The promoted synthesis of minoxidil by magnetic nanoparticles of cobalt ferrite (CoFe2O4) as a heterogeneous reusable catalyst

Article abstract of DOI:10.3906/kim-1903-46

Minoxidil (2,4-diamino-6-piperidinopyrimidine 3-oxide) was primarily recognized as a drug for reducing vascular resistance to blood flow. It was later introduced as a more important medicine for topical stimulation of hair growth and baldness reverting as well as treatment of androgenic alopecia through increasing prostaglandin endoperoxide synthesis. In this study, magnetic nanoparticles (MNPs) of spinel ferrites (MFe 2 O 4, M = Co, Ni, Fe, Cu, and Zn) via solid-state grinding procedure were prepared and then characterized using X-ray diffraction, scanning electron microscopy, transmission electron microscopy, vibrating sample magnetometer, and Fourier transform infrared techniques. The prepared nanoferrites were utilized as efficient and green heterogeneous catalysts for N -oxidation of 2,6-diamino-4-chloro-pyrimidine with H 2 O 2 in refluxing ethanol giving 2,6-diamino-4-chloro-pyrimidine N -oxide as a starting material for the synthesis of 2,4-diamino-6-piperidinopyrimidine 3-oxide (minoxidil). Among the examined nanoferrites, CoFe 2 O 4 MNPs exhibited prominent catalytic activity giving the product in 95% yield within 60 min. Moreover, the reusability of nano-CoFe 2 O 4 was examined for 6 consecutive cycles without significant loss of catalytic activity and magnetic property.

Full text of DOI:10.3906/kim-1903-46

Turk J Chem
Turkish Journal of Chemistry
(2019) 43: 1425 – 1435
© TÜBİTAK
http://journals.tubitak.gov.tr/chem/
doi:10.3906/kim-1903-46
Research Article
The promoted synthesis of minoxidil by magnetic nanoparticles of cobalt ferrite
(CoFe2 O4 ) as a heterogeneous reusable catalyst
1
1
2
3,∗
Ronak EISAVI ,, Fatemeh AHMADI ,, Behzad ZEYNIZADEH ,, Mehri KOUHKAN
,
1
Department of Chemistry, Payame Noor University, Tehran, Iran
2
Faculty of Chemistry, Urmia University, Urmia, Iran
3
Department of Pharmacy, Urmia University of Medical Sciences, Urmia, Iran
Received: 17.03.2019
•
Accepted/Published Online: 29.08.2019
•
Final Version: 07.10.2019
Abstract: Minoxidil (2,4-diamino-6-piperidinopyrimidine 3-oxide) was primarily recognized as a drug for reducing
vascular resistance to blood flow. It was later introduced as a more important medicine for topical stimulation of hair
growth and baldness reverting as well as treatment of androgenic alopecia through increasing prostaglandin endoperoxide
synthesis. In this study, magnetic nanoparticles (MNPs) of spinel ferrites (MFe2 O4 , M = Co, Ni, Fe, Cu, and Zn) via
solid-state grinding procedure were prepared and then characterized using X-ray diffraction, scanning electron microscopy,
transmission electron microscopy, vibrating sample magnetometer, and Fourier transform infrared techniques. The
prepared nanoferrites were utilized as efficient and green heterogeneous catalysts for N -oxidation of 2,6-diamino-4-
chloro-pyrimidine with H2 O2 in refluxing ethanol giving 2,6-diamino-4-chloro-pyrimidine N -oxide as a starting material
for the synthesis of 2,4-diamino-6-piperidinopyrimidine 3-oxide (minoxidil). Among the examined nanoferrites, CoFe2 O4
MNPs exhibited prominent catalytic activity giving the product in 95% yield within 60 min. Moreover, the reusability of
nano-CoFe2 O4 was examined for 6 consecutive cycles without significant loss of catalytic activity and magnetic property.
Key words: Androgenic, Cobalt ferrite, Hydrogen peroxide, magnetic nanoparticles, minoxidil, solid-state
1. Introduction
Minoxidil was primarily recognized as an effective antihypertensive and peripheral vasodilator drug for reducing
vascular resistance to blood flow [1,2]. However, it was later introduced as a more important medicine for topical
stimulation of hair growth [3], baldness reverting [4], and treatment of androgenic alopecia through increasing
prostaglandin endoperoxide synthesis [5]. Recently, magnetic nanoparticles of ferrites have been widely used as
green and efficient heterogeneous catalysts in the synthesis of organic compounds. These NPs provide prominent
advantages such as simple synthetic procedure, high catalytic activity due to huge surface area to volume ratio
[6], chemical reactivity and thermal stability [7,8], easy separation using an external magnetic field without
utilizing further traditional filtration process and perfect reusability [9,10]. Moreover, they have received a
considerable interest because of their wide useful capabilities in drug delivery, magnetic resonance imaging,
and biomedical technology [11–16]. It is notable that in pharmaceutical industry, the recovery and complete
separation of magnetic nanocatalysts is important, because the presence of residual metals in final products
may have dangerous consequences.
The development and characterization of nanoferrites have been quite significant to meet a number of
∗Correspondence: mehrikouhkan@gmail.com
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This work is licensed under a Creative Commons Attribution 4.0 International License.

