bath for 101 min
and then let stand overnight. The white and pale yellow solids
were mixed with several portions of water (total 30 mL). Solid
was collected after each treatment with water. The combined
solid was washed with 2x3 mL water and sucked with the vac-
uum for 2 h, off white crystalline solid (major crop), 0.611 g
(42.7%), negative Beilstein test (no Cl), mp 107-109°. An
unmeasured amount of hard pale yellow solid could not be dis-
lodged from the bottom of the flask and hence was discarded.
To the combined filtrate from the major crop, 10 mL of water
were added. The mixture was let stand at room temperature
overnight and cooled in ice for 11 min. The solid was collected,
using 2 mL water to complete the transfer, washed with 2x2 mL
water, sucked with the vacuum for 85 min, off white crystalline
solid (minor crop), 0.229 g (16.0%), mp 105-107°, negative
Beilstein test (no Cl).
The major crop was recrystallized from the solvent pair of
95% ethanol (20 mL) and water (20 mL), letting the final mixture
stand at room temperature for 7 days. The mixture, consisting of
yellow oil and clear colorless liquid, was concentrated on the
steam bath to 10 mL. The concentrate was cooled in ice for 10
min and let stand for 3 days. The crusty crystalline cream col-
ored solid was collected, using four portions of water (total 15
mL) to complete the transfer, washed with 6 mL water, sucked
with the vacuum (mp 107-108°), and let stand over Drierite for 2
days, 0.414 g (29.0%).
1
111.5°. H nmr (CDCl ): δ 1.47-1.57 and 1.71-1.77 (each cm,
3
4xβ-H, 4xγ-H, and 2xδ-H, heptamethyleneimine), 2.20 (s, 3H, 6-
CH , pyrimidine), 3.53 (bs, 4H, 4xα-H, heptamethyleneimine),
3
4.79 (bs, 2H, 2-NH , pyrimidine), 5.71 (s, 1H, 5-H, pyrimidine).
2
Anal. Calcd. for C
H N : C, 65.42; H, 9.15; N, 25.43.
12 20 4
Found: C, 66.00, 65.97; H, 9.11, 9.55; N, 25.26, 25.01.
4-Methyl-6-[octahydroisoquinolin-2(1H)-yl]pyrimidin-2-amine
(11).
A mixture of 1.00 g (0.00694 mol) of 2-amino-4-chloro-6-
methylpyrimidine (mp 178-181°) and 3.22 mL of 96% pure per-
hydroisoquinoline (mixture of cis and trans isomers, d 0.936),
equivalent to 2.89 g (0.0208 mol) of 100% pure amine, was heated
on the steam bath for 2.5 h and then let stand for 44.5 h. The mix-
ture of tan and brown solids and hard yellow brown glass was
This solid was recrystallized from the solvent pair of 95%
ethanol (2.5 mL) and water, letting the final mixture stand for 2

1294
I. Becker
Vol. 42
broken up and treated with 2x2 mL and 4 mL water with brief
warming, collecting solid after each treatment with water. Then
2x4 mL water were used to complete the transfer. The solid was
washed with 4.5 mL water, sucked with the vacuum for 25 min,
and dried at 62° for 2 h, essentially all pale yellow solid, 0.735 g,
mp 105-113°, weak positive Beilstein test (some Cl present).
This product was recrystallized from the solvent pair of 95%
ethanol and water, letting the final mixture stand for 8 min. The
mixture, consisting of orange oil (2 mL) and cloudy white liquid
(5 mL), was cooled in ice for 78 min and then vigorously stirred,
whereupon the oil solidified. The mixture was cooled in ice for
14 min. The solid was collected, using 2x2 mL and 1 mL water
to complete the transfer, sucked with the vacuum for 14 min, and
dried at 63° for 102 min, pale yellow solid, 0.436 g (25.5%), mp
117-120.5°, negative Beilstein test (no Cl). Prior to analysis this
solid was let stand over Drierite for 67 h and dried at 62-63° for
dried at 61-62° for 16 h, let stand over Drierite for 20.5 h, and
dried at 64-66° for 104 min, cream colored solid (Solid E), 0.107
1
g (6.6%), mp 126-129°. H nmr (CDCl ): δ 2.18 (s, 3H, 4-CH ,
3
3
pyrimidine), 4.46 (d, 2H, benzyl CH ), 4.73 (bs, 2H, 2-NH ,
2
2
pyrimidine), 4.96 (bs, 1H, 4-NH, pyrimidine), 5.64 (s, 1H, 5-H,
pyrimidine), 7.02 and 7.26 (each m, 4H, phenyl).
