Preparation of derivatives of 1-(2-pyrimidinyl)piperazine as potential antianxiety, antidepressant, and antipsychotic agents

Article abstract of DOI:10.1002/jhet.5570450410

(Chemical Equation Presented) This paper describes the preparation of twenty-eight derivatives of 1-(2-pyrimidinyl)piperazine as potential antianxiety, antidepressant, and antipsychotic agents. In twenty-six of the preparations a chloro nitrogen heterocycle was caused to react with an excess of 1-(2-pyrimidinyl)piperazine in the absence of solvent. A specific example is given above.

Full text of DOI:10.1002/jhet.5570450410

Jul-Aug 2008
1005
Preparation of Derivatives of 1-(2-Pyrimidinyl)piperazine as
Potential Antianxiety, Antidepressant, and Antipsychotic Agents
Irwin Becker
Department of Chemistry, Villanova University, Villanova, PA l9085
Received May 10, 2007
N
NO2
HN
N
NO2
Cl
N
N
N
O
N
CH3
N
N
3:1 mole ratio
O
N
CH3
steam bath 2.5 h
stand RT 8 days
21%
mp 127.2-1280
This paper describes the preparation of twenty-eight derivatives of 1-(2-pyrimidinyl)piperazine as
potential antianxiety, antidepressant, and antipsychotic agents. In twenty-six of the preparations a chloro
nitrogen heterocycle was caused to react with an excess of 1-(2-pyrimidinyl)piperazine in the absence of
solvent. A specific example is given above.
J. Heterocyclic Chem., 45, 1005 (2008).
studied the affinity of these derivatives for the serotonin
receptor sites on neurons in the rat brain.
INTRODUCTION
Serotonin, released from nerve terminals in virtually all
regions of the brain, plays a direct role in normal
functions of the central nervous system and in mental
In 1990 and 1991 Matsumoto and coworkers
[11,12] reported the preparation of nine derivatives
of 1-(2-pyrimidinyl)piperazine (see Table 1). To
CH2 CH2 NH2
HO
Table 1
N
H
N
N
N
N
N
N
N
N
N
N
N
N
N
N
serotonin
5-hydroxytryptamine
5-HT
N
N
Cl
N
N
N
N
diseases such as anxiety, depression, psychosis, obsessive
compulsive disorders, aggression, and eating disorders.
The role of serotonin receptors in the brain is being
actively studied with respect to normal and abnormal
functions of the brain. Fourteen different serotonin
receptors are known. Serotonin receptor dysfunction is
implicated in many neuropsychiatric disorders [1-9].
Greengard and coworkers [9] have determined that the
protein p11 binds to the serotonin receptor 5-HT1B. Low
levels of p11 in mice and in humans are associated with
depression. When the workers provided the mice with
antidepressants, the p11 levels increased. In other
experiments, administration of p11 alleviated depression
symptoms. Also, they found that high levels of p11
increase the number of receptors on the surface of
neurons, enhancing serotonin signaling.
N
CF3
N
N
N
N
N
N
N
N
N
N
N
CF3
N
N
N
N
N
N
N
N
N
N
N
N
S
N
N
N
CF3
In 1994 Makrosz and coworkers [10] reported the
preparation of the seven alkyl derivatives of 1-(2-
pyrimidinyl)piperazine indicated below. These workers
prepare these derivatives Matsumoto and coworkers
caused chloro nitrogen heterocycle, such as
a
chloropyrazine, to react with 1-(2-pyrimidinyl)-
piperazine in the presence of triethylamine in
tetrahydrofuran at 100° under high pressure for four
days. No biological testing of the nine compounds is
reported in the two papers.
N
N
N
N
RX, K2CO3
acetone, RT
N
NH
N
N R
1-(2-pyrimidinyl)piperazine
where R = CH3-, C2H5-, n-C3H7-,
n-C4H9-, n-C5H11-, n-C6H13-, n-C8H17
-

1006
I. Becker
Vol 45
agent [16]. The 4-pyrimidinyl isomer of C, interestingly
enough, was much less active than C [16]. Compounds A,
B, and C contain the 1-(2-pyrimidinyl)piperazinyl moiety.
The structural formulas of buspirone, gepirone,
ipsapirone, tandospirone, and zalospirone are given in
Table 3. These five compounds, collectively called
azapirones, have been extensively evaluated in animals
and in man [17]. The azapirones have antianxiety and
antidepressant properties. Structurally the azapirones have
in common the 1-(2-pyrimidinyl)piperazinyl moiety. 1-(2-
Pyrimidinyl)piperazine itself is a metabolic breakdown
product—a metabolite—of the azapirones. Indeed, the 1-
(2-pyrimidinyl)piperazine formed in vivo is considered to
be partly responsible for the efficacy of the azapirones in
the treatment of depression. Pinder believes that the
efficacy of antidepressants could be improved by the use
of combination therapy [18].
N
N
HN
N
N
N
N
N
N
N
Cl
N
N
chloropyrazine
Arranz and coworkers [13] and Vega and coworkers
[14] have prepared seven compounds that are structurally
related to each other and to the anxiolytic drug ipsapirone
(see Table 2). Each compound contains the 1-(2-
pyrimidinyl)piperazinyl moiety and a sulfone ring. These
seven compounds have not yet been evaluated as possible
antianxiety and antidepressant drugs [14].
Compounds A and B have exhibited antiinflammatory,
adrenolytic, and central nervous system depressant
activity [15]. The substituted quinazoline C has displayed
excellent long lasting efficacy as an antihypertensive
Table 2
N
N
O
O
O
O
S
(CH2)3
N
N
N
N
S
N
N
(CH2)4
N
N
N
N
S
N
H
O
O
Ipsapirone
N
O
O
N
N
S
(CH2)4
N
N
O
O
N
S
(CH2)4 N
N
N
S
N
O
S
N
O
CH3
H
N
N
O
S
O
N
N
O
O
(CH2)3
N
N
N
S
(CH2)4 N
N
N
CH3
N
S
N
H
O
N
H
O
N
N
O
O
O
O
N
N
CH2
S
(CH2)4
N
N
N
S
N
N
N
N
CH3
N
CH3
N
N
H
O
O
N
Br
The most notable azapirone is buspirone, also called
buspar. Buspirone is manufactured by Bristol-Myers
Squibb. This drug was first marketed in June 1985. It is
used to treat general anxiety disorders and depression.
Adverse reactions of buspirone are light headedness,
nausea, and headaches.
N
N
N
N
N
N
N
N
N
N
H
N
N
N
N
N
N
H
B
A
N
N
N
CH3
CH3
O
O
N
N
N
CH2
N
N
N
N
H
N
N
C
NH2
NGD94-1

Jul-Aug 2008
Potential Antianxiety, Antidepressant, and Antipsychotic Agents
1007
Table 3
Azapirones
O
O
N
O
N
N
N
N
CH3
N
N
(CH2)4
N
O
N
N
(CH2)4
gepirone
buspirone
O
O
N
N
N
N
N
N
(CH2)4
N
N
N
(CH2)4 N
S
O
O
O
tandospirone
ipsapirone
O
N
N
N
(CH2)4 N
N
O
zalospirone
The compound called NGD94-1, prepared by Thurkauf
and coworkers [19], has exhibited antipsychotic activity
in a model system in rats. This activity has prompted
evaluation of this compound as a possible treatment for
schizophrenia [19-21]. NGD94-1 is a derivative of 1-(2-
pyrimidinyl)piperazine.
are commonly being prescribed. These drugs are given in
Table 4. Structurally, clozapine, olanzapine, and quetiapine are
1,4-disubstituted piperazine compounds. Risperidone contains
a condensed pyrimidine ring and a benzoisoxazole moiety.
RESULTS AND DISCUSSION
Chlorpromazine (also called thorazine) is the oldest anti-
psychotic drug prescribed by doctors. At least five other drugs
These considerations have prompted us to prepare
derivatives of 1-(2-pyrimidinyl)piperazine as potential
Table 4
Antipsychotic Drugs
CH3
CH3
N
N
(CH2)3
N
CH3
N
Cl
N
HCl
Cl
S
N
Chlorpromazine
(thorazine)
H
Chlozapine
CH3
N
N
O
CH3
CH2
CH2
N
N
N
N
F
CH3
N
H
S
Risperidone
N
O
Olanzapine
CH2 CH2
O CH2 CH2 OH
N
O
C
OH
N
F
CH2 CH2 CH2 N
N
Haloperidol
S
Cl
Quetiapine

1008
I. Becker
Vol 45
antianxiety, antidepressant, and antipsychotic agents.
We report herein the preparation of twenty-eight
derivatives of 1-(2-pyrimidinyl)piperazine (see Table 5).
purine, theophylline, quinazoline, pyridine, pyrazine,
quinoxaline, pyridazine, imidazole, tetrazole, and
benzoxazole. Two of the derivatives (11 and 12) contain
two 1-(2-pyrimidinyl)piperazinyl moieties; the rest contain
one. In two other derivatives (27 and 28) the 1-(2-
pyrimidinyl)piperazinyl moiety is bonded directly to a
carbon atom in a substituted benzene ring.
N
N
N
nitrogen heterocyclic ring
N
The preparation of two of the derivatives (2 and 17) by
the reaction of 1-(2-pyrimidinyl)piperazine with a chloro
nitrogen heterocycle is illustrated in Scheme 1. The
preparation of another derivative (15) is illustrated in the
graphic in the abstract.
In twenty-six of these derivatives one of the nitrogen atoms
in the piperazine ring is bonded directly to a carbon atom in
a nitrogen heterocyclic ring. The nitrogen heterocyclic
rings found in these derivatives are pyrimidine, uracil,
Table 5
Derivatives of 1-(2-Pyrimidinyl)piperazine
N
N
N
N
N
NO2
N
CH3CH2
N
N
N
N
1
2
N
N
N
N
N
N
21
22
11
N
N
N
N
N
N
CH3
N
N
N
N
N
N
CF3
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
3
N
N
N
N
N
N
N
12
13
H2N
OCH3
N
N
N
N
N
N
H2N
H2N
H2N
4*
NO2
N
N
N
N
O
N
N
23
24
N
CH3
N
N
N
N
N
N
N
N
N
N
N
N
CH3
N
N
5
O2N
14
15
N
N
N
OCH3
N
N
N
N
N
N
N
N
N
N
H
N
N
N
NO2
N
N
N
6
7
N
N
N
N
N
CH3 O
O2N
NH2
N
25
N
N
N
C
N
N
N
N
H
H2N
NO2
N
N
N
16
17
H2N
N
N
N
N
CH3
N
O
N
N
N
O
N
8
9
C
N
26
N
N
N
N
N
N
CH3
N
N
CH3
N
N
N
N
N
N
CH2 CH2 C N
O
N
N
CH3
O
N
N
N
N
N
N
18
19
N
N
N
N
F
N
N
27
28
N
N
N
H
N
CH3
N
N
N
N
N
N
N
N
N
N
N
N
N
N
F
N
10
N
N
N
20
N
N
* see [22]
N
N

Jul-Aug 2008
Potential Antianxiety, Antidepressant, and Antipsychotic Agents
1009
Scheme 1
N
Cl
N
N
N
N
CF3
N
N
3:1 mol ratio
steam bath 2.5 h
83.9%
N
CF3
mp 159.5-1610
2
N
N
N
NH
1-(2-pyrimidinyl)piperazine
C
N
C
N
N
Cl
CH3
N
N
3:1 mol ratio
steam bath 3 h
stand RT 20.5 h
48.3%
N
N
N
CH3
mp 107-1090
17
A few of the derivatives prepared in this work deserve
additional comment. Three of the starting compounds
contain both an active chlorine atom and an active
methoxy group (see Scheme 2). We found that only the
chlorine atom was displaced by 1-(2-pyrimidinyl)-
piperazine, giving the products 3, 5, and 15. In the
pyridine starting compound, the chlorine atom is made
much more reactive than the methoxy group by the
adjacent nitro substituent.
Subsequent to our preparation of the pyrazine
derivative 18 carried out in 2005 we discovered that
Matsumoto and coworkers [12] had prepared 18 in
1991
by
heating
a
mixture
of
1-(2-
pyrimidinyl)piperazine (6 mmol), chloropyrazine (7
mmol), triethylamine (10 mmol), and an unspecified
amount of tetrahydrofuran at 100° under high pressure
Scheme 2
N
Cl
N
N
N
N
N
OCH3
N
N
3:1 mol ratio
steam bath 2.5 h
stand RT 69.25 h
59.0%
OCH3
3
Cl
N
H2N
N
N
N
N
N
N
N
N
N
OCH3
H2N
N
NH
3:1 mol ratio
steam bath 2.5 h
stand RT 12 days
39.7%
OCH3
1-(2-pyrimidinyl)piperazine
5
NO2
Cl
NO2
N
CH3O
N
N
3:1 mol ratio
steam bath 2.5 h
stand RT 8 days
21.1%
CH3O
N
N
N
15