EISAVI et al./Turk J Chem
scientific and technological requirements especially in environmental and medical issues. Ferrites have been
developed using different methods such as coprecipitation [17], hydrothermal [18], and solid-state [19]. Among
these methods, solid-state procedure is a facile approach with great economic and technical advantages to obtain
highly crystalline nanoparticles.
As a part of our research program on the synthesis of nanomagnetic materials and their application
in functional group transformations [20–22], herein, we wish to introduce nanospinel ferrites as efficient and
reusable heterogeneous catalysts for N -oxidation of 6-chloro-2,4-diaminopyrimidine to 2,6-diamino-4-chloro-
pyrimidine N -oxide by H2 O2 in ethanol under reflux conditions. Then, through the nucleophilic reaction
of piperidine with 2,6-diamino-4-chloro-pyrimidine N -oxide, minoxidil (2,4-diamino-6-piperidino-pyrimidine 3-
oxide) was produced in high yield and purity (Figure 1).
Figure 1. Synthesis of minoxidil.
2. Experimental
2.1. General
All reagents and materials were purchased from Merck and Aldrich chemical companies with high quality
and used without further purification. Scanning electron microscopy (SEM) images of NPs were recorded on
FESEM-TESCAN. TEM images were recorded on Philips CM30 at electron energy at 300 KeV. Characterization
of nanocatalysts were carried out by X-Ray diffraction (XRD) using a Bruker D8-Advanced diffractometer
with graphite-monochromatized Cu Kαradiation (λ=1.54056 Å) at room temperature. Magnetic properties of
nanoferrites were measured using a vibrating sample magnetometer (VSM, Meghnatis Daghigh Kavir Co., Iran)
1
13
at room temperature. Fourier transform infrared (FT-IR) and H/ C NMR spectra were recorded on Thermo
Nicolet Nexus 670 FT-IR and 500 MHz Bruker Avance spectrometers, respectively. Products were identified
through spectral analysis and then compared with authentic data in the literature. All yields refer to isolated
pure products.
2.2. Preparation of CoFe2 O4 magnetic nanoparticles
Magnetic nanoparticles (MNPs) of CoFe2 O4 were prepared through a solid-state grinding procedure. In an
agate mortar, a mixture of CoCl2 , Fe(NO3)3·9H2 O, NaOH, and NaCl in a molar ratio of 1:2:8:2 was prepared
and then ground for 45 min at room temperature. The reaction was started with the release of heat and the
change of color from yellow to dark brown after 4 min. After the reaction was completed (45 min), the excess
amount of salt was removed from the reaction mixture through washing with distilled water. The obtained
residue was dried in an oven at 80 ◦ C for 60 min. The resulting powder was smoothly calcinated at 300,
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500, 700, and 900 ◦ C within 80 min (20 min at each temperature) affording CoFe2 O4 MNPs. Consequently,
MgFe2 O4 , NiFe2 O4 , ZnFe2 O4 , and CuFe2 O4 MNPs were prepared through similar procedure and then
characterized (supplementary information).
2.3. Synthesis of 2,6-diamino-4-chloro-pyrimidine N-oxide