Anal. Calcd. for C
H N F: C, 62.06; H, 5.64; N, 24.12.
12 13 4
Found: C, 62.37; H, 5.49; N, 24.28.
4
N -(3,5-Difluorobenzyl)-6-methylpyrimidin-2,4-diamine (13).
A mixture of 1.00 g (0.00694 mol) of 2-amino-4-chloro-6-
methylpyrimidine (soft silky white needles, mp 180°) and 2.55
mL of 96% pure 3,5-difluorobenzylamine (d 1.21), equivalent to
2.97 g (0.0208 mol) of 100% pure amine, was heated on the
steam bath for 2.5 h and let stand for 18 min. The pale yellow
solid and orange gel were mixed well with 2 mL water. The solid
was broken up. The mixture was cooled in ice for 2 min. The
solid was collected, using 6x2 mL water to complete the transfer,
washed with 7 mL water, sucked with the vacuum for 30 min,
and dried at 52° for 68 h, cream colored solid, 0.753 g (43.3%),
mp 122.5-123.5°, negative Beilstein test (no Cl).
1
33 min. H nmr (CDCl ): δ 1.23-1.91 (12H, octahydroisoquino-
3
line, but not the 4x α-H), 2.19 (s, 3H, 4-CH , pyrimidine), [3.09-
3
3.18 (bt), 3.19-3.22 (dd), 3.79-3.83 (dd), and 4.05 (bd): all per-
tain to the 4x α-H of octahydroisoquinoline], 4.74 (bs, 2H, 2-
NH , pyrimidine), 5.8l (s, 1H, 5-H, pyrimidine).
2
Anal. Calcd. for C
H N F : C, 57.59; H, 4.83; N, 22.39.
Anal. Calcd. for C
H N : C, 68.26; H, 9.00; N, 22.74.
12 12 4 2
14 22 4
Found: C, 57.84; H, 4.65; N, 22.20.
Found: C, 68.01; H, 9.27; N, 22.67.
This product was recrystallized from the solvent pair of 95%
ethanol and water, letting the final mixture (8 mL) stand for 12
min. The mixture, consisting of orange oil and cloudy white liq-
uid, was cooled in ice for 144 min whereupon the oil solidified.
The white solid above crusty tan solid was collected first, using
5x1 mL water to complete the transfer. Then the tan solid was
collected on the same funnel. The combined solid was washed
with 2x6 mL water, sucked with the vacuum for 11 min, and
dried at 52-56° for 45 h, light tan solid, 0.393 g (22.6%), mp 122-
4
N -(4-Fluorobenzyl)-6-methylpyrimidin-2,4-diamine (12).
A mixture of 1.00 g (0.00694 mol) of 2-amino-4-chloro-6-
methylpyrimidine (mp 176.5-178.5°) and 2.44 mL of 97% pure
4-fluorobenzylamine (d 1.10), equivalent to 2.60 g (0.0208 mol)
of 100% pure amine was heated on the steam bath for 2 h, giving
a tan mush. The solid was collected, using 2x2 mL and 2x3 mL
water to complete the transfer, washed with 3.5 mL and 4 mL
water, sucked with the vacuum for 5 min, let stand over Drierite
for 20 h, and dried at 60-63° for 1 h, soft white needles (x100)
(Solid A), 0.422 g, strong positive Beilstein test (Cl present).
The combined filtrate from Solid A, consisting of pale yellow
oil and cloudy white liquid, was cooled in ice for 49 min. The
solid that formed was collected, using 4x5 mL water to complete
the transfer, washed with 2x7 mL water, sucked with the vacuum
for 10 min, let stand over Drierite for 20 h, and dried at 60-63° for
1 h, soft white needles (x100) (Solid B), 0.492 g, mp 108-126°,
negative Beilstein test (no Cl).