1010
I. Becker
Vol 45
N
N
presence of Triton B as catalyst [23] (see Scheme 3). Our
mol ratio of acrylonitrile to 6-chloropurine was 14:1 in
one experiment and 19:1 in another experiment. The
reactants were refluxed (acrylonitrile has a normal boiling
point of 77°) for 1 h in one experiment and 2 h in another
experiment [24].
HN
N
N
N
N
N
N
N
N
N
Cl
chloropyrazine
18
Subsequently in 1965 Baker and Tanna [25]
reported the preparation of 29 by the reaction of 6-
chloropurine with acrylonitrile in dimethyl-
formamide as solvent using potassium carbonate, not
Triton B, as catalyst. They stirred the reaction
mixture at room temperature for 4 h and then let the
mixture stand at room temperature for 70 h. In l985
Rosemeyer and Seela [26] prepared 29 using the
method of Baker and Tanna. Baker and Tanna [25]
and Rosemeyer and Seela [26] provided spectral
evidence that cyanoethylation of 6-chloropurine
occurred at N-9, and not at N-7, of the purine ring.
Recently we prepared 26 by heating 29 with an excess
of 1-(2-pyrimidinyl)piperazine. We also prepared 26 by
first reacting 6-chloropurine with an excess of 1-(2-
pyrimidinyl)piperazine [27] to give 24 and then reacting
24 with an excess of acrylonitrile in the presence of Triton
for four days. Their mol ratio of chloropyrazine to 1-
(2-pyrimidinyl)piperazine was 0.9:1. Their yield of
product (mp 117-118°) was 31%. Our conditions of
reaction differed markedly from those of Matsumoto
and coworkers. We heated a mixture of 0.0261 mol of
1-(2-pyrimidinyl)piperazine and 0.00870 mol of
chloropyrazine on the steam bath for 3.5 h. Our mol
ratio of amine to chloropyrazine was 3:1. Our yield of
analytically pure product (mp 105.5-106°) was 42.6%.
The 1H nmr spectrum of our product confirmed its
structure. Matsumoto and coworkers give no spectral
data for their product.
We obtained an 8% yield of the theophylline
derivative 9. In duplicate CHN analyses the found
%C and %H values were acceptable but the found
1
%N values were low. No H nmr spectrum could be
obtained on 9 because the compound was insoluble
in a number of deuterated solvents. The mp of 9 was
greater than 292°. The infrared spectrum of 9
showed a medium band at 3138-3164 cm-1 indicating
the presence of the N-H group in the imidazole
moiety and showed strong bands at 1651 cm-1 and
1707 cm-1, each indicating a lactam carbonyl group.
In early 1961 we prepared 29 by cyanoethylation of 6-
chloropurine with an excess of acrylonitrile in the
1
B as catalyst [28]. The H nmr spectrum of 26 prepared
1
from 29 was identical to the H nmr spectrum of 26
prepared from 24.
Two derivatives of 1-(2-pyrimidinyl)piperazine,
namely 27 and 28, were prepared by a reaction that
did not use 1-(2-pyrimidinyl)piperazine as
a
reactant. The preparation of these derivatives is
illustrated in Scheme 4 [29].
Scheme 3
Cl
N
Cl
N
N
N
CH2 CH
C N
N
N
N
H
Triton B
N
CH2 CH2
C
N
6-chloropurine
29
N
N
N
N
HN
N
HN
N
N
N
N
N
N
N
N
N
N
N
CH2 CH
C
N
N
N
N
Triton B
N
H
N
N
CH2 CH2
C N
24
26

Jul-Aug 2008
Potential Antianxiety, Antidepressant, and Antipsychotic Agents
1011
Scheme 4
HN
N
F
N
N
N
N
F
3:1 mol ratio
steam bath 2.5 h
78%
mp 114-1160
27
N
N
Cl
2-chloropyrimidine
F
F
HN
N
N
N
N
3:1 mol ratio
steam bath 2 h
50%
N
mp 44-480
28
Single crystal x-ray diffraction analysis, an exciting
analytical method, was used to prove and describe the
structures of compounds 5, 10, and 21. Each X-ray
structure and its companion structural formula are
illustrated below.
parent compound itself might be efficacious; (b) the 1-(2-
pyrimidinyl)piperazine metabolite formed from the parent
compound might be efficacious; (c) the compound that is
formed after severance of the 1-(2-pyrimidinyl)-
piperazinyl moiety from the parent compound might be
efficacious. None of the compounds prepared in this work
have yet been tested for biological activity.
The potential efficacy of the compounds prepared in
this work might be manifested on three levels: (a) the
N
N
O
N
N
CH3
N
N
H2N
5
N
N
N
N
N
N
10

1012
I. Becker
Vol 45
N
N
N
N
NO2
N
N
CH3
21
The following table describes X-ray diffraction parameters for compounds 5, 10, and 21:
5
10
21
Empirical Formula
Formula Weight
Color, habit
C26H34N14O2
574.67
C22H20N6
C12H15N7O2
289.31
368.44
colorless, rods
Monoclinic
colorless, rods
Orthorhombic
yellow, blades
Monoclinic
Crystal System
Space group
A, Å
P21/n
17.783(3)
6.7547(13)
23.883(5)
90
P212121
7.7499(9)
13.4983(16)
17.334(2)
90
P21/c
11.392(2)
7.7360(17)
14.680(3)
90
b, Å
c, Å
ꢀ, deg
ꢁ, deg
ꢂ, deg
V (Å3)
107.211(2)
90
90
90
93.482(2)
90
2740.4(9)
4
100
1813.3(4)
4
100
1291.3(5)
4
100
Z
Temperature (K)
Densitycalc, (g cm-3)
2ꢃ range, deg
GOF (F2)
μ(Mo, Kꢀ), mm-1
R(F)/Rw(F)
1.393
1.350
1.488
1.69-28.19
1.043
1.91-28.41
1.030
1.79-28.40
1.038
0.096
0.085
0.108
0.0621/0.2136
0.0370/0.0986
0.0400/0.1048
mol) of 100% pure amine, was heated on the steam bath for 3 h.
The mixture, consisting mostly of light brown solid, was let
stand for 67.5 h. The hard waxy solid was broken up and mixed
with 2x10 mL water, collecting solid after each treatment with
water. Larger pieces of solid in the funnel were removed,
pulverized, and returned to the funnel. The solid was washed
with 2x5 mL water, sucked with the vacuum for 10 min, dried at
65° for 2.75 h, and let stand over Drierite for 68 h, tan solid,
1.97 g (100%), mp 99-100.5° after softening at 98.5-99°,
EXPERIMENTAL
All chemicals, except as noted, were purchased from Sigma
Aldrich Company. In almost all reactions the mole ratio of 1-(2-
pyrimidinyl)piperazine to the chloro nitrogen heterocycle was
3:1. No solvent was used in the reactions.
Melting points were determined on
a Thomas-Hoover
Unimelt apparatus and are uncorrected. CHN analyses were
determined by Schwarzkopf Microanalytical Laboratory Inc, 56-
19 37th Avenue, Woodside, NY 11377. H nmr spectra were
1
1
negative Beilstein test (no Cl). H nmr (CDCl3): ꢀ 1.20 (t, 3H,
ethyl CH3), 2.48 (q, 2H, ethyl CH2), 3.90 (q, 8H, piperazine),
6.51 (t, 1H, 5-H, monosubstituted pyrimidine), 8.21 (s, 2H, 4-H
& 6-H, disubstituted pyrimidine), 8.33 (d, 2H, 4-H & 6-H,
monosubstituted pyrimidine). Anal. Calcd. for C14H18N6: C,
62.20; H, 6.71; N, 31.09. Found: C, 62.12; H, 6.91; N, 31.05.
determined and interpreted by Spectral Data Services Inc, 818
Pioneer Street, Champaign, IL 61820. Infrared spectra were
determined at Villanova University using a Perkin-Elmer
Spectrum One FT-IR/Attenuated Total Reflectance Accessory.
5-Ethyl-2-(4-pyrimidin-2-yl-piperazin-1-yl)pyrimidine (1).
A mixture of 0.880 mL of 97% pure 2-chloro-5-ethylpyrimidine
(d 1.17), equivalent to 0.999 g (0.00699 mol) of 100% pure
compound, and 3.03 mL of 98% pure 1-(2-pyrimidinyl)-
piperazine (Acros Fisher, d 1.16), equivalent to 3.44 g (0.0210
2-(4-Pyrimidin-2-yl-piperazin-1-yl)-4-(trifluoromethyl)-
pyrimidine (2). A mixture of 1.05 g of 99% pure 2-chloro-4-
(trifluoromethyl)pyrimidine (d 1.51), equivalent to 1.04 g
(0.00568 mol) of 100% pure compound, and 2.60 mL of 98%

Jul-Aug 2008
Potential Antianxiety, Antidepressant, and Antipsychotic Agents
1013
pure 1-(2-pyrimidinyl)piperazine (d 1.16), equivalent to 2.96 g
(0.0180 mol) of 100% pure amine, was heated on the steam bath
for 2.5 h. The cool mixture of white and orange solids was
mixed well with 14 mL water. The solid was collected, using 6
mL and 5x4 mL water to complete the transfer, washed with 2x8
mL water, sucked with the vacuum for 12 min, and dried at 70-
71° for 67 h, white solid, 1.31 g (74.4%), mp 158-159.5°,
negative Beilstein test (no Cl).
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
collected, 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).
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 2 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 colored solid, mp 188-189° after softening at 187-
188°. 1H nmr (CDCl3): ꢀ 2.23 (s, 3H, 4-CH3, trisubstituted
pyrimidine), 3.68 (ct, 4H, piperazine), 3.89 (ct, 4H, piperazine),
4.82 (bs, 2H, 2-NH2, trisubstituted pyrimidine), 5.87 (s, 1H, 5-H,
trisubstituted pyrimidine), 6.54 (t, 1H, 5-H, monosubstituted
Anal. Calcd. for C13H13N6F3: C, 50.32; H, 4.22; N, 27.09.
Found: C, 50.98; H, 3.98; N, 27.25.
The combined filtrate, consisting of colorless liquid and solid,
was let stand for 69 h. The solid was collected, using 5 mL water
to complete the transfer, washed with 4 mL water, sucked with
the vacuum for 13 min, and dried at 70-72° for 69 h, white solid,
0.167 g (9.5%), mp 159.5-161°, negative Beilstein test (no Cl).
1H nmr (CDCl3): ꢀ 3.91-3.98 (cm, 8H, piperazine), 6.53 (t, 1H,
5-H, monosubstituted pyrimidine), 6.79 (d, 1H, 5-H, disubsti-
tuted pyrimidine), 8.34 (d, 2H, 4-H & 6-H, monosubstituted
pyrimidine), 8.52 (d, 1H, 6-H, disubstituted pyrimidine). Anal.
Calcd. for C13H13N6F3: C, 50.32; H, 4.22; N, 27.09. Found: C,
50.66; H, 4.08; N, 27.20.
pyrimidine), 8.34 (d, 2H, 4-H
& 6-H, monosubstituted
pyrimidine). Anal. Calcd. for C13H17N7: C, 57.55; H, 6.32; N,
36.14. Found: C, 57.68; H, 6.51; N, 35.99.
4-Methoxy-2-(4-pyrimidin-2-yl-piperazin-1-yl)pyrimidine
(3). An intimate mixture of 1.02 g of 98% pure 2-chloro-4-
methoxypyrimidine (mp 54-57°), equivalent to 1.00 g (0.00690
mol) of 100% pure compound, and 2.98 mL of 98% pure 1-(2-
pyrimidinyl)piperazine (d 1.16), equivalent to 3.39 g (0.0207
mol) of 100% pure amine, was heated on the steam bath for 2.5
h and let stand for 69.25 h. To the mixture, 15 mL water was
added. Finely divided solid was collected. Hard solid left in the
reaction flask was broken up and collected in the same funnel,
using 2x10 mL and 2x5mL water to complete the transfer. Large
pieces of hard solid were removed from the funnel, pulverized,
and returned to the funnel. The solids were washed with 2x10
mL water, sucked with the vacuum for 45 min, and dried at 72-
73° for 93.5 h, off white solid (Solid A), 1.45 g (77.1%), mp 94-
96° after softening at 93-94°, negative Beilstein test (no Cl).
Solid A was recrystallized from the solvent pair of 95%
ethanol (12 mL) and enough hot water to impart cloudiness
to the mixture. The mixture (19 mL) was let stand for 4 min
and cooled in ice for 106 min. The solid that formed was
collected, using 4x5 mL water to complete the transfer, and
dried at 72° for 45.5 h, white solid (Solid B), 1.11 g (59.0%),
mp 93-95.5°. 1H nmr (CDCl3): ꢀ 3.90 (s, 8H, piperazine),
3.91 (s, 3H, CH3-O), 6.01 (d, 1H, 5-H, disubstituted
pyrimidine), 6.51 (t, 1H, 5-H, monosubstituted pyrimidine),
8.08 (d, 1H, 6-H, disubstituted pyrimidine), 8.33 (d, 2H, 4-H
4-Methoxy-6-(4-pyrimidin-2-yl-piperazin-1-yl)pyrimidin-
2-ylamine (5). An intimate mixture of 95% pure 2-amino-4-
chloro-6-methoxypyrimidine (mp 168-171°), equivalent to 1.00
g (0.00625 mol) of 100% pure compound, and 2.71 mL of 98%
pure 1-(2-pyrimidinyl)piperazine ( d 1.16), equivalent to 3.08 g
(0.0188 mol) of 100% pure amine, was heated on the steam bath
for 2.5 h and let stand for 12 days. To the solid, 6 mL water was
added. Some of the solid was broken up and collected. To the
hard button of solid left in the flask, 4 mL water was added and
hard solid was partially broken up. More solid was collected on
the same funnel. The button of solid and another piece of solid
were removed from the flask, pulverized, and transferred to the
same funnel. The solid was washed with 2x10 mL water, sucked
with the vaccum for 43 min, and dried at 71-72° for 45.75 h,
cream colored solid (Solid A), 1.45 g (81%), mp 176.5-181°
after shrinking some at 175-176.5°, negative Beilstein test (no
Cl). The CHN analysis was poor. Anal. Calcd. for C13H17N7O: C,
54.34; H, 5.96; N, 34.12. Found: C, 52.18; H, 5.49; N, 32.14.
A 0.3077 g sample of Solid A was recrystallized from 30 mL
of 95% ethanol, letting the hot nearly colorless filtrate stand for
71.5 h. The crystals that formed were collected, using 4x2 mL
95% ethanol to complete the transfer, sucked with the vacuum
for 17 min, and dried at 72° for 7 days, short fine sparkling pale
yellow needles (Solid B), 0.158 g (8.83%), mp 183-184.5°.
Anal. Calcd. for C13H17N7O: C, 54.34; H, 5.96; N, 34.12. Found:
C, 54.70; H, 5.20; N, 34.15.
&
6-H, monosubstituted pyrimidine). Anal. Calcd. for
C13H16N6O: C, 57.34; H, 5.92; N, 30.86. Found: C, 57.83,
57.17; H, 6.23, 5.54; N, 30.68, 29.97.
4-Methyl-6-(4-pyrimidin-2-yl-piperazin-1-yl)pyrimidin-2-
amine (4). A mixture of 1.00 g (0.00694) 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 was added. The solids were broken up and
collected, using 2 mL and 4 mL water to complete the transfer.
The solids were removed from the funnel, pulverized, returned
to the 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).
The rest of Solid A was recrystallized from 68 mL of 95%
ethanol, letting the hot filtrate stand for 22.75 h. The crystals
that formed were collected, using 6x2 mL 95% ethanol to
complete the transfer, sucked with the vacuum for 34 min, and
dried at 72-73° for 6 days, short fine sparkling pale yellow
needles (Solid C), 0.554 g (30.9%), mp 183-184.5°. 1H nmr
(CDCl3): ꢀ 3.63 (cm, 4H, piperazine), 3.84 (s, 3H, 4-OCH3,
trisubstituted pyrimidine), 3.89 (cm, 4H, piperazine), 4.72 (bs,
2H, 2-NH2, trisubstituted pyrimidine), 5.35 (s, 1H, 5-H,
trisubstituted pyrimidine), 6.52 (t, 1H, 5-H, monosubstituted
pyrimidine), 8.33 (d, 2H, 4-H
& 6-H, monosubstituted
pyrimidine). The structure of 5 was proved by single crystal X-
ray diffraction analysis. Anal. Calcd. for C13H17N7O: C, 54.34;