In a two-neck round-bottom flask equipped with magnetic stirrer and condenser, a mixture of 2,6-diamino-4-
chloro-pyrimidine (1 mmol, 0.14 g) and CoFe2 O4 MNPs (0.01 g, 0.05 mmol, 5 mol%) in EtOH (5 mL) was
placed. The mixture was stirred for 1 min at 40 ◦ C, and then H2 O2 (30%, 0.5 mL) was added dropwise into
the reaction mixture. The resulting mixture was then magnetically stirred under reflux conditions for 60 min.
Progress of the reaction was monitored by thin layer chromotography (TLC) [eluent: CHCl3 :MeOH:EtOAc
(5:4:1)]. After the completion of reaction, the mixture was cooled to room temperature and MNPs of CoFe2 O4
were separated from the reaction mixture using an external magnetic field. The final product was filtered and
washed with ethanol, recrystallized from hot water and dried in oven at 80 ◦ C affording 2,6-diamino-4-chloro-
1
pyrimidine N -oxide as a white solid (95% yield, 0.15 g, mp. 189 ◦ C). H NMR (d6 -DMSO) δ (ppm) 7.57 (bs,
13
4H, 2NH2), 6.09 (s, 1H, Ar-H); CNMR (d6 -DMSO) δ (ppm) 153.76, 153.52, 145.34, 92.52; FT-IR (νmax
,
cm−1 , neat) 3473, 3415, 3339, 3284, 3143, 1618, 1567, 1483, 1372, 1205, 1158, 922, 795, 767, 736, 651, 611, 539,
530, 505.
2.4. Synthesis of 2,4-diamino-6-piperidinopyrimidine 3-oxide (minoxidil)
In a round-bottom flask equipped with magnetic stirrer and condenser, a mixture of piperidine (1.8 mL, 1.55
g, 18.2 mmol) and 2,6-diamino-4-chloro-pyrimidine N -oxide (0.16 g, 1 mmol) was placed and then stirred in
boiling piperidine (106 ◦ C) for 120 min. Progress of the reaction was monitored by TLC. After the reaction was
completed, the excess amount of piperidine was removed by evaporation under reduced pressure. The resulting
solid material was washed with water, recrystallized from hot water affording minoxidil as a colorless crystalline
1
solid (80% yield, 0.17g, mp. 258?260 ◦ C). H NMR (d6 -DMSO) δ (ppm) 6.83 (bs, 4H, 2NH2), 5.35 (s, 1H,
13
Ar-H), 3.36 (t, J = 5.32 Hz, 4H, 2CH2 -N), 1.62-1.44 (m, 6H, 3CH2); C NMR (d6 -DMSO) δ (ppm) 155.52,
153.47, 152.27, 73.52, 45.39, 25.36, 24.58; FT-IR (νmax , cm−1 , neat) 3307, 2932, 2853, 2261, 2140, 1651, 1611,
1475, 1445, 1374, 1287, 1249, 1228, 1150, 1124, 1083, 1023, 1004, 876, 820, 761, 481.
3. Results and discussions
3.1. Preparation of CoFe2 O4 MNPs
MNPs of CoFe2 O4 were synthesized through solid-state grinding of CoCl2 , Fe(NO3)3·9H2 O, NaCl, and NaOH
in a molar ratio of 1:2:8:2 (Figure 2). The resulting dark brown residue was washed, dried, and then calcinated at
300–900 ◦ C. The prepared CoFe2 O4 MNPs were then characterized using XRD, vibrating sample magnetometer
(VSM), SEM, transmission electron microscopy (TEM), and FT-IR techniques.
Figure 2. Synthesis of CoFe2 O4 MNPs.
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3.2. Characterization of CoFe2 O4 MNPs
3.2.1. X-Ray Diffraction (XRD)
Figure 3 displays XRD pattern of CoFe2 O4 MNPs. The pattern showed the reflection planes of (3 1 1), (4 4
0), and (5 1 1) corresponding to 2θ = 35.57◦ , 62.71◦ and 57.12◦ , respectively. Comparison of the obtained
