p-Tyrosol: a new synthetic method and new types of pharmacological activity

Article abstract of DOI:10.1007/s11172-015-1140-y

A new method for the synthesis of p-tyrosol, i.e., 2-(4-hydroxyphenyl)ethanol, has been developed, which considerably simplified the process of preparation of this pharmaceutical substance. The method includes nitration of 2-phenylethanol, catalytic hydrogenation of 2-(4nitrophenyl)ethyl nitrate, and nitrosation of 2-(4-aminophenyl)ethanol, followed by acid hydrolysis of the intermediate diazo compound. The method is easily feasible, furnishes the pharmaceutical substance of high quality, and is quite acceptable for commercialization. Antihypertensive and hemorheologic activities of p-tyrosol in spontaneously hypertensive rats were investigated per se and in combination with captopril. p-Tyrosol in the course administration with captopril was found to enhance the antihypertensive effect of the latter and eliminate its negative effect on red blood cell aggregation.

Full text of DOI:10.1007/s11172-015-1140-y

Russian Chemical Bulletin, International Edition, Vol. 64, No. 9, pp. 2210—2214, September, 2015
2210
pꢀTyrosol: a new synthetic method and new types of pharmacological activity*
S. V. Sysolyatin,a Yu. A. Kryukov,a V. V. Malykhin,a K. K. Muradov,a G. A. Chernysheva,b O. I. Aliev,b
V. I. Smol´yakova,b A. M. Anishchenko,b A. V. Sidekhmenova,b A. Yu. Shamanaev,b and M. B. Plotnikovb
aInstitute for Problems of Chemical and Energetic Technologies, Siberian Branch of the Russian Academy of Sciences,
1 ul. Sotsialisticheskaya, 659322 Biisk, Russian Federation.
Fax: +7 (385 4) 30 1725. Eꢀmail: admin@ipcet.ru
bE. D. Gol´dberg Institute of Pharmacology and Regenerative Medicine,
3 prosp. Lenina, 634028 Tomsk, Russian Federation.
Fax: +7 (382 2) 41 8379. Eꢀmail: mbp2001@mail.ru
A new method for the synthesis of pꢀtyrosol, i.e., 2ꢀ(4ꢀhydroxyphenyl)ethanol, has been
developed, which considerably simplified the process of preparation of this pharmaceutical
substance. The method includes nitration of 2ꢀphenylethanol, catalytic hydrogenation of 2ꢀ(4ꢀ
nitrophenyl)ethyl nitrate, and nitrosation of 2ꢀ(4ꢀaminophenyl)ethanol, followed by acid hydroꢀ
lysis of the intermediate diazo compound. The method is easily feasible, furnishes the pharmaꢀ
ceutical substance of high quality, and is quite acceptable for commercialization. Antihyperꢀ
tensive and hemorheologic activities of pꢀtyrosol in spontaneously hypertensive rats were invesꢀ
tigated per se and in combination with captopril. pꢀTyrosol in the course administration with
captopril was found to enhance the antihypertensive effect of the latter and eliminate its
negative effect on red blood cell aggregation.
Key words: pꢀtyrosol, 2ꢀphenylethanol, 2ꢀ(4ꢀnitrophenyl)ethyl nitrate, 2ꢀ(4ꢀaminoꢀ
phenyl)ethanol, 2ꢀ(4ꢀhydroxyphenyl)ethanol, nitration, catalytic hydrogenation, nitrosation,
antihypertensive activity, hemorheological activity, red blood cell aggregation, red blood cell
deformability.
pꢀTyrosol, 2ꢀ(4ꢀhydroxyphenyl)ethanol (1), possesses
a wide range of pharmacological activity: antiradical, antiꢀ
oxidant, neuroprotective, psychostimulant, antiischemic,
hemorheological, and other kinds of activity.1—10 Thereꢀ
fore, compound 1 is very promising parent material for the
design of new medicines. At the same time, development
of new medicinal agents requires a highꢀquality pharmaꢀ
ceutical material with the high content of the main
compound.
One of the approaches to the preparation of pꢀtyrosol 1
is the extraction of the product from natural substrates.11—13
In this case, a low concentration of the target compound
in biological raw materials and its low recovery rate stimuꢀ
lated development of synthetic methods for the preparaꢀ
tion of pꢀtyrosol 1. However, most of the known methods
for the synthesis of compound 1 have a theoretical rather
than a practical value. Production of compound 1 on
a large scale using organometallic compounds, ethylene
oxide, and organometallic synthesis14—16 is hardly reaꢀ
sonable because of technical difficulties, increased fire danꢀ
ger, and high cost. Methods of thermal deꢀtertꢀbutylation
of 4ꢀ(hydroxyalkyl)phenols17,18 are hardly applicable on
the industrial scale either, since they require special exꢀ
pensive vacuum technique for establishing and maintainꢀ
ing high vacuum conditions while isolating target prodꢀ
ucts. An industrially easy to implement method for the
preparation of compound 1 from phenol is complicated by
the use of acetic anhydride, the circulation of which in the
Russian Federation is restricted. Thus, most of the known
methods for the preparation of pꢀtyrosol 1 turned out to be
little suitable for industrial implementation because of their
technical complexity, high cost of the final products, and
the use of poorly available raw materials. Preparation of
compound 1 from commercially available 2ꢀphenylethaꢀ
nol seems the most promising for practical purposes.19,20
The purpose of the present work is to develop a new,
suitable for industrial implementation method for the synꢀ
thesis of pꢀtyrosol 1, which furnishes pharmaceutical subꢀ
stance of high quality, as well as to study new types of
pharmacological activity of this compound.
Results and Discussion
We suggested a simple method for the preparation of
pꢀtyrosol 1 from 2ꢀphenylethanol which includes nitraꢀ
tion of the starting compound, catalytic hydrogenation of
* Dedicated to Academician of the Russian Academy of Sciences
N. S. Zefirov on the occasion of his 80th birthday.
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 9, pp. 2210—2214, September, 2015.
1066ꢀ5285/15/6409ꢀ2210 © 2015 Springer Science+Business Media, Inc.