1014
I. Becker
Vol 45
H, 5.96; N, 34.12. Found: C, 54.68; H, 5.40; N, 34.14. Solid B
plus Solid C constituted a yield of 0.712 g (39.7%) of once
recrystallized product, mp 183-184.5°.
h and let stand for 69.5 h. The mixture of white and yellow
solids was mixed with 15 mL water. Large pieces of solid were
broken up. The solid was collected, using 2x5 mL water to
complete the transfer, washed with 10 mL water, sucked with
the vacuum for 62 min, and dried at 72-73° for 45 h, cream
colored solid (Solid A), 1.72 g (94.0%), negative Beilstein test
(no Cl). On taking a mp the sample did not melt by 270° but
underwent darkening. When a sample was ignited on the flat end
of a metal spatula, the sample melted completely to a black
liquid that burned with a flame and disappeared completely upon
strong heating. Thus the melting point of the sample was greater
6-(4-Pyrimidin-2-yl-piperazin-1-yl)pyrimidine-2,4-diamine
(6). A mixture of 1.02 g of 98% pure 4-chloro-2,6-diamino-
pyrimidine, equivalent to 1.00 g (0.00709 mol) of 100% pure
compound, and 3.10 g of 98% pure 1-(2-pyrimidinyl)piperazine
(d 1.16), equivalent to 3.60 g (0.0220 mol) of 100% pure amine,
was heated on the steam bath for 7 h. The mixture of viscous
brownish orange liquid and white solid was let stand for 23.5 h.
To this mixture, 6 mL water was added. The hard white solid
was broken up. Virtually all of the solid was scooped out of the
mixture, put on filter paper to absorb liquid, pulverized, and let
stand over Drierite for an unmeasured period of time. This solid
(Solid A) did not melt up to 230° and gave a persistent positive
Beilstein test (Cl present).
1
than 270°. ir: 2214 cm-1 medium (CꢁN). H nmr (D2O/HCl): ꢀ
3.23 (bs, 8H, piperazine), 4.65 (s, 1H, HDO), 6.22 (t, 1H, 5-H,
monosubstituted pyrimidine), 7.55 (s, 1H, 4-H, trisubstituted
pyrimidine), 7.74 (d, 2H, 4-H
& 6-H, monosubstituted
pyrimidine). The found %N was low. Anal: Calcd. for C13H14N8:
C, 55.31; H, 5.00; N, 39.69. Found: C, 54.89, 55.11; H, 4.92,
4.92; N, 38.82, 39.02.
A mixture of 0.1220 g of Solid A and 25 mL of 95% ethanol
was heated on the steam bath with stirring for several minutes.
The solid in the milky mixture was collected, sucked with the
vacuum for 2 h, and dried at 72° for 70.75 h, cream colored solid
(Solid C), 0.0765 g (61.9% recovery). Anal. Calcd. for C13H14N8:
C, 55.31; H, 5.00; N, 39.69. Found: C, 55.63, 55.36; H, 4.82,
5.05; N, 39.66, 39.78.
The pale orange cloudy liquid remaining in the 25 mL round
bottom reaction flask contained a small amount of white
particles. To this mixture, 11 mL water was added. The mixture
was let stand for 20.5 h. The solid that separated was collected,
using 5x2 mL water to complete the transfer, washed with 9 mL
water, sucked with the vacuum for 1.5 h, and dried at 75-83° for
68 h, soft cottony solid (Solid B) that was pale yellow on the
surface and white underneath the surface, 0.312 g (15.9%), mp
187-189.5° after softening at 186-187°, negative Beilstein test
(no Cl). The CHN analysis on Solid B was poor. Anal. Calcd.
for C12H16N8: C, 52.93; H, 5.92; N, 41.15. Found: C, 53.67; H,
6.07; N, 39.90.
1,3-Dimethyl-6-(4-pyrimidin-2-yl-piperazin-1yl)-1H-
pyrimidine-2,4-dione (8). A mixture of 1.04 g of 99% pure 6-
chloro-1,3-dimethyluracil (Acros Fisher, mp 109-113°),
equivalent to 1.03 g (0.00589 mol) of 100% pure compound, and
2.50 mL of 98% pure 1-(2-pyrimidinyl)piperazine (solid melted
on the steam bath, d 1.16), equivalent to 2.84 g (0.0177 mol) of
100% pure amine, was heated on the steam bath for 3 h 9 min
and let stand for 45 h. To the mixture of viscous orange liquid
and dirty yellow solid, 7 mL water were added. The mixture was
heated for 30 s. Hard solid was partially broken up. The
remaining button of solid was removed from the reaction flask,
pulverized, and returned to the flask. The solids in the flask were
collected, using 3x3 mL water to complete the transfer, washed
with 2x3.5 mL and 4.5 mL water, and dried at 63-65° for 46 h,
light cream colored solid (Solid A), 0.905 g (50.8%), mp 199-
203° after softening at 197.5-199°, negative Beilstein test (no
Cl). ir: 1640 cm-1 (strong), 1692 cm-1 (strong) (each, lactam
carbonyl). 1H nmr (CDCl3): ꢀ 3.01 (cm, 4H, piperazine), 3.33 (s,
3H, CH3-N, uracil), 3.46 (s, 3H, CH3-N, uracil), 3.98 (bs, 4H,
piperazine), 5.27 (s, 1H, 5-H, uracil), 6.58 (t, 1H, 5-H,
Solid B was recrystallized from the solvent pair of 95%
ethanol (3 mL) and water (3 mL), letting the final mixture stand
for 29 min, cool in ice for 23 min, and stand for 20 h. The
impressive needles that formed were collected, using 5x1.5 mL
water to complete the transfer, washed with 3x3 mL water,
sucked with the vacuum for 32 min, let stand over Drierite for
69.5 h, and dried at 60-63° for 2.5 h, cream colored needles
(Solid C), 0.125 g (6.4%), mp 189.5-191.5° after softening at
188-189° and after some darkening over several degrees before
188°. The found %C and %N were unacceptable. Anal. Calcd.
for C12H16N8: C, 52.93; H, 5.92; N, 41.15. Found: C, 53.41; H,
6.08; N, 40.39.
The combined filtrate from Solid C consisted of cloudy
colorless liquid and solid. This solid was collected, using 1 mL
water to complete the transfer, washed with 2x1 mL water,
sucked with the vacuum for 10 min, let stand over Drierite for
68.5 h, and dried at 60-63° for 2.5 h, off white solid (Solid D),
21 mg (1.1%), mp 190-191.5° after softening at 189-190° and
monosubstituted pyrimidine), 8.34 (d, 2H, 4-H
& 6-H,
1
monosubstituted pyrimidine). Anal. Calcd. for C14H18N6O2: C,
55.62; H, 6.00; N, 27.80. Found: C, 55.64, 56.19; H, 5.89, 5.87:
N, 27.25, 27.73.
after some darkening over several degrees before 189°. H nmr
(CDCl3): ꢀ 3.60-3.63 (cm, 4H, piperazine), 3.87-3.90 (cm, 4H,
piperazine), 4.40 and 4.57 (each bs, each 2H, 2-NH2 & 4-NH2,
trisubstituted pyrimidine), 5.17 (s, 1H, 5-H, trisubstituted
pyrimidine), 6.52 (t, 1H, 5-H, monosubstituted pyrimidine), 8.33
(d, 2H, 4-H & 6-H, monosubstituted pyrimidine). Anal. Calcd.
for C12H16N8: C, 52.93; H, 5.92; N, 41.15. Found: C, 53.34; H,
5.87; N, 40.87.
The remaining Solid A (0.672 g) was recrystallized from 50
mL of 95% ethanol, letting the filtrate (45 mL) stand for 71.5 h.
During this time the volume of the filtrate spontaneously
reduced to 40 mL. The crystals that separated were collected,
using 3x3.5 mL 95% ethanol to complete the transfer, washed
with 4 mL 95% ethanol, sucked with the vacuum for 18 min,
and dried at 72° for 47.5 h, impressive light cream colored
crystals, 0.466 g (26.1%), mp 203-205° after a little softening at
201-203°. Anal. Calcd. for C14H18N6O2: C, 55.62; H, 6.00; N,
27.80. Found: C, 55.52; H, 5.49; N, 27.63.
4-Amino-2-(4-pyrimidin-2-yl-piperazin-1-yl)pyrimidine-5-
carbonitrile (7). An intimate mixture of 1.03 g of 97% pure 4-
amino-2-chloropyrimidine-5-carbonitrile (mp 200° dec),
equivalent to 1.00 g (0.00645 mol) of 100% pure compound, and
2.79 mL of 98% pure 1-(2- pyrimidinyl)piperazine (mp 29-36°,
solid was melted on the steam bath; and used some liquid amine
from another container, d 1.16), equivalent to 3.18 g (0.0194
mol) of 100% pure amine, was heated on the steam bath for 2.5
1,3-Dimethyl-8-(4-pyrimidin-2-yl-piperazin-1-yl)-3,9-
dihydropurine-2,6-dione (9). A mixture of 1.02 g of 98% pure
8-chlorotheophylline (mp 290° dec), equivalent to 1.00 g