1
123°. H nmr (CDCl ): δ 2.13 (s, 3H, 6-CH , pyrimidine), 4.46
3
3
(d, 2H, benzyl CH ), 5.25 (bs, 2H, 2-NH , pyrimidine), 5.59 (s,
2
2
1H, 5-H, pyrimidine), 5.75 (bs, 1H, 4-NH, pyrimidine), 6.65-6.69
(ct, 1H between the two F atoms, phenyl), 6.79-6.80 (d, 2H,
phenyl).
Anal. Calcd. for C
H N F : C, 57.59; H, 4.83; N, 22.39.
12 12 4 2
Found: C, 58.10; H, 4.63; N, 22.32.
4
6-Methyl-N -[3-(trifluoromethyl)benzyl]pyrimidin-2,4-diamine
(14).
Solid B was recrystallized from the solvent pair of 95%
ethanol and water, letting the final mixture cool in ice for 72 min.
The solid was collected, washed with 2 mL and 3 mL water,
sucked with the vacuum for 15 min, dried at 58-64° for 75 min,
let stand over Drierite for 70 h, and dried at 60-61° for 1 h, soft
white solid (Solid C), 36 mg (2.2%), mp 121-128°.
A mixture of 1.00 g (0.00694 mol) of 2-amino-4-chloro-6-
methylpyrimidine (mp 176.5-178.5°) and 3.04 mL of 98% pure
3-(trifluoromethyl)benzylamine (d 1.22), equivalent to 3.64 g
(0.0208 mol) of 100% pure amine, was heated on the steam bath
for 90 min, let stand for 43.5 h, and heated on the steam bath for
35 min more. The cool mixture was mixed with 6 mL water. The
solid was collected, using 6x1 mL water to complete the transfer,
washed with 2x2 mL water, sucked with the vacuum for 5 min,
and dried at 66° for 2.5 h, off white solid, 0.178 g. This solid
proved to be mostly unreacted 4-chloro compound.
The combined filtrate from this solid, consisting of cloudy white
liquid and pale yellow oil, was cooled in ice for 1 h and let stand
for 9 days. The lower layer of pale yellow oil was separated from
the upper aqueous layer. The oil was concentrated by heating on
the steam bath. The viscous concentrate was cooled in ice for 134
min, let stand for 7 days, and cooled in ice for 105 min. The con-
centrate now consisted of solid and yellow liquid. The solid was
collected, using 4x1 mL water to complete the transfer, washed
with 2x1 mL water, sucked with the vacuum for 10 min, and dried
Anal. Calcd. for C
Found: C, 61.48; H, 5.71; N, 24.26.
H N F: C, 62.06; H, 5.64; N, 24.12.
12 13 4
What was left on the bottom of the crystallization beaker after
Solid C was collected was a white and pale yellow crusty solid.
This solid was broken up and collected, using 3x3 mL water to
complete the transfer, washed with 2x5 mL water, sucked with
the vacuum for 10 min, dried at 58-61° for 30 min, let stand over
Drierite for 70 h, and dried at 60-61° for 1 h, light cream colored
solid (Solid D), 0.243 g (15.1%), mp 122-127°.
Solid D was recrystallized from the solvent pair of 95%
ethanol and water, letting the final mixture stand for 15 min and
cool in ice for 49 min. The crusty solid was broken up, collected,
using 1.5 mL and 2 mL water to complete the transfer, washed
with 2 mL and 3 mL water, sucked with the vacuum for 10 min,

Nov-Dec 2005
Preparation of Pyrimidine Derivatives as Potential Medicinal Agents
1295
164 (1988); [h] D. S. Robinson, K. Rickels, J. Feighner, L. F. Fabre, Jr,
R. E. Gammans, R. C. Shrotriya, D. R. Alms, J. J. Andary, and M. E.
Messina, J. Clinical Psychopharmacology, 10, 67S-76S (1990); [i] D. P.
Taylor, Annals NY Academy of Sciences, 600, 545 (1990); [j] K. Rickels,
J. D. Amsterdam, C. Clary, G. Puzzuoli, and E. E. Schweizer, J. Clinical
Psychiatry, 52, 34 (1991); [k] R. M. Pinder, and J. H. Wieringa,
Medicinal Research Reviews, 13, 259 (1993).
at 65-68° for 141 min, sparkling white crusty crystals, 0.210 g
(10.7%), mp 103-109°, negative Beilstein test (no Cl). Covalent F
does not give a positive Beilstein test. Prior to analysis the sample
1
was let stand over Drierite for 47 h. H nmr (CDCl ): δ 2.14 (s,
3
3H, 6-CH , pyrimidine), 4.54 (d, 2H, benzyl CH ), 5.07 (bs, 2H, 2-
3
2
NH , pyrimidine), 5.47 (bs, 1H, 4-NH, pyrimidine), 5.62 (s, 1H, 5-
2
H, pyrimidine), 7.41-7.54 (m, 4H, phenyl).