patterns with standard data (JCPDS card no. 22-1086) exhibited that the laboratory sample of CoFe2 O4 had
high phase purity and crystallinity. Moreover, the average crystal size of CoFe2 O4 using Scherrer equation was
calculated to be 66 nm [23].
Figure 3. XRD pattern of CoFe2 O4 MNPs.
3.2.2. Vibrating sample magnetometer (VSM)
Figure 4 shows the magnetic property of CoFe2 O4 MNPs which was plotted using a VSM instrument under
an external magnetic field of up to 20 kOe. It has been reported that the magnetization saturation value (Ms)
of a nanomaterial is a direct function of its dimensions, such that by increase of the agglomeration and size of
NPs, Ms value is also increased [24]. The shape of magnetization curve verfied that CoFe2 O4 MNPs behaved
as hard ferromagnetic materials [25]. Moreover, it was shown that Ms value and coercivity of CoFe2 O4 MNPs
?1
were 128 emu g and 800 Oe, respectively.
3.2.3. Scanning electron microscopy (SEM)
Morphology of the surface of CoFe2 O4 MNPs was investigated using SEM technique (Figure 5). SEM images
demonstrated that agglomeration of NPs occurred to some extent affording spherical segments with diameters
64-66 nm.
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Figure 4. Magnetization curve of CoFe2 O4 MNPs.
3.2.4. Fourier transform infrared spectroscopy (FT-IR)
FT-IR spectrum of CoFe2 O4 MNPs is shown in Figure 6. The spectrum represents a strong absorption band at
576 cm−1 corresponding to stretching vibration of metal-oxygen (M-O) bond indicating the formation of spinal
ferrite structure. The absorption peaks at 1616 and 3430 cm−1 are also attributed to bending and stretching
vibrations of O-H groups on the surface of CoFe2 O4 MNPs and the adsorbed water by sample, respectively
[26]. The latter absorption signal for adsorbed water could be weakened by the calcination of NPs.
3.3. Synthesis of minoxidil
Minoxidil was synthesized in a two-step procedure: i) N -oxidation of 2,6-diamino-4-chloro-pyrimidine and ii)
preparation of 2,4-diamino-6-piperidinopyrimidine 3-oxide through the reaction of piperidine with 2,6-diamino-
4-chloro-pyrimidine N -oxide (Figure 7).
3.3.1. Preparation of 2,6-diamino-4-chloro-pyrimidine N-oxide
Synthesis of 2,6-diamino-4-chloro-pyrimidine N -oxide was carried out via N -oxidation of 6-chloro-2,4-diaminopyrimidine
with H2 O2 in the presence of various magnetic nanocatalysts (CoFe2 O4 , MgFe2 O4 , CuFe2 O4 , NiFe2 O4 and
ZnFe2 O4) under different reaction conditions including the change of quantities of nanocatlysts and hydro-
gen peroxide, temperature and reaction solvent. The results of this investigation are summarized in Table.
Observation of the results represented that N -oxidation of 6-chloro-2,4-diaminopyrimidine with H2 O2 in the
absence of any nanoferrite catalyst did not proceed. However, using a small amount of spinel ferrites dramati-
cally affected N -oxidation of pyrimidine ring. More examinations also exhibited that among various nanospinel
ferrites, CoFe2 O4 MNPs showed excellent catalytic activity. In addition, using 5 mol% of CoFe2 O4 and 0.5