Jul-Aug 2008
Potential Antianxiety, Antidepressant, and Antipsychotic Agents
1015
(0.00465 mol) of 100% pure compound, and 3.00 mL of 98%
pure 1-(2-pyrimidinyl)piperazine (d 1.16), equivalent to 3.41 g
(0.0208 mol) of 100% pure amine, was heated on the steam bath
for 5.5 h and let stand for 43.5 h. The mixture of liquid and solid
was mixed with 10 mL water. Large pieces of solid were broken
up. The solid was collected, using 2x2 mL water to complete the
transfer, washed with 2x5 mL water, sucked with the vacuum
for 47 min, and dried at 67-78° for 70 h, white solid, 0.132 g
(8.3%), mp > 292°, negative Beilstein test (no Cl). On ignition
on a metal surface, the sample melted rapidly, produced no
smoky flame, and disappeared completely. ir: 3138-3164 cm-1
(medium) (NH, imidazole moiety), 1651 cm-1 (strong), 1707 cm-
1 (strong) (each, lactam carbonyl). No 1H nmr spectrum could be
obtained because the product was insoluble in a number of
deuterated solvents. The duplicate %N values were low. Anal.
Calcd. for C15H18N8O2: C, 52.62; H, 5.30; N, 32.73. Found: C,
52.86, 52.42; H, 5.46, 5.33; N, 32.16, 31.78.
This product was recrystallized from the solvent pair of 95%
ethanol and water with unusual results. Not all of the solid
dissolved in the hot 95% ethanol. This insoluble solid was
discarded. The final mixture was let stand for 19 h. No solid
separated. To the solution, 15 mL water were added. The
resulting solution was let stand for 3 h and then cooled in ice for
5 min with vigorous stirring and scratching. No solid separated.
The solution (100 mL) was concentrated on the steam bath to 35
mL. The concentrate, consisting of liquid and solid, was cooled
in ice for 10 min and let stand for 20 h. The solid was collected,
using 2x3 mL water to complete the transfer, washed with 3 mL
and 4 mL water, sucked with the vacuum for 10 min, and dried
at 64-66° for 3 h, brown solid, 0.159 g, mp 157.5-180° melted
completely to a clear dark orange liquid after gradually
softening, shrinking, and sintering. Apparently the solid
decomposed during recrystallization and concentration. The
combined filtrate from this solid was discarded.
2-Phenyl-4-(4-pyrimidin-2-yl-piperazin-1-yl)quinazoline
(10). A mixture of 1.00 g of 97% pure 4-chloro-2-phenyl-
quinazoline, equivalent to 0.970 g (0.00402 mol) of 100% pure
compound, and 4.40 mL of 98% pure 1-(2-pyrimidinyl)-
piperazine (d 1.16), equivalent to 5.00 g (0.0305 mol) of 100%
pure amine, was heated on the steam bath for 3 h and let stand
for 20 min. The mixture was mixed well with 2x10 mL and 2x4
mL water, collecting solid after each treatment with water. Large
pieces of solid were broken up during these treatments. The
solid was washed with 2x5 mL water, sucked with the vacuum
for 10 min, and dried at 67-68° for 18.5 h, off white solid with
slight pinkish coloration, 1.49 g (100%), mp 162-164.5° after
4,6-Bis-(4-pyrimidin-2-yl-piperazin-1-yl)pyrimidin-2-yl-
amine (12). A mixture of 1.01 g of 99% pure 2-amino-4,6-
dichloropyrimidine, equivalent to 1.00 g (0.00609 mol) of 100%
pure compound, and 5.27 mL of 98% pure 1-(2-
pyrimidinyl)piperazine (d 1.16), equivalent to 5.99 g (0.0365
mol) of 100% pure amine, was heated to 120° over 12 min.
Thereafter, the total heating time was 3.5 h (210 min). About
80% of this time (about 167 min) the temperature was kept at
120-161° and about 20% of this time (about 43 min) the
temperature was kept at 107-119°. The resulting mixture of
yellow and brown solids was let stand for 66 h. To this mixture,
20 mL water was added. Large pieces of hard solid in the
reaction flask were broken up. Larger pieces of solid were
removed from the flask, pulverized, and collected. All solids
remaining in the flask were collected, using 54 mL water in
seven portions to complete the transfer. The solids were sucked
with the vacuum (pasty solid), dried at 68-77° for 46 h, and let
stand over Drierite for 24 h, dark tan solid, 2.46 g (96.5%), mp
180-184° after softening over many degrees before 180°, weak
fleeting positive Beilstein test (a little Cl present).
1
softening at 160-162°, negative Beilstein test (no Cl). H nmr
(CDCl3): ꢀ 3.91-3.94 and 4.07-4.09 (each t, 8H, piperazine),
6.52 (t, 1H, 5-H, pyrimidine), 7.41-7.51 (cm, 4H, 2xmeta-H,
each benzene ring), 7.71-7.75 (t, 1H, para-H, monosubstituted
benzene), 7.93 and 7.99 (each d, 2H, 2xortho-H of benzene ring
at the fusion with pyrimidine ring), 8.34 (d, 2H, 4-H & 6-H,
pyrimidine), 8.57 (cd, 2H, 2x ortho-H, monosubstituted
benzene). The structure of 10 was proved by single crystal x-ray
diffraction analysis. Anal. Calcd. for C22H20N6: C, 71.72; H,
5.47; N, 22.81. Found: C, 71.58; H, 5.54; N, 23.00.
A small portion of this solid was recrystallized from the
solvent pair of 95% ethanol and water. Not all of the solid
dissolved in the hot 95% ethanol. This insoluble solid was
discarded. The final mixture was let stand for 7 days.
4,6-Bis-(4-pyrimidin-2-yl-piperazin-1-yl)pyrimidine (11).
A mixture of 1.03 g of 97% pure 4,6-dichloropyrimidine,
equivalent to 1.00 g (0.00671 mol) of 100% pure compound, and
5.81 mL of 98% pure 1-(2-pyrimidinyl)piperazine (d 1.16),
equivalent to 6.61 g (0.0403 mol) of 100% pure amine, was
heated from room temperature to 120° over 15 min. Thereafter
the mixture was heated for 195 min. During this time the
temperature of the reaction mixture varied from 92° to 118° over
72 min (37% of the heating time) and from 120° to 157° over
123 min (63% of the heating time). Then 10 mL water was
added. The hard solid was broken up, collected, using 3x5 mL
water to complete the transfer, washed with 2x10 mL water,
sucked with the vacuum for 10 min, and dried at 69-71° for 67 h,
tan solid, 2.36 g (87.1%), mp 216-221° melted completely to a
clear dark brown liquid after darkening and slight shrinking over
The solid that formed was collected, washed with 3 mL water,
sucked with the vacuum for 10 min, and dried at 69-71° for 3
days, pale yellow crispy solid, mp 177.5-184° after shrinking,
darkening, and softening at 172-177.5°, negative Beilstein test
(no Cl). Prior to analysis the sample was let stand over Drierite
for 7 days. 1H nmr (CDCl3): ꢀ about 1.70 (vbs, water), 3.66-3.68
and 3.90-3.93 (each cm, 16H, both piperazine rings), about 4.80
(vbs, 2H, 2-NH2, trisubstituted pyrimidine), 5.20 (s, 1H, 5-H,
trisubstituted pyrimidine), 6.53 (t, 2H, 5-H, both
monosubstituted pyrimidine rings), 8.34 (d, 4H, 4-H & 6-H,
both monosubstituted pyrimidine rings). Anal. Calcd. for
C20H25N11 • ꢁ H2O: C, 55.48; H, 6.17; N, 35.58. Found: C,
55.54; H, 6.40; N, 35.29.
2-[4-(3-Nitropyridin-2-yl)piperazin-1-yl]pyrimidine (13). A
mixture of 1.01 g of 99% pure 2-chloro-3-nitropyridine (mp
101-104°), equivalent to 1.00 g (0.00629 mol) of 100% pure
compound, and 2.72 g of 98% pure 1-(2-pyrimidinyl)piperazine
( d 1.16), equivalent to 3.10 g (0.0189 mol) of 100% pure amine,
was heated on the steam bath for 2.25 h and let stand for 21.25
h. To the mixture of orange brown viscous liquid and orange
brown solid, 10 mL water were added. The mixture, now
1
many degrees before 216°, negative Beilstein test (no Cl). H
nmr (CDCl3): ꢀ 3.70-3.72 and 3.93-3.95 (each cm, 16H, both
piperazine rings), 5.65 (s, 1H, 5-H, disubstituted pyrimidine),
6.53 (t, 2H, 5-H, each monosubstitured pyrimidine ring), 8.30 (s,
1H, 2-H, disubsubstituted pyrimidine), 8.35 (d, 4H, 4-H & 6-H,
each monosubstituted pyrimidine ring). Anal. Calcd. for
C20H24N10 • ꢀ H2O: C, 58.74; H 6.04; N, 34.25. Found: C, 58.55;
H, 5.87; N, 34.27.

1016
I. Becker
Vol 45
yellow, was heated briefly on the steam bath. Hard solid was
partially broken up. The solids were mixed well with the water
and collected, using 2x5.5 mL and 2x4.5 mL water to complete
the transfer. Large pieces of hard solid were removed from the
funnel, pulverized, and returned to the funnel. The solid was
washed with 2x7 mL water, sucked with the vacuum for 15 min,
and dried at 36-41° for 46.25 h, orange solid (Solid A), 1.35 g
(75.0%), mp 55.5-64° after softening at 54-55.5°, negative
Beilstein test (no Cl). The found %N was low. Anal. Calcd. for
C13H14N6O2: C, 54.54; H, 4.93; N, 29.36. Found: C, 54.16; H,
5.11; N, 28.29.
Solid A was recrystallized from the solvent pair of 95%
ethanol (10 mL) and enough water to reach the cloud point. The
final mixture was let stand for 15 min and cooled in ice for 25
min. The solid and gummy material that separated was collected,
using 10 mL water to complete the transfer, and sucked with the
vacuum for 10 min. The contents in the funnel, now all solid,
was put in a 20 mL beaker. The beaker was sealed. In this way
the solid was let stand for 69 h. Then the crusty solid was
pulverized and dried at 36-37° for 23.15 h, dark orange solid
(Solid B), 0.569 g (31.6%), mp 66.5-73° after softening at 64.5-
66.5°. 1H nmr (CDCl3): ꢀ 3.57 (ct, 4H, piperazine), 3.74 (ct, 4H,
piperazine), 6.53 (t, 1H, 5-H, pyrimidine), 6.79 (dd, 1H, ꢁ-H,
pyridine), 8.17 (d, 1H, ꢂ-H or ꢃ-H, pyridine), 8.34 (d, 2H, 4-H &
6-H, pyrimidine), 8.36 (d, 1H, ꢂ-H or ꢃ-H, pyridine). The found
%N was low. Anal. Calcd. for C13H14N6O2: C, 54.54; H, 4.93; N,
29.36. Found: C, 54.67; H, 4.94; N, 28.48.
Solid B was recrystallized from 95% ethanol (5 mL). The hot
ethanolic solution was filtered. Orange solid (Solid C, see
below) separated almost immediately from the filtrate. This
mixture was let stand for 6 min. The clear orange liquid (Liquid
A) above Solid C was decanted into a 20 mL beaker. Shortly
thereafter orange solid (Solid D) separated from Liquid A.
Liquid A was let stand for 84 min. The solid (Solid D) in Liquid
A was collected, using 5 mL and 3 mL methanol to complete the
transfer, washed with 3 mL methanol, sucked with the vacuum
for 7 min, and dried at 38-40° for 69.75 h, dark orange crystals
(Solid D), 69 mg (3.8%), mp 73-75° after softening at 72-73°.
Prior to analysis Solid D was let stand over Drierite for 49 h.
Anal. Calcd. for C13H14N6O2: C, 54.54; H, 4.93; N, 29.36.
Found: C, 54.85; H, 5.07; N, 29.44.
Solid C (see above) was collected, using 2x2 mL water to
complete the transfer, washed with 3 mL water, sucked with the
vacuum for 32 min, and dried at 38-40° for 70.5 h, dark orange
crystals (Solid C), 85 mg (4.7%), mp 72-75.5° after softening at
69-72° and shrinking slightly. Prior to analysis Solid C was let
stand over Drierite for 49 h. Anal. Calcd. for C13H14N6O2: C,
54.54; H, 4.93; N, 29.36. Found: 54.75, H, 4.86; N, 29.36.
The combined filtrate from Solid D, consisting of liquid and
solid, was let stand for 70.5 h. The solid was collected, washed
with 2.5 mL hexane, sucked with the vacuum for 25 min, and
dried at 46-47° for 45 h, orange solid (Solid E), 9 mg (0.5%),
mp 72-73°. Prior to analysis Solid E was let stand over Drierite
for 2 h. Anal. Calcd. for C13H14N6O2: C, 54.54; H, 4.93; N,
29.36. Found: C, 54.69; H, 4.89; N, 29.36.
To the hard yellow solid, 15 mL water was added. The solid was
broken up, mixed well with the water, collected, using 4x3.5 mL
water to complete the transfer, washed with 6.5 mL water,
sucked with the vacuum for 10 min, and dried at 64-72° for 4
days, yellow solid, 1.68 g (97.1%), mp 211.5-213° after some
darkening, sintering, and shrinking at 208.5-211.5°, negative
1
Beilstein test (no Cl). H nmr (CDCl3): ꢀ 2.64 (s, 3H, ꢃ-CH3,
pyridine), 3.85 (ct, 4H, piperazine), 3.97 (ct, 4H, piperazine),
6.41 (s, 1H, ꢁ-H, pyridine), 6.57 (t, 1H, 5-H, pyrimidine), 8.36
(d, 2H, 4-H & 6-H, pyrimidine), 9.01 (s, 1H, ꢂ-H, pyridine).
Anal. Calcd. for C14H16N6O2: C, 55.99; H, 5.37; N, 27.98.
Found: C, 56.50, 56.10; H, 5.34, 5.28; N, 27.84, 27.62.
2-[4-(6-Methoxy-3-nitropyridin-2-yl)piperazin-1-yl]pyrim-
idine (15). An intimate mixture of 1.02 g of 98% pure 2-chloro-
6-methoxy-3-nitropyridine (mp 78-80°), equivalent to 1.00 g
(0.00532 mol) of 100% pure compound, and 2.30 mL of 98%
pure 1-(2-pyrimidinyl)piperazine ( d 1.16), equivalent to 2.62 g
(0.0160 mol) of 100% pure amine, was heated on the steam bath
for 2.5 h and let stand for 8 days. To the mixture, 10 mL water
was added. Solid was broken up as much as possible and
collected. Another 10 mL water was added. The mixture was
heated briefly on the steam bath. More solid was broken up and
collected on the same funnel, using 6 mL and 4.5 mL water to
complete the transfer. Some of the solid seemed slightly gummy.
A button of hard solid and other solid were removed from the
funnel, pulverized, and returned to the funnel. The solid was
sucked with the vacuum for 30 min and let stand over Drierite
for 2 days (Solid A), strong positive Beilstein test (Cl present).
Solid A was recrystallized from 75 mL of 95% ethanol. A
small amount of Solid A did not dissolve in the hot 95% ethanol.
The hot filtrate (60 mL) was let stand for 69.5 h. Only the loose
crystals were collected, sucked with the vacuum for 45 min, and
dried at 71-73° for 5 days, impressive mats of bright yellow
needles (Solid B), 0.355 g (21.1%), mp 127.2-128° melted
completely to an opaque yellow liquid after softening and
shrinking slightly at 126-127.2°, negative Beilstein test (no Cl).
Solid B was recrystallized from 28 mL of 95% ethanol, letting
the filtrate stand for 102 min. Only the loose crystals were
collected, washed with 5 mL 95% ethanol, sucked with the
vacuum for 20 min, and dried at 71-72° for 46 h, mats of bright
yellow needles (Solid C), 0.153 g (9.11%), mp 127.2-128° melted
completely to a clear yellow liquid after softening at 126.5-127.2°.
1H nmr (CDCl3): ꢀ 3.61 (ct, 4H, piperazine), 3.96 (s, 3H, CH3O),
3.99 (ct, 4H, piperazine), 6.18 (d, 1H, ꢁ-H, pyridine), 6.54 (t, 1H,
5-H, pyrimidine), 8.25 (d, 1H, ꢃ-H, pyridine), 8.34 (d, 2H, 4-H &
6-H, pyrimidine). Anal. Calcd. for C14H16N6O3: C, 53.16; H, 5.10;
N, 26.57. Found: C, 53.12; H, 5.21; N, 26.60.
2-[4-(3,5-Dinitropyridin-2-yl)piperazin-1-yl]pyrimidine (16).
A mixture of 1.01 g of 99% pure 2-chloro-3,5-dinitropyridine
(mp 64-66°), equivalent to 1.00 g (0.00490 mol) of 100% pure
compound, and 2.12 mL of 98% pure 1-(2-pyrimidinyl)-
piperazine (d 1.16), equivalent to 2.41 g (0.0147 mol) of 100%
pure amine, was heated on the steam bath for 2.25 h and let
stand for 21.5 h. To the orange brown and yellow solids, 10 mL
water was added. The hard solid was broken up and collected,
using 3x5 mL water to complete the transfer. Large pieces of
hard solid in the funnel were removed, pulverized, and returned
to the funnel. The solid was washed with 2x9 mL water, sucked
with the vacuum for 20 min, and dried at 63-68° for 23 h, dark
mustard colored solid, 1.50 g (92.6%), mp 171.5-173° after
softening, shrinking, and darkening at 168-171.5°, negative
Beilstein test (no Cl). 1H nmr (CDCl3): ꢀ 3.77 (ct, 4H,
2-[4-(4-Methyl-5-nitropyridin-2-yl)piperazin-1-yl]pyrim-
idine (14). A mixture of 1.03 g of 97% pure 2-chloro-4-methyl-
5-nitropyridine (mp 37-39°), equivalent to 1.00 g (0.00578 mol)
of 100% pure compound, and 2.50 mL of 98% pure 1-(2-
pyrimidinyl)piperazine (solid was melted on the steam bath, d
1.16), equivalent to 2.84 g (0.0173 mol) of 100% pure amine,
was heated on the steam bath for 3 h and let stand for 20.75 h.