pꢀTyrosol: synthesis and activities
Russ.Chem.Bull., Int.Ed., Vol. 64, No. 9, September, 2015 2211
Table 1. Nitration of 2ꢀphenylethanol with nitric acid
pꢀnitro derivative 2a, skipping the nitro ester hydrolysis
step. Subsequent nitrosation of 2ꢀ(4ꢀaminophenyl)ethanol
(3) led to diazo derivative, which was hydrolyzed to give
the target product 1 (Scheme 1).
Entry T/C CHNO (wt.%) Product composition (%)
3
2a
2b
2с
1
2
3
4
5
–10
35
0
15
20
98
98
93
93
93
49
35
70
69
68
25
24
29.5
29
27
26
31
0.5
2
5
Scheme 1
The previous studies22 showed that an increase in temꢀ
perature leads to the decrease in the yield of the nitration
products, whereas percentage of 2a in the nitration prodꢀ
ucts decreases and that of 2c increases as the concentraꢀ
tion of the acid increases (Table 1). These data showed
that the best results were obtained in the nitration with
93% HNO3 at 0 C. The amount of dinitro derivative 2c in
this case is minimal.
When the H2SO4—HNO3 mixture is used for the niꢀ
tration (Scheme 3), the amount of dinitro derivatives in
the reaction products increases (Table 2).
An increase in temperature leads to the increase in the
amount of 2c and 2d. Thus, we consider it unreasonable to
use the H2SO4—HNO3 mixture for the preparation of
compound 2a.
Reagents: i. HNO3; ii. H2, Pd/C, TsOH; iii. NaNO2, TsOH.
Nitro derivative 2a was hydrogenated with hydroꢀ
gen in the presence of a catalyst (5% Pd/C) at atmospherꢀ
ic pressure in isopropyl alcohol. We found the optimal
conditions for the process: at 40 C, the concentration of
the starting compound in the reaction mixture of 2 wt.%,
the amount of the catalyst of 0.2 g per 1 g of the substrate,
and the reaction time of 3 h, the yield of compound 3 was
96%. After the washing with hot isopropyl alcohol, the
This method considerably shortens the time of the proꢀ
cess as compared to the known analogues and decreases
the cost of the agent. The high price of the catalyst (Pd/C)
is compensated by its multiple reuse.
It is known21 that the nitration of 2ꢀphenylethanol
with nitric acid leads to the mixture of monoꢀ and dinitro
derivatives 2a—c (Scheme 2).
Scheme 2
Scheme 3
Reagents: HNO3 (60 wt.%), H2SO4 (40 wt.%).

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Sysolyatin et al.
Table 2. Nitration of 2ꢀphenylethanol with the
H2SO4—HNO3 mixture (60 wt.% HNO3, 40 wt.%
H2SO4)
The nitrosation of compound 3 in the presence of
2 moles of TsOH•H2O gave pꢀtyrosol 1 in 46—50% yield.
After recrystallization from water with charcoal, the