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EISAVI et al./Turk J Chem
Figure 5. SEM image of CoFe2 O4 MNPs.
mL of H2 O2 per 1 mmol of 6-chloro-2,4-diaminopyrimidine in ethanol under reflux conditions (entry 6, Table)
were the optimum requirements for the completion of reaction.
The green aspect of this methodology was also studied through the reusability investigation of the
applied CoFe2 O4 towards N -oxidation of 6-chloro-2,4-diaminopyrimidine with H2 O2 under optimized reaction
conditions. In this context, when the reaction of N -oxidation was completed, the nanocatalyst was recovered
from the reaction mixture using an external magnetic field. After washing with EtOAc and drying in an oven, the
vessel of N -oxidation reaction was charged with fresh 6-chloro-2,4-diaminopyrimidine, H2 O2 and the recovered
CoFe2 O4 for a second run. Figure 8 clearly shows that CoFe2 O4 MNPs could be reused for 6 consecutive
cycles without significant loss of its catalytic activity and magnetic property.
3.3.2. Synthesis of 2,4-diamino-6-piperidinopyrimidine 3-oxide
2,4-Diamino-6-piperidinopyrimidine 3-oxide (minoxidil) was successfully synthesized from the nucleophilic sub-
stitution reaction of piperidine with 2,6-diamino-4-chloro-pyrimidine N -oxide in boiling piperidine (106 ◦ C)
under neat conditions. The reaction was completed within 120 min affording minoxidil product in high yield
(80 %) and purity without requiring any further purification. Minoxidil was in a tautomeric equilibrium with
6-amino-1,2-dihydro-1-hydroxy-2-imino-4-piperidinylpyrimidine (Figure 7).
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Figure 6. FT-IR spectrum of CoFe2 O4 MNPs.
Figure 7. Two-step procedure for synthesis of minoxidil.
Although the exact mechanism of this synthetic protocol is not clear, the mechanism depicted in Figure
9 shows the role of nanocatalyst in promoting the synthesis of minoxidil in a two-step procedure. The figure
shows that due to the Lewis acidity of transition metals existing in spinel ferrites, 6-chloro-2,4-diaminopyrimidine
interacted with the surafce of nanocatalyst [27-32]. Then, by the addition of H2 O2 and its interaction with the
surface of nanocatalyst, N -oxidation of pyrimidine ring was carried out giving 2,6-diamino-4-chloro-pyrimidine
N -oxide. Next, through the nucelophic attack of piperidne with 2,6-diamino-4-chloro-pyrimidine N -oxide,
minoxidil product was successfully produced.
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Table 1. Nano MFe2 O4 catalyzed N -oxidation of 6-chloro-2,4-diaminopyrimidine with H2 O2 under different
a
conditions .
b
Entry Catalyst (mol%)
H2O2 (mL) Conditions
Time (min) Conversion (%)
Yield (%)
1
2
3
4
5
6
7
8
-
0.5
0.5
0.5
0.5
0.5
0.5
0.5
EtOH/reflux
EtOH/reflux
EtOH/reflux
EtOH/reflux
EtOH/reflux
EtOH/reflux
EtOH/reflux
EtOH/reflux
EtOH/reflux
EtOH/reflux
EtOH/reflux
MeOH/reflux
H2O/reflux
60
90
100
120
130
60
90
55
150
90
60
0
0
CuFe2O4 (5 mol%)
NiFe2O4 (5 mol%)
MgFe2O4 (5 mol%)
ZnFe2O4 (5 mol%)
CoFe2O4 (5 mol%)
CoFe2O4 (3 mol%)
100
100
100
100
100
100
100
100