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Potential Antianxiety, Antidepressant, and Antipsychotic Agents
1017
piperazine), 4.05 (ct, 4H, piperazine), 6.59 (t, 1H, 5-H,
pyrimidine), 8.36 (d, 2H, 4-H & 6-H, pyrimidine), 8.95 (d, 1H,
ꢀ-H or ꢁ-H, pyridine), 9.15 (d, 1H, ꢀ-H or ꢁ-H, pyridine). Anal.
Calcd. for C13H13N7O4: C, 47.13; H, 3.96; N, 29.60. Found: C,
47.58, 47.61; H, 3.87, 3.99: N, 29.11, 29.33.
2x2.5 mL water, sucked with the vacuum for 8 min, and dried at
62° for 20.75 h, white solid (Solid B), 0.103 g (4.9%), mp
105.5-106° after softening at 104-105.5°, negative Beilstein test
(no Cl). Prior to analysis Solid B was let stand over Drierite for
1
26 h. H nmr (CDCl3): ꢃ 3.69-3.71 (ct, 4H, piperazine), 3.96-
3.99 (ct, 4H, piperazine), 6.54 (t, 1H, 5-H, pyrimidine), 7.88 (d,
1H, 6-H, pyrazine), 8.09 (dd, 1H, 5-H, pyrazine), 8.19 (d, 1H, 3-
H, pyrazine), 8.35 (d, 2H, 4-H & 6-H, pyrimidine). Anal. Calcd.
for C12H14N6: C, 59.49; H, 5.82; N, 34.69. Found: C, 59.47; H,
5.80; N, 34.68.
A 50 mg sample of the analytical compound described
immediately above was dissolved in 17 mL boiling 95% ethanol
and the yellow solution was filtered. The filtrate (11 mL) was let
stand for 67 min. The crystals that formed were collected and
dried at 70-71° for 45 h, golden yellow crystals, 15 mg (0.92%),
mp 170-171° after softening at 168-170°. Anal. Calcd. for
C13H13N7O4: C, 47.13; H, 3.96; N, 29.60. Found: C, 47.34; H,
3.03; N, 29.73.
2-(4-Pyrimidin-2-yl-piperazin-1-yl)quinoxaline (19).
A
mixture of 1.02 g of 98% pure 2-chloroquinoxaline (mp 47-50°),
equivalent to 1.00 g (0.00606 mol) of 100% pure compound, and
2.62 mL of 98% pure 1-(2-pyrimidinyl)piperazine (heated on the
steam bath to melt solid, d 1.16), equivalent to 2.98 g (0.0182
mol) of 100% pure amine, was heated on the steam bath for 3.5
h and let stand for 7 days. To the mixture of orange and yellow
solids, 10 mL water was added. Hard solid was partially broken
up. The liberated fine solid was collected. A large button of hard
solid in the reaction flask was broken up. To this mixture 7 mL
water were added and more fine-solid was collected. Larger
pieces of solid remaining in the reaction flask were removed,
pulverized, and returned to the flask. The solid in the flask was
mixed with 10 mL water and collected, using 3.5 mL and 2 mL
water to complete the transfer. The solid was washed with 6 mL
and 7.5 mL water, sucked with the vacuum for 15 min, let stand
over Drierite for 15 days, and dried at 63-70° for 138 min,
yellow solid, 1.25 g (70.6%), mp 178-181°, negative Beilstein
test (no Cl). Prior to analysis the compound was let stand over
6-Methyl-2-(4-pyrimidin-2-yl-piperazin-1-yl)nicotinonitrile
(17). An intimate mixture of 1.02 g of 98% pure 2-chloro-6-
methyl-3-pyridinecarbonitrile (mp 114-116°), equivalent to 1.00
g (0.00654 mol) of 100% pure compound, and 2.82 mL of 98%
pure 1-(2-pyrimidinyl)piperazine (d 1.16), equivalent to 3.21 g
(0.0196 mol) of 100% pure amine, was heated on the steam bath
for 3 h and let stand for 25.5 h. To the mixture of soft pink and
hard white solids, 10 mL water was added. Hard solid was
broken up. Then 5 mL water was added. Large pieces of solid
were removed from the reaction flask, pulverized, and returned
to the flask. The solid was collected, using 5 mL and 2x2.5 mL
water to complete the transfer, washed with 2x8 mL water,
sucked with the vacuum for 62 min, and dried at 72° for 45.75 h,
chalky poorly wettable light tan solid (Solid A), 1.26 g (68.9%),
mp 105-111°, negative Beilstein test (no Cl).
Solid A was recrystallized from the solvent pair of 95% ethanol
(20 mL) and water (7 mL), letting the final mixture stand for 105
min. The solid that formed was collected, using 6 mL and 2x4 mL
water to complete the transfer, washed with 7 mL and 8 mL water,
sucked with the vacuum for 14 min, and dried at 71-72° for 21.75
h, light tan crystalline solid (Solid B), 0.884 g (48.3%), mp 107-
109° after softening at 105-107°. ir: 2212 cm-1 medium (CꢂN). 1H
nmr (CDCl3): ꢃ 2.43 (s, 3H, ꢀ-CH3, pyridine), 3.81 (m, 4H,
piperazine), 3.98 (m, 4H, piperazine), 6.53 (t, 1H, 5-H,
pyrimidine), 6.63 (d, 1H, ꢄ-H, pyridine), 7.67 (d, 1H, ꢁ-H,
pyridine), 8.34 (d, 2H, 4-H & 6-H, pyrimidine). The found %N in
the first two CHN analyses was low. Thereafter, Solid B was let
stand over Drierite at room temperature in the dark for 24 days
and then subjected to a third CHN analysis. Anal. Calcd. for
C15H16N6: C, 64.27; H, 5.75; N, 29.98. Found: C, 64.40, 64.27,
64.89; H, 5.92, 5.70, 5.81; N, 29.50, 29.45, 29.73.
1
Drierite for 46 h. H nmr (CDCl3): ꢃ 3.89 (ct, 4H, piperazine),
4.02 (ct, 4H, piperazine), 6.55 (t, 1H, 5-H, pyrimidine), 7.41 and
7.60 (each t, 2H, both meta-H, benzene ring), 7.72 and 7.90
(each d, 2H, both ortho-H, benzene ring), 8.36 (d, 2H, 4-H & 6-
H, pyrimidine), 8.63 (s, lone H, pyrazine moiety). Anal. Calcd.
for C16H16N6: C, 65.74; H, 5.52: N, 28.75. Found: C, 65.96; H,
5.28; N, 28.34.
3-Phenyl-6-(4-pyrimidin-2-yl-piperazin-1-yl)pyridazine (20).
A mixture of 1.02 g of 98% pure 3-chloro-6-phenylpyridazine
(mp 154-161°), equivalent to 1.00 g (0.00524 mol) of 100%
pure compound), and 4.10 mL of 98% pure 1-(2-
pyrimidinyl)piperazine (mp 31-33°, mostly solid, warmed on the
steam bath to give a clear pale yellow liquid, d 1.16), equivalent
to 4.67 g (0.0284 mol) of 100% pure amine, was heated on the
steam bath for 3.5 h and let stand for 44 h. To the light brown
and pinkish hard solids, 20 mL water was added. This mixture
was heated on the steam bath for 30 s. The hard solid was
broken up, collected, using three portions of water (7 mL total)
to complete the transfer, washed with 7 mL and 9 mL water,
sucked with the vacuum for 17 min, and dried at 61-63° for 70.5
h, white solid (Solid A), 1.49 g, mp 178-197° after gradually
softening, negative Beilstein test (no Cl).
4-Pyrimidin-2-yl-3,4,5,6-tetrahydro-2H-[1,2ꢀ]bipyrazinyl
(18). A mixture of 0.797 mL of 98% pure chloropyrazine (d
1.28), equivalent to 1.00 g (0.00870 mol) of 100% pure
compound, and 3.77 mL of 98% pure 1-(2-pyrimidinyl)-
piperazine (solid was melted on the steam bath, d 1.16),
equivalent to 4.28 g (0.0261 mol) of 100% pure amine, was
heated on the steam bath for 3.5 h and let stand for 69 h. To the
yellow and pink crystalline solids, 10 mL water was added.
Solids were broken up, collected, using 3x3 mL water to
complete the transfer, washed with 3 mL and 2x4 mL water,
sucked with the vacuum for 10 min, and dried at 61-62° for 22 h,
white solid (Solid A), 0.799 g (37.7%), mp 102.5-105° after
softening at 101-102.5°, negative Beilstein test (no Cl). Prior to
analysis Solid A was let stand over Drierite for 26 h. Anal.
Calcd. for C12H14N6: C, 59.49; H, 5.82; N, 34.69. Found: C,
59.62; H, 5.89; N, 34.40.
When an attempt was made to recrystallize Solid A from the
solvent pair of 95% ethanol and water, only a small part of Solid
A dissolved in 15 mL of boiling 95% ethanol. The liquid part of
this hot mixture was filtered by gravity. The clear colorless
filtrate gave rise to flocculent solid. This mixture was heated on
the steam bath. An unmeasured volume of 95% ethanol was
added. The flocculent solid disappeared, giving a colorless
solution. To this hot solution, 5 mL of hot water was added. The
resulting solution (18 mL) was let stand for 5 days. The solid
that formed was collected, using 3x2 mL water to complete the
transfer, washed with 2x3 mL water, sucked with the vacuum
The solid in the combined filtrate from Solid A was collected,
using 2x2.5 mL water to complete the transfer, washed with