[5] N. R. Shah, F. Y. Lee, P. Chen, D. Norris, and C. L. Sawyers,
Science, 305, 399 (2004).
Anal. Calcd. for C
H N F : C, 55.32; H, 4.64; N, 19.85.
13 13 4 3
Found: C, 55.54, 55.89; H, 4.58, 4.77; N, 19.81, 20.04.
[6] Subsequent to our preparation of 4-(4-benzylpiperazin-1-yl)-
6-methylpyrimidin-2-amine (3) carried out in 2003, we discovered that
Badran and Youssef [7d,7e] had prepared 3 earlier. Badran and Youssef
refluxed a mixture of 0.010 mol of 1-benzylpiperazine and 0.010 mol of
2-amino-4-chloro-6-methylpyrimidine in aqueous hydrochloric acid for
3 h. Their mol ratio of amine to the 4-chloropyrimidine was 1:1. The mp
of their product was 60°. They give no yield of product. Our conditions
of reaction differed from those of Badran and Youssef. We heated a mix-
ture of 0.0204 mol of the amine and 0.00694 mol of the 4-chloropyrimi-
dine on the steam bath for 1 h. The mol ratio of our reactants was 2.9:l.
The mp of our analytically pure product was 139.5-142° which is
Acknowledgement.
I thank Professor Walter Boyko, Director of NMR Services at
1
Villanova University, for the determination of three of the H nmr
spectra and for his sagacious interpretation of most of the spectra.
I thank Professor James Barnes for preparing the computer disk
of the manuscript.
Dedication.
1
markedly different from Badran and Youssef’s mp of 60°. The H nmr
This paper is dedicated to the memory of my brother
Milton Becker. In addition to being a deeply devoted husband,
father, and grandfather, Milton was a superb modern
impressionist artist.
spectrum of our product confirmed its structure. Badran and Youssef
give no spectral data.
[7a] D. J. Brown, The Pyrimidines, Interscience Publishers, NY,
1962, pp 181-182 and pp 187-201; [b] D. D. Dischino, R. R. Covington,
C. M. Combs, and R. E. Gammans, J. Labelled Compounds and
Radiopharmaceuticals, 25, 359 (1987); [c] K. Matsumoto, S. Hashimoto,
H. Minatogawa, M. Munakata, and S. Otani, Chemistry Express, 5, 473
(1990); [d] M. M. Badran and K. Youssef, Egypt. J. Pharm. Science, 31,
407 (1990); [e] M. M. Badran and K. Youssef, Revue Roumaine de
Chimie, 37, 283 (1992); [f] J. L. Mokrosz, L. Strekowski, B. Duszynska,
D. B. Harden, M. J. Mokrosz, and A. J. Bojarski, Pharmazie, 49, 801
(1994); [g] I. Becker, Master of Arts Thesis, Temple University, Phila.,
PA, June 1956 and references cited therein; [h] I. Becker, J. Heterocyclic
Chem., 41, 343 (2004) and references cited therein.
[8a] R. Andrisano and G. Modena, Gazz. Chim. Ital., 81, 398
(1951); [b] T. E. Young and E. D. Amstutz, J. Am. Chem. Soc., 73, 4773
(1951); [c] A. Maggiolo and A. P. Phillips, J. Org. Chem., 16, 376
(1951); [d] K. R. Brower, W. R. Samules, J. W. Way, and E. D. Amstutz,
J. Org. Chem.,18, 1648 (1953); [e] K. R. Brower, W. R. Samules, J. W.
Way, and E. D. Amstutz, J. Org. Chem., 19, 1830 (1954); [f] N. B.
Chapman and C. W. Rees, J. Chem. Soc., 1190 (1954); [g] C. K. Banks,
J. Am. Chem. Soc., 66, 1127 (1954); [h] D. J. Brown, The Pyrimidines,
Interscience Publishers, NY, 1962, pp 181-182.
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