100
100
100
10
80
85
85
70
95
90
95
80
85
94
90
-
CoFe2O4 (10 mol%) 0.5
9
CoFe2O4 (5 mol%)
CoFe2O4 (5 mol%)
CoFe2O4 (5 mol%)
CoFe2O4 (5 mol%)
CoFe2O4 (5 mol%)
CoFe2O4 (5 mol%)
CoFe2O4 (5 mol%)
CoFe2O4 (5 mol%)
CoFe2O4 (5 mol%)
0.1
0.3
0.7
0.5
0.5
0.5
0.5
0.5
0.5
10
11
12
13
14
15
16
17
60
240
360
240
60
CH3CN/reflux
CHCl3/reflux
EtOH/r.t.
50
20
0
100
-
-
?
80
◦
Solvent-free, 70 C 60
a
b
All reactions were carried out with 1 mmol of 6-chloro-2,4-diaminopyrimidine. Conversion less than 100%
was determined on the basis of the recovered 6-chloro-2,4-diaminopyrimidine.
Figure 8. Reusability of CoFe2 O4 MNPs in N -oxidation of 6-chloro-2,4-diaminopyrimidine.I) N -oxidation of 2,6-
diamino-4-chloro-pyrimidine II) Nucleophilic reaction of piperidine on 2,6-diamino-4-chloro-pyrimidine N -oxide
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Figure 9. A proposed mechanism for synthesis of mioxidil catalyzed by CoFe2 O4 MNPs.
4. Conclusion
In this study, we have introduced an easy protocol for the synthesis of minoxidil drug by the reaction of
piperidine with 2,6-diamino-4-chloro-pyrimidine N -oxide under neat conditions. 2,6-Diamino-4-chloro-pyrimi-
dine N -oxide was primarily synthesized from N -oxidation of 6-chloro-2,4-diaminopyrimidine using H2 O2 in the
presence of CoFe2 O4 magnetic nanocatalyst in ethanol under reflux conditions. The effect of other magnetic
nanocatalysts such as CuFe2 O4 , NiFe2 O4 , MgFe2 O4 , and ZnFe2 O4 was also investigated. Based on the
obtained results, the current protocol had prominent advantages in terms of cost-effectiveness, easy synthesis,
and great reusability of the magnetic nanocatalyst, as well as magnetic separation of the catalyst instead of
using traditional filtration process, short reaction time, and high yield of final product.
Acknowledgment
The authors gratefully appreciate the financial support of this work by the Research Council of Urmia University
of Medical Sciences.
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Supplementary Information
FT-IR, 1H/13C NMR spectra of 2,6-diamino-4-chloro-pyrimidine N-oxide and minoxidil as well as VSM, SEM,
TEM, XRD and FT-IR spectrum of MgFe2O4, CuFe2O4, NiFe2O4 and ZnFe2O4 were given in supplementary
information.
Figure S1. 1H NMR spectrum of 2,6-diamino-4-chloro-pyrimidine N-oxide.
Figure S2. 13C NMR spectrum of 2,6-diamino-4-chloro-pyrimidine N-oxide.
1

Figure S3. FT-IR (KBr) spectrum of 2,6-diamino-4-chloro-pyrimidine N-oxide.
Figure S4. 1H NMR spectrum of minoxidil.
2

Figure S5. 13C NMR spectrum of minoxidil.
Figure S6. FT-IR (KBr) spectrum of minoxidil.
3

Figure S7. a) X-ray diffraction, b) TEM image and c) FT-IR (KBr) spectrum of CuFe2O4 MNP.
4

Figures S8. a) X-ray diffraction, b) SEM image, c) TEM image, d) FT-IR (KBr) spectrum, and e) magnetization curve of
NiFe2O4 MNPs.
5

Figures S9. a) X-ray diffraction, b) SEM image, c) FT-IR (KBr) spectrum, and d) magnetization curve of MgFe2O4
MNPs.
6

Figures S10. a) X-ray diffraction, b) SEM image, c) FT-IR (KBr) spectrum, and d) magnetization curve of ZnFe2O4
MNPs.
7