1018
I. Becker
Vol 45
for 10 min, dried at 64-65° for 4 h, and let stand over Drierite for
12 days, white solid (Solid B), 47 mg (2.8%), mp 132-144°.
Another attempt was made to recrystallize the remaining
Solid A (most of the original Solid A) from the solvent pair of
95% ethanol and water. Again only a small part of Solid A
dissolved in the hot 95% ethanol. The liquid portion of the
mixture was filtered by gravity. The filtrate gave rise to
flocculent solid. The mixture was heated on the steam bath. An
unmeasured volume of hot 95% ethanol was added to the hot
filtrate. The flocculent solid disappeared. To the hot colorless
solution, 8 mL hot water was added. The resulting solution (52
mL) was let stand for 5 days. The crystals that formed were
collected, using 2 mL water to complete the transfer, washed
with 3 mL water, sucked with the vacuum for 23 min, dried at
64-65° for 4 h, and let stand over Drierite for 12 days,
impressive well formed transparent long thin needles with blunt
ends (Solid C), 61 mg (3.6%), mp 194.5-196°. 1H nmr (CDCl3):
ꢀ 3.81-3.84 (ct, 4H, piperazine), 4.00-4.03 (ct, 4H, piperazine),
6.54 (t, 1H, 5-H, pyrimidine), 7.03 (d, 1H, 4-H, pyridazine), 7.40
(ct, 1H, para-H, phenyl), 7.45 (ct, 2H, 2xmeta-H, phenyl), 7.68
(d, 1H, 5-H, pyridazine), 8.04 (d, 2H, 2xortho-H, phenyl), 8.35
(d, 2H, 4-H & 6-H, pyrimidine). Anal. Calcd. for C18H18N6: C,
67.90; H, 5.70; N, 26.40. Found: C, 68.11; H, 5.69; N, 26.54. No
further work was carried out on the alcohol insoluble portion
(7.63%), mp 133-136° after softening at 131-133°. The low mp
was surprising. The found %C and %N were both low. Anal.
Calcd. for C12H15N7O2: C,49.82; H, 5.23; N, 33.89. Found: C,
49.31; H, 5.32; N, 33.31.
Solid C was let stand over Drierite for 16 days and dried at
74-78° for 69.5 h (Solid D), mp 162-163° melted completely to a
clear yellow liquid. The structure of 21 was proved by single
crystal x-ray diffraction analysis. Anal. Calcd. for C12H15N7O2:
C, 49.82; H, 5.23; N, 33.89. Found: C, 49.67; H, 5.47: N, 33.62.
2-[4-(1-Phenyl-1H-tetrazol-5-yl)piperazin-1-yl]pyrimidine
(22). An intimate mixture of 1.03 g of 97% pure 5-chloro-1-
phenyl-1H-tetrazole (mp 122-124°), equivalent to 1.00
g
(0.00552 mol) of 100% pure compound, and 2.40 mL of 98%
pure 1-(2-pyrimidinyl)piperazine ( mp 29-36°, melted on the
steam bath, d 1.16), equivalent to 2.72 g (0.0166 mol) of 100%
pure amine, was heated on the steam bath for 2.25 h and let
stand for 70 h. To the mixture of tan and white solids, 5 mL
water was added. Hard solid was broken up. The solid was
collected, using 3 mL and 2 mL water to complete the transfer.
Large pieces of solid were removed from the funnel, pulverized,
and returned to the funnel. The solid was washed with 2x6 mL
water, sucked with the vacuum for 10 min, let stand over
Drierite for 9 days, dried at 73-78° for 68 h, and let stand over
Drierite for 48.5 h, cream colored chalky solid (Solid A), 1.38 g
(81.2%), mp formed a dark yellow brown melt by 178°, gave a
fleeting faintly green color in the Beilstein test.
(the major portion) of Solid
recrystallizations.
A
left from the two
2-[4-(3-Methyl-5-nitro-3H-imidazol-4-yl)piperazin-1-yl]-
pyrimidine (21). A mixture of 1.02 g of 98% pure 5-chloro-1-
methyl-4-nitro-1H-imidazole (mp 148-150°), equivalent to 1.00
g (0.00617 mol) of 100% pure compound, and 2.66 mL of 98%
pure 1-(2-pyrimidinyl)piperazine (d 1.16), equivalent to 3.03 g
(0.0185 mol) of 100% pure amine, was heated on the steam bath
for 2.5 h and let stand for 20.5 h. To the mixture, 10 mL water
was added. Hard solid was broken up and mixed well with the
water. The solid was collected, using 2x3 mL water to complete
the transfer. Nearly all of the solid was finely divided and
yellow. A small amount of solid was hard and darker. Most of
the hard darker solid was removed from the funnel, pulverized,
and returned to the funnel. The solid was washed with 2x7 mL
water, sucked with the vacuum for 20 min, and dried at 64-78°
for 45.5 h, yellow solid (Solid A), 1.32 g (68.0%), mp 153-
156.5° after some softening and shrinking over several degrees
prior to 153°, negative Beilstein test (no Cl). The found %N was
low. Anal. Calcd. for C12H15N7O2: C, 49.82; H, 5.23; N, 33.89.
Found: C, 49.93; H, 5.18; N, 33.10.
Solid A was recrystallized from the solvent pair of 95%
ethanol (25 mL) and water (18 mL). The hot mixture was let
stand for 40 min, cooled in ice for 85 min, and let stand for 9
days. The crystals that formed were collected, using 4.5 mL
water to complete the transfer, washed with 4 mL water, sucked
with the vacuum for 34 min, dried at 66-68° for 47.5 h, and let
stand over Drierite for 5 days, slightly cream colored nacreous
poorly wettable crystals (Solid B), 0.394 g (23.2%), mp 159-
171° after softening at 145-159°, negative Beilstein test (no Cl).
For the duplicate CHN analysis, Solid B was let stand over
Drierite for 20 days more. 1H nmr (CDCl3): ꢀ 3.33 (ct, 4H,
piperazine), 3.88 (ct, 4H, piperazine), 6.54 (t, 1H, 5-H,
pyrimidine), 7.53-7.66 (m, 5H, phenyl), 8.31 (d, 2H, 4-H & 6-H,
pyrimidine). Anal. Calcd. for C15H16N8: C, 58.43; H, 5.23; N,
36.34. Found: C, 58.51, 58.35; H, 5.41, 5.08; N, 35.81, 35.21.
Solid B was recrystallized from the solvent pair of 95%
ethanol (10 mL) and water (2 mL). The hot mixture was let
stand for 70 min. The crystals that formed were collected, using
5 mL water to complete the transfer, washed with 5 mL water,
sucked with the vacuum for 17 min, and dried at 72-74°for 68 h,
white crystals (Solid C), 0.111 g (6.5%), mp 172.5-174° after
softening at 170-172.5°. The sample of Solid C used for the
duplicate CHN analysis had stood over Drierite for 3 days prior
to analysis. Anal. Calcd. for C15H16N8: C, 58.43; H, 5.23; N,
36.34. Found: C, 59.15, 58.59; H, 5.25, 5.18; N, 36.49, 36.23.
2-(4-Pyrimidin-2-yl-piperazin-1-yl)benzoxazole (23). A 25
mL round bottomed flask was charged with 0.913 g of 99% pure
2-chlorobenzoxazole ( bp 95-96°/20 mm Hg, mp 7°, d 1.32),
equivalent to 0.904 g (0.00587 mol) of 100% pure compound.
To this 2-chloro compound, 2.80 mL of 98% pure 1-(2-
pyrimidinyl)piperazine ( mp 29-36°, melted on the steam bath, d
1.16), equivalent to 3.19 g (0.0195 mol) of 100% pure amine,
were added. An immediate reaction occurred, giving dense
white fumes and white solid. This mixture of solid and liquid
was shaken briefly, heated on the steam bath for 2 h, and let
stand for 45.5 h. To this mixture, 10 mL water was added. Large
Solid A was recrystallized from the solvent pair of 95%
ethanol (30 mL) and enough water to reach the cloud point. The
mixture (28 mL) was let stand for 46 h. The crystals were
collected, using 2x3 mL water to complete the transfer, washed
with 2x5.5 mL water, sucked with the vacuum for 1 h, and dried
at 62-65° for 71.75 h, impressive long thin sparkling needles
(Solid B), 0.592 g (30.5%), mp 159-162° after softening at 157-
1
159°. H nmr (CDCl3): ꢀ 3.24 (ct, 4H, piperazine), 3.65 (s, 3H,
3-CH3, imidazole), 4.00 (bs, 4H, piperazine), 6.55 (t, 1H, 5-H,
pyrimidine), 7.30 (s, 1H, ꢁ-H, imidazole), 8.34 (d, 2H, 4-H & 6-
H, pyrimidine). The found %N was low. Anal. Calcd. for
C12H15N7O2: C, 49.82; H, 5.23; N, 33.89. Found: C, 49.76; H,
5.42; N, 33.14.
Solid B was recrystallized from 10 mL 95% ethanol. The hot
filtrate was let stand for 28 min. The crystals were collected,
sucked with the vacuum for 16 min, and dried at 63-66° for 45.5
h, sparkling short fine yellow needles (Solid C), 0.148 g

Jul-Aug 2008
Potential Antianxiety, Antidepressant, and Antipsychotic Agents
1019
pieces of solid were broken up. The solid was collected, using
5.5 mL, 4.5 mL, and 3.0 mL water to complete the transfer,
washed with 7.5 mL water, sucked with the vacuum for 45 min,
and dried at 72-73° for 44.75 h, light tan solid (Solid A), 1.54 g
(93.3%), mp 176-181° melted completely to a slightly opaque
colorless liquid after softening at 174-176°, negative Beilstein
test (no Cl).
Solid A was recrystallized from the solvent pair of 95%
ethanol and water, letting the final solution (61 mL) stand for 45
min. The solid that formed was collected, using 10 mL water to
complete the transfer, washed with 10 mL water, sucked with
the vacuum for 15 min, and dried at 72° for 119.5 h, soft white
crystalline solid (Solid B), 0.774 g (46.9%), mp 179-181°
melted completely to a clear colorless liquid after softening at
178-179°. 1H nmr (CDCl3): ꢀ 3.78 (m, 4H, piperazine), 3.99 (m,
4H, piperazine), 6.55 (t, 1H, 5-H, pyrimidine), 7.04 (t, 1H, H of
benzene ring meta to fusion point), 7.19 (t, 1H, H of benzene
ring meta to fusion point), 7.28 (d, 1H, H of benzene ring ortho
to fusion point), 7.39 (d, 1H, H of benzene ring ortho to fusion
point), 8.34 (d, 2H, 4-H & 6-H, pyrimidine). Anal. Calcd. for
C15H15N5O: C, 64.04; H, 5.37; N, 24.90. Found: C, 64.78, 64.40;
H, 5.18, 4.99; N, 25.33, 24.90.
6-(4-Pyrimidin-2-yl-piperazin-1-yl)-9H-purine (24). An
intimate mixture of 1.92 g of 99% pure 6-chloropurine (mp >
300°), equivalent to 1.90 g (0.0123 mol) of 100% pure
compound, and 5.37 mL of 98% pure 1-(2-pyrimidinyl)-
piperazine (d 1.16), equivalent to 6.05 g (0.0369 mol) of 100%
pure amine, was heated on the steam bath for 3.5 h, let stand for
67 h, heated on the steam bath for 4 h more, and let stand for 45
h. The mixture was mixed with 20 mL water. Solid was broken
up and collected, using 3 mL and 3x3.5 mL water to complete
the transfer. Larger pieces of solid in the funnel were put back
into the reaction flask and mixed with 3x3.5 mL water, each
time breaking up solid. The solid was collected on the same
funnel. The solid was sucked with the vacuum for 2 h and dried
at 70-71° for 44 h, greenish gray solid (Solid A), 2.79 g (80.4%).
On taking a melting point Solid A did not melt and did not
undergo any change up to 200° when the determination was
stopped. On ignition on the flat end of a metal spatula, Solid A
melted completely, produced a few streaks of flame, and left no
residue. In the Beilstein test Solid A produced a fleeting green
color.
25 min, and dried at 70-71° for 46 h, pale yellow solid (Solid B),
0.122 g (63.9% recovery), fleeting green color in the Beilstein
test. H nmr (DMSO-d6): ꢀ 3.89 (ct, 4H, piperazine), 4.32 ( bs,
1
4H, piperazine), 6.67 (t, 1H, 5-H, pyrimidine), 8.17 (s, 1H, 2-H
or 8-H, purine), 8.26 (s, 1H, 2-H or 8-H, purine), 8.41 (d, 2H, 4-
H & 6-H, pyrimidine), 13.1 (bs, 1H, 9-H, purine). Anal. Calcd.
for C13H14N8: C, 55.31; H, 5.00; N, 39.69. Found: C, 55.32; H,
4.94; N, 39.34.
A 0.4000 g sample of Solid A was recrystallized from the
solvent pair of 95% ethanol and water. Not all of the sample
dissolved in 40 mL of boiling 95% ethanol. The mixture was
filtered by gravity. The filtrate (33 mL), clear and pale olive,
was let stand for 40 min and cooled in ice for 113 min. The solid
that formed was collected, sucked with the vacuum for 37 min
(pasty solid), and dried at 71° for 44 h, pale greenish yellow
solid (Solid C), 92 mg (23% recovery), fleeting green color in
the Beilstein test.
A 0.4000 g sample of Solid A was recrystallized from 20 mL
dimethylformamide. Not all of the sample dissolved in the hot
solvent. The recrystallized solid (Solid D), light grey, was dried
at 71° for 140 min, 0.103 g (25.7% recovery).
A 0.5032 g sample of Solid A was recrystallized from the
solvent pair of 95% ethanol and water. Four 20 mL portions of
hot 95% ethanol were used to dissolve most of the solid. The
ethanolic filtrate was concentrated to 30 mL. To this
concentrate, 28 mL of hot water was added. The resulting
mixture was let stand for 69 h. The solid that formed was
collected, using 1 mL water to complete the transfer, sucked
with the vacuum for 50 min, and dried at 71° for 48 h, pale
greenish yellow solid (Solid E), 0.156 g (31.0% recovery).
Concentration of the combined filtrate from Solid E, gave,
after drying at 71-72° for 46.5 h, pale greenish yellow solid
(Solid F), 17 mg (3.3% recovery).
The five recrystallized products (B-F) were combined to give
Solid G (0.394 g). Solid G was used in the cyanoethylation
reaction, giving 26.
6-(4-Pyrimidin-2-yl-piperazin-1-yl)-9H-purin-2-ylamine (25).
An intimate mixture of 1.01 g of 99% pure 2-amino-6-
chloropurine (mp >300°), equivalent to 1.00 g (0.00588 mol) of
100% pure compound, and 5.08 mL of 98% pure 1-(2-
pyrimidinyl)piperazine (mp 29-36°, solid melted on the steam
bath, d 1.16), equivalent to 5.78 g (0.0352 mol) of 100% pure
amine, was heated on the steam bath for 2.25 h, let stand for 68
h, and heated on the steam bath for 3.75 h more. The soft solid,
mostly light tan was let stand for 45 h. The solid was mixed with
20 mL water. The pasty solid was collected, using 2.5 mL water
to complete the transfer, sucked with the vacuum for 65 min,
and dried at 72° for 7 days, cream colored solid (Solid A), l.64 g
(93.3%), mp 269.5-277° after gradually darkening to a black
solid.
Solid A was insoluble in cold and hot 95% ethanol, insoluble
in cold and hot hexane, insoluble in cold and hot water,
insoluble in cold and hot 2-propanol, and insoluble in cold but
soluble in hot dimethylformamide. Solid A was recrystallized in
small portions.
A 0.1909 g sample of Solid A was recrystallized from the
solvent pair of 95% ethanol and water. A significant amount of
Solid A did not dissolve in 40 mL of hot 95% ethanol. The
mixture was filtered by gravity. The hot clear pale olive filtrate
(37 mL) was let stand for 47 min and cooled in ice for 22 min.
To the cold solution 40 mL water were added. The cloudy
mixture was cooled in ice for 89 min and let stand for 92 h. The
mixture was filtered by gravity to remove a small amount of
greenish grey flocculent solid. The filtrate (65 mL), consisting of
clear and nearly colorless liquid, was concentrated by heating on
the steam bath for 38 min. The concentrate, consisting of
crystals and pale yellow liquid, was transferred to a 50 mL
beaker, using 1 mL water to complete the transfer. The mixture
was cooled in ice for 51 min. The crystals were collected, using
2 mL water to complete the transfer, sucked with the vacuum for
Solid A was recrystallized from the solvent pair of 95%
ethanol (105 mL) and water (25 mL). A significant amount of
solid A did not dissolve in the hot 95% ethanol. The final hot
solution was let stand for 10 days. A minor amount of tan solid
ringed the glassware above the main mixture. This tan solid was
not disturbed when the product was collected. The main product
was collected, using 7 mL and 3 mL water to complete the
transfer, washed with 5 mL water, sucked with the vacuum for
50 min, and dried at 72° for 45.25 h, soft white solid (Solid B),
0.460 g (26.3%), negative Beilstein test (no Cl). When solid B
was ignited on the flat end of a metal spatula, the sample melted
1
rapidly and the liquid evaporated completed. H nmr (DMSO-

1020
I. Becker
Vol 45
d6): ꢀ 3.84 (ct, 4H, piperazine), 4.22 (bs, 4H, piperazine), 5.80
(bs, 2H, 2-NH2, purine), 6.66 (t, 1H. 5-H, pyrimidine), 7.73 (s,
1H, 8-H, purine), 8.40 (d, 2H, 4-H & 6-H, pyrimidine), 12.23
(bs, 1H, 9-H, purine). Anal. Calcd. for C13H15N9: C, 52.52; H,
5.09: N, 42.40. Found: C, 52.49, 52.83; H, 5.00, 5.15; N, 41.76,
42.19.
equivalent to 5.20 g (0.0317 mol) of 100% pure amine, was
heated on the steam bath for 3 h, let stand for 19 h, and heated
on the steam bath for 2.5 h more. To the cool mixture 6.5 mL
water were added. The mixture was stirred well. Large pieces of
solid were broken up. The mixture was cooled in ice for 5 min.
The solid was collected, using 5x1 mL water to complete the
transfer, washed with 4.5 mL and 7 mL water, sucked with the
vacuum for 13 min, and dried at 64-65° for 118 h, chalky cream
colored poorly wettable solid (Solid A), 0.997 g (61.9%), mp
175-177°, positive Beilstein test (Cl present), insoluble in cold
but soluble in boiling 95% ethanol, and insoluble in cold and hot
water.
3-(6-Chloropurin-9-yl)propionitrile (29). An intimate
mixture of 0.500 g (0.00323 mol) of 6-chloropurine (Francis
Earle Laboratories), 3.00 mL of acrylonitrile (Eastman Kodak, d
0.811), equivalent to 2.43 g (0.0458 mol) of the compound, and
seven small drops of 40% Triton B #1 was refluxed for 1 h and
cooled in ice for 30 min. The solid that precipitated was
collected, using several small portions of water to complete the
transfer, washed with two small portions of water, and let stand
over calcium chloride for 28.5 h, pale yellow finely divided
solid (Solid A), mp 147-152.5°.
The solid in the combined yellow filtrate from Solid A was
collected, using a few small portions of water to complete the
transfer, washed with two small portions of water, and let stand
over calcium chloride for 28.5 h, straw colored solid (Solid B),
mp 145-146.5° after some shrinking prior to 145°.
The combined filtrate from Solid B was cooled in the
refrigerator for 3 months. The solid was collected, washed once
with water, and dried at 80° for 23 h, pale yellow solid (Solid
C), 57 mg (8.5%), mp 145-152° after some shrinking prior to
145°.
Solids A and B were combined to give Solid D, 0.323 g
(48.1%), small rod shaped crystals (x100) for the most part.
Solid D was soluble in hot water, soluble in cold absolute
ethanol, and insoluble in cold but soluble in hot benzene. Solid
D was recrystallized (charcoal) from the solvent pair of benzene
(40 mL) and cyclohexane (35 mL), allowing the final hot
mixture to stand for 23.5 h. The crystals that separated were
collected, washed with two portions of benzene, and dried at 80°
for 14 h, small faintly pale yellow needles (Solid E), 0.228 g
(34.0%), mp 149.5-151.5°.
Solid E was recrystallized (tiny amount of charcoal) from the
solvent pair of benzene (30 mL) and cyclohexane. The hot
benzene solution was filtered through two pieces of quantitative
filter paper. The filtrate was heated briefly and filtered through
clean quantitative filter paper and clean funnel. Hot cyclohexane
(unmeasured volume) was added to the filtrate. Much solid
separated. The mixture was heated on the steam bath. Several
milliters of warm benzene were added in order to cause virtually
all of the solid to dissolve. To this mixture several milliters of
warm cyclohexane were added. The mixture was heated on the
steam bath. The hot mixture (75 mL) was let stand for 162 min.
The crystals that separated were collected, using two generous
portions of cyclohexane to complete the transfer, washed with
four generous portions of cyclohexane, and dried at 80° for 15 h,
small fine white needles with a faint yellow tint (Solid F), 0.109
g (16.2%), mp 149-150.5°, positive Beilstein test (Cl present). ir:
2250 cm-1 weak (CꢁN). 1H nmr (CDCl3): ꢀ 3.09 (t, 2H, CH2-
CꢁN), 4.16 (t, 2H, CH2-N), 8.24 (s, 1H, 2-H or 8-H, purine),
8.78 (s, 1H, 2-H or 8-H, purine). Anal. Calcd. for C8H6N5Cl: C,
46.28; H, 2.91; N, 33.73. Found: C, 46.54, 46.62; H, 3.12, 3.09;
N, 33.58.
Solid A was recrystallized from the solvent pair of 95%
ethanol and water. An appreciable amount of Solid A did not
dissolve in the 57 mL of hot 95% ethanol. The hot mixture was
filtered by gravity, giving a clear colorless filtrate (40 mL). Hot
water (20 mL) was added to the filtrate. The mixture was let
stand for 69 h. The solid in the mixture was collected, using 3.5
mL and 4 mL water to complete the transfer, washed with 3.5
mL water, sucked with the vacuum for 17 min, and dried at 62-
76° for 47 h, white solid with a faint yellow color (Solid B),
0.349 g (21.7%), mp 175-176° after softening with a little
darkening at 173-175°, gave a fleeting green color in the
1
Beilstein test. H nmr (CDCl3): ꢀ 3.03 (t, 2H, CH2-CꢁN), 4.01
(ct, 4H, piperazine), 4.40 (bs) and 4.48 (m) (4H, piperazine),
4.48 (t, 2H, N-CH2), 6.54 (t, 1H, 5-H, pyrimidine), 7.86 (s, 1H,
2-H or 8-H, purine), 8.35 (d, 2H, 4-H & 6-H, pyrimidine), 8.36
(s, 1H, 2-H or 8-H, purine). The CHN analysis was poor. Anal.
Calcd. for C16H17N9: C, 57.30; H, 5.11; N, 37.59. Found: C,
58.14; H, 5.12; N, 35.42.
The combined filtrate (63 mL) from Solid B, consisting of
cloudy white liquid and a tiny amount of solid, was concentrated
to 13 mL by heating on the steam bath for 56 min. The
concentrate, consisting of colorless liquid and much solid, was
put in a 20 mL beaker and let stand for 93.5 h. The solid was
collected, using 3.5 mL water to complete the transfer, washed
with 6.5 mL water, sucked with the vacuum for 1 h, and dried at
69-74° for 74 h, white solid (Solid C), 65 mg (4.0%), mp 174.5-
176° after softening at172-174.5°, fleeting positive Beilstein
test. Solids B and C were combined to give Solid D.
Solid D was recrystallized from the solvent pair of 95%
ethanol (22 mL) and water (12 mL), letting the final hot mixture
stand for 45.5 h. The solid that formed was collected, using 1.5
mL and 5 mL water to complete the transfer, washed with 5.5
mL water, sucked with the vacuum for 1.5 h, and dried at 73° for
70.5 h, white solid (Solid E), 0.146 g (9.07%), mp 174.5-177°
after softening at 173-174.5°, fleeting positive Beilstein test. The
CHN analysis was poor. Anal. Calcd. for C16H17N9: C, 57.30; H,
5.11; N, 37.59. Found: C, 58.06; H, 5.16; N, 35.90.
The combined filtrate from Solid E was let stand for 5 days.
The solid in the filtrate was collected, using 2 mL water to
complete the transfer, sucked with the vacuum for 2 h, and dried
at 73° for 45.5 h, pure white solid (Solid F), 66 mg (4.1%), mp
176-178° after softening at 175-176°, fleeting positive Beilstein
test. ir: 2251 cm-1 weak (CꢁN). The found %C was
unacceptable. Anal. Calcd. for C16H17N9: C, 57.30; H, 5.11; N,
37.59. Found: C, 57.84, 58.01; H, 5.05, 5.30; N, 37.18, 37.28.
Solid E was recrystallized from the solvent pair of 95%
ethanol (10 mL) and enough hot water to reach the cloud point.
The hot mixture (15 mL) was let stand for 23 min, cooled in ice
for 15 min, and let stand for 46.5 h. The solid that formed was
collected, using 2x2.5 mL water to complete the transfer,
3-[6-(4-Pyrimidin-2-yl-piperazin-1-yl)purin-9-yl]propio-
nitrile (26) from 3-(6-Chloropurin-9-yl)propionitrile (29) and
1-(2-Pyrimidinyl)piperazine. An intimate mixture of 1.00 g
(0.00481 mol) of dry 3-(6-chloropurin-9-yl)propionitrile and
4.58 mL of 98% pure 1-(2-pyrimidinyl)piperazine ( d 1.16),

Jul-Aug 2008
Potential Antianxiety, Antidepressant, and Antipsychotic Agents
1021
washed with 3 mL water, sucked with the vacuum for 2 h, and
dried at 71-73° for 68.5 h, pure white solid (Solid G), 57 mg
(3.6%), mp 174.5-177.5° after softening and shrinking at 174-
174.5°. 1H nmr (CDCl3): ꢀ 3.03 (t, 2H, CH2-CꢁN), 3.99 (ct, 4H,
piperazine), 4.40 (bs, 4H, piperazine), 4.49 (t, 2H, N-CH2), 6.54
(t, 1H, 5-H, pyrimidine), 7.85 (s, 1H, 2-H or 8-H, purine), 8.35
(d, 2H, 4-H & 6-H, pyrimidine), 8.36 (s, 1H, 2-H or 8-H,
purine). Anal. Calcd. For C16H17N9: C, 57.30; H, 5.11; N, 37.59.
Found: C, 57.67; H, 5.03; N, 37.43. The 1H nmr spectrum of this
Beilstein test (no Cl). Anal. Calcd. for C14H15N4F: C, 65.10; H,
5.85; N, 21.69. Found: C, 65.05; H, 5.75: N, 21.69.
Solid A was recrystallized from the solvent pair of 95%
ethanol and water. When the hot 95% ethanolic solution was
filtered by gravity, much solid settled out on the filter paper. The
solid was carefully scraped from the filter paper and returned to
the initial 20 mL beaker. More 95% ethanol was used to dissolve
this solid. The hot ethanolic solution was filtered again. The
same thing happened and the same procedure was followed.
During the third filtration, virtually no solid settled out on the
filter paper. The final solution (15 mL, clear and pale yellow)
was let stand for 18 min and cooled in ice for 1.5 h. The solid
that formed was collected, using 2x1 mL water to complete the
transfer, washed with 8 mL water, sucked with the vacuum for
10 min, and dried at 59-61° for 44 h, fine silky white needles
(Solid B), 0.467 g (20.8%), mp 116-117° after softening at 115-
1
product was identical to the H nmr spectrum of the product
formed from the cyanoethylation of 6-(4-pyrimidin-2-yl-
piperazin-1-yl)-9H-purine (24).
3-[6-(4-Pyrimidin-2-yl-piperazin-1-yl)purin-9-yl]propio-
nitrile (26) from the Cyanoethylation of 6-(4-Pyrimidin-2-yl-
piperazin-1-yl)-9H-purine (24). An intimate mixture of 0.394 g
(0.00140 mol) of 6-(4-pyrimidin-2-yl-piperazin-1-yl)-9H-purine
(composite of five once recrystallized products), 1.76 mL of
99% pure acrylonitrile (d 0.806), equivalent to 1.41 g (0.0266
mol) of 100% pure compound, and 7 small drops of 40% in
water Triton B was heated on the steam bath for 1.5 h and
cooled in ice for 5 min. To the dark brown viscous syrup, 10 mL
water was added. The mixture was cooled in ice for 55 min and
transferred to a 50 mL beaker. The mixture, consisting of pale
yellow liquid and brown gum on the bottom of the beaker, was
let stand for 68.5 h. The pale yellow solid in the mixture was
collected, taking care to collect only the pale yellow solid.
However, a tiny amount of finely divided brown particles also
was collected. The solid was sucked with the vacuum for 65 min
(tan pasty solid) and dried at 71° for 46 h. The solid now was
brown, 0.213 g (45.4%). The solid was let stand over Drierite for
48 h and then pulverized. The solid now was powdery and pale
dull orange (Solid A), mp 155-170° after softening and
shrinking at 146-154°.
1
116°. H nmr (CDCl3): ꢀ 3.16 (ct, 4H, piperazine), 3.98 (ct, 4H,
piperazine), 6.51 (t, 1H, 5-H, pyrimidine), 6.90-7.00 (m, 4H,
phenyl), 8.33 (d, 2H, 4-H & 6-H, pyrimidine). Anal. Calcd. for
C14H15N4F: C, 65.10; H, 5.85; N, 21.69. Found: C, 65.01; H,
5.73; N, 21.54.
The combined filtrate from Solid B, consisting of solid and
pale yellow liquid, was let stand for 46 h. The solid was
collected, using 1 mL water to complete the transfer, washed
with 3 mL water, sucked with the vacuum for 8 min, and dried at
62° for 23 h, fluffy cream colored solid, 35 mg (1.6%), mp 114-
115.5°.
2-[4-(2-Fluorophenyl)piperazin-1-yl]pyrimidine (28).
A
mixture of 1.00 g of 98% pure 2-chloropyrimidine (Acros Fisher),
equivalent to 0.980 g (0.00852 mol) of 100% pure compound, and
4.25 mL of 97% pure 1-(2-fluorophenyl)piperazine (d 1.14),
equivalent to 4.70 g (0.0261 mol) of 100% pure amine, was heated
on the steam bath for 2 h and cooled in ice for 3 min. The solid
was collected, using 15 mL water to complete the transfer, washed
with 2 mL water, sucked with the vacuum for 3 min, and let stand
over Drierite for 21 h, pinkish solid (Solid A), 0.491 g, strong
positive Beilstein test (Cl present).
The combined filtrate from Solid A, consisting of pinkish
gummy solid and cloudy liquid, was put in a 25 mL flask, using
2 mL water to complete the transfer. The mixture was let stand
for 21.5 h. The solid was collected, using 2x2 mL water to
complete the transfer, washed with 2x5 mL water, sucked with
the vacuum for 8 min, and let stand over Drierite for 4 days,
light pink crystalline solid (Solid B), 1.13 g (50.4%), mp 44-46°,
negative Beilstein test (no Cl).
Solid A was recrystallized from the solvent pair of 95%
ethanol (10 mL) and water (14 mL). The final hot mixture was
let stand for 70 h. The solid that formed was collected, using 3
mL and 1.5 mL water to complete the transfer, sucked with the
vacuum for 67 min, and dried at 71-72° for 45 h, pale yellow
solid (Solid B), 84 mg (18%), mp 169-173° after some shrinking
1
and softening at 164-169°. ir: 2248 cm-1 weak (CꢁN). H nmr
(CDCl3): ꢀ 3.03 (t, 2H, CH2-CꢁN), 3.99 (ct, 4H, piperazine),
4.40 (bs, 4H, piperazine), 4.48 (t, 2H, N-CH2), 6.54 (t, 1H, 5-
H, pyrimidine), 7.86 (s, 1H, 2-H or 8-H, purine), 8.35 (d, 2H, 4-
H & 6-H, pyrimidine), 8.36 (s, 1H, 2-H or 8-H, purine). Anal.
Calcd. for C16H17N9: C, 57.30; H, 5.11; N, 37.59. Found: C,
1
57.21; H, 5.25; N, 37.26. The H nmr spectrum of this product
The combined filtrate from Solid B was let stand for 4 days. The
solid was collected, using 1.5 mL water to complete the transfer,
sucked with the vacuum for 14 min, and let stand over Drierite for
7 days, dark pinkish crystalline solid (Solid C), mp 40-43°.
was identical to the 1H nmr spectrum of the product formed from
the reaction of 1-(2-pyrimidinyl)piperazine with 3-(6-chloro-
purin-9-yl)propionitrile (29).
2-[4-(4-Fluorophenyl)piperazin-1-yl]pyrimidine (27).
mixture of 1.02 g of 98% pure 2-chloropyrimidine (Acros
Fisher), equivalent to 1.00 g (0.00870 mol) of 100% pure 2-
A
Solid B was recrystallized from the solvent pair of 95%
ethanol and water, letting the final mixture stand for 2 min and
cool in ice for 50 min. The mixture was transferred to a 25 mL
flask, using 3x1 mL water to complete the transfer. The mixture
was let stand for 47 h. The hard solid in the mixture was broken
up, collected, using 5x2 mL water to complete the transfer,
washed with 2x3 mL water, sucked with the vacuum for 20 min,
and let stand over Drierite for 5 days, light pinkish crystalline
solid (Solid D), 0.787 g (35.1%), mp 41-44°. 1H nmr (CDCl3): ꢀ
3.15 (ct, 4H, piperazine), 4.00 (ct, 4H, piperazine), 6.51 (t, 1H,
5-H, pyrimidine), 6.96 and 7.06 (each cm, 4H, phenyl), 8.34 (d,
2H, 4-H & 6-H, pyrimidine). Anal. Calcd. for C14H15N4F: C,
65.10; H, 5.85; N, 21.69. Found: C, 65.29; H, 5.84; N, 21.62.
chloropyrimidine, and 4.66
g of 98% pure 1-(4-fluoro-
phenyl)piperazine (mp 30-33°, formed a colorless liquid upon
warming), equivalent to 4.57 g (0.0254 mol) of 100% pure
amine, was heated on the steam bath for 2.5 h and let stand for
15 min, giving a butterscotch colored mush and hard dark brown
solid. This mixture was mixed with 4x5 mL water, each time
partially breaking up hard solid and collecting the liberated
solid. The solid in the funnel was washed with 10 mL water,
sucked with the vacuum for 20 min and dried at 63-66° for 20 h,
light tan solid (Solid A), 1.74 g (77.7%), mp 114-116°, negative

1022
I. Becker
Vol 45
M.; Kurtz, N. M.; Robinson, D. S.; Lancaster, S. P.; Copp, J. E.
Psychopharmacology Bull. 1988, 24, 164. [n] Jajoo, H. K.; Mayol, R. F.;
LaBudde, J. A.; Blair, I. A. Drug Metabolism and Disposition 1989, 17,
634. [o] Taylor, D. P. Ann. NY Academy of Sciences 1990, 600, 545. [p]
Rausch, J. L.; Ruegg, R.; Moeller, F. G. Psychopharmacology Bull.
1990, 26, 169. [q] Heller, A. H.; Beneke, M.; Kuemmel, B.; Spencer, D.;
Kurtz, N. M. Psychopharmacology Bull. 1990, 26, 219. [r] Robinson, D.
S.; Rickels, K.; Feighner, J.; Fabre Jr, L. F.; Gammans, R. E.; Shrotriya,
R. C.; Alms, D. R.; Andary, J. J.; Messina, M. E. J. Clinical
Psychopharmacology 1990, 10 (3 suppl.), 67S-76S. [s] Jenkins, S. W.;
Robinson, D. S.; Fabre Jr, L. F.; Andary, J. J.; Messina, M. E.; Reich, L.
A. J. Clinical Psychopharmacology 1990, 10 (3 suppl.), 77S-85S. [t]
Rickels, K.; Amsterdam, J. D.; Clary, C.; Puzzuoli, G.; Schweizer, E. E.
J. Clin. Psychiatry 1991, 52, 34. [u] Pinder, R. M.; Weiringa, J. H.
Medical Research Reviews 1993, 13, 259. [v] Kerns, E. H.; Volk, K. J.;
Hail, M. E.; Whitney, J. L.; Rourick, R. A.; Klohr, S. E.; Leel, M. S.
Paper originally presented at The 1996 International Symposia on
Laboratory Atomation and Robotics (ISLAR 96). [w] Barradell, L. B.;
Acknowledgement. I thank Dr. William G. Dougherty and
Dr. W. Scott Kassel for carrying out the single crystal X-ray
diffraction analyses on compounds 5, 10, and 21 under grant
NSF-MRI 0521062. I thank Professor Walter Boyko, Director of
NMR Services at Villanova University, for his comments on the
interpretation of many of the 1H nmr spectra. I thank my
colleague Professor James Barnes for his expert help with the
electronic composition of this manuscript.
Dedication. This paper is dedicated to the memory of my
friend Judy Ostro. I met Judy when she was a twenty-eight year
old widow. Her husband had died of cancer. Struggling with
adverse emotional aspects of her past, Judy nevertheless raised
two fine daughters who have borne seventeen grandchildren,
eight of whom Judy knew during her lifetime. One month before
her forty-eighth birthday Judy lost her battle with acute
leukemia. Judy was an Ayshes Chayil—a woman of valour.
Fitton, A. CNS Drugs 1996, 5, 147. [x]
CNS Drugs 1997, 7, 68.
[18] Pinder, R. M. Psychopharmacology: Recent Advances and
Future Prospects 1986, pp. 44-62.
Fulton, B.; Brogden, R. N.
REFERENCES AND NOTES
[1] Saudour, F.; Amara, D.A.; Dierich, A.; LeMeur, M.; Ramboz,
S.; Segu, L.; Buhot, M-C.; Hen, R. Science, New Series 1994, 265, 1875.
[2] Duman, R. S.; Heninger, G. R.; Nestler, E. J. Archives of
General Psychiatry 1997, 57, 597.
[3] Uphouse, L. Neuroscience and Biochemical Reviews 1997, 21,
679.
[4] Meltzer, H. Y. Neuropsychopharmacology 1999, 21, 106 S.
[5] Barnes, N. M.; Sharp, T. Neuropharmacology 1999, 38, 1083.
[6] Moret, C.; Briley, M. Eur. J. Pharmacology 2000, 404, 1.
[7] Gingrich, J. A.; Hen, R. Psychopharmacology (Berlin) 2001,
155, 1.
[19] Thurkauf, A.; Yuan, J.; Chen, X.; He, X. S.; Wasley, J. W. F.;
Hutchinson, A.; Woodruff, K. H.; Meade, R.; Hoffman, D. C.; Donovan, H.;
Jones-Hertzog, D. K. J. Med. Chem. 1997, 40. 1.
[20] Tallman, J. F.; Primos, R. J.; Brodbeck, R.; Cornfield, L.;
Meade, R.; Woodruff, K.; Ross, P.; Thurkauf, A.; Gallagher, J. J. of
Pharmacology and Experimental Therapeutics 1997, 282, 1011.
[21] Schaus, J. M.; Bymaster, F. B. Annual Reports in Medicinal
Chemistry 1998, 33, 1.
[22] We had prepared 4 earlier. The preparation of 4 is described in
the paper by I. Becker J. Heterocyclic Chem. 2005, 42, 1289. The same
preparative details are given in this paper.
[8] Manji, H. K.; Drevets, W. C.; Charney, D. S. Nature Medicine
2001, 7, 541.
[9] Svenningssen, P.; Chergui, K.; Rachleff, I.; Flagjolet, M.;
Zhana, X.; El Yacoubi, M.; Vaugeois, J. M.; Nomikos, G. S.; Greengard, P.
Science 2006, 311, 77.
[10] Mokrosz, J. M.; Strekowski, L.; Buszynska, B.; Harden, D. B.;
Mokrosz, M. J.; Bajarski, A. J. Pharmazie 1994, 49, 801.
[11] Matsumoto, K.; Hashimoto, S.; Minatogawa, H.; Munakata, M.;
Otani, S. Chemistry Express 1990, 5, 473.
[12] Matsumoto, K.; Hashimoto,S.; Toda, M.; Hashimoto, M.; Otani,
S. Chemistry Express 1991, 6, 775.
[13] Arranz, M. E.; Diaz, J. A.; Vega, S.; Campos-Toimil, M.;
Orallo, F.; Cardelus, I.; Llenas, J.; Fernandez, A. G. Eur. J. Med. Chem.
2000, 35, 751.
[14] Vega, S.; Arranz, M. E.; Aran, V. J. J. Heterocyclic Chem.
2005, 42, 763.
[23] I. Becker, PhD Dissertation, Temple University, Phila., PA,
1961, pp 105-107. Our experimental procedure was patterned after that
described by Whitmore, F. C.; Mosher, H. S.; Adams, R. R.; Taylor, R. B.;
Chapin, E. C.; Weisel, C.; Yanko, W. J. Am. Chem. Soc. 1944, 66, 725 and
after procedures given by Bruson, H. A. Cyanoethylation in Organic
Reactions Adams, R., ed., John Wiley and Sons, Inc, NY, 1949, Vol. 5,
pages 109ff.
[24] The structure of 29 was confirmed by a positive Beilstein test
(Cl present), by CHN analyses, by an ir spectrum that indicated the presence
of an aliphatic CꢀN group in the molecule, and by a 1H nmr spectrum.
[25] Baker, B. R.; Tanna, P. M. J. Org. Chem. 1965, 30, 2857.
[26] Rosemeyer, H.; Seela, F. Heterocycles 1985, 23, 2669.
[27] The preparation of 24 had been reported earlier by Regnier, G.;
Canevari, R.; LeDouarec, J-C.; Laubie, M. Chimie Therapeutique 1972, 7,
192. But specific experimental details for the preparation of 24 are not given
in this paper. Instead, details are given for the preparation of a compound of
analogous structure. Apparently, then, they prepared 24 by refluxing a
mixture of 1-(2-pyrimidinyl)piperazine and 6-chloropurine (2:1 mol ratio) in
dimethylformamide (normal bp 153°) for 7 h. Their product, recrystallized
from dimethylformamide, had mp greater than 350°. They give no spectral
data for their product.
[15] Regnier, G.; Canevari, R.; Le Douarec, J. C.; Laubie, M.
Chimica Therapeutica 1972, 7, 192.
[16] Campbell, S. F.; Plews, R. M. J. Med. Chem. 1987, 30, 1794.
[17a] Goldberg, H. L.; Finnerty, R. J. Am. J. Psychiatry 1979, 136,
1184. [b] Rickels, K. J. Clinical Psychiatry 1981, 42, 40. [c] Gammans,
R. E.; Mayol, R. F.; LaBudde, J. A.; Gasten, G. P. Federation Proc.
1982, 41, 1335, abstract no. 6223. [d] Riblet, L. A.; Taylor, D. P.; Eison,
M. S.; Stanton, H. C. J. Clinical Psychiatry 1982, 43, 11. [e] Newton, R.
E.; Casten, G. P.; Alms, D. R.; Benes, C. O.; Marunycz, J. D. J. Clinical
Psychiatry 1982, 43, 100. [f] Feighner, J. P.; Meredith, C. H.;
Hendrickson, G. A. J. Clinical Psychiatry 1982, 43, 103. [g] Caccia, S.;
Conti,I.; Vigano, G.; Garattini, S. Pharmacology 1986, 33, 46. [h]
Schweizer, E. E.; Amsterdam, J.; Rickels, K.; Kaplan, M.; Droba, M.
Psychopharmacology Bulletin 1986, 22, 183. [i] Gammans, R. E.;
Mayol, R. F.; LaBudde, J. A. The American Journal of Medicine 1986,
80 (suppl.3B), 41. [j] Dischino, D. D.; Covington, R. R.; Combs, C. M.;
Gammans, R. E. J. Labelled Compounds and Pharmaceuticals 1987, 25,
359. [k] Amsterdam, J. D.; Berwish, N.; Potter, L.; Rickels, K. Current
Therapeutic Research 1987, 41, 185. [l] Bianchi, G.; Caccia, S.; Della
Vedova, F.; Garattini, S. Eur. J. Pharmacol. 1988, 151, 365. [m] Cott, J.
Our preparation of 24 differed significantly from that of Regnier and
coworkers. In our preparation a mixture of 6.05 g (0.0369 mol) of 1-(2-
pyrimidinyl)piperazine and 1.90 g (0.0123 mol) of 6-chloropurine (3:1 mol
ratio of amine to 6-chloropurine) was heated on the steam bath for 3.5 h, let
stand for 67 h, heated on the steam bath for 4 h more, and let stand for 45 h.
Our crude product gave
a negative Beilstein test (no Cl). It was
recrystallized from the solvent pair of 95% ethanol and water. Our once
recrystallized product gave an acceptable CHN analysis, and gave a 1H nmr
spectrum that confirmed its structure.
[28] Our product 26, prepared by cyanoethylation of 24, gave an
acceptable CHN analysis, gave an ir spectrum that indicated the presence of
an aliphatic CꢀN group in the molecule, and gave a 1H nmr spectrum that
confirmed its structure.
[29] SciFinder lists no references for either 27 or 28 but does list five
commercial sources for 27 and one commercial source for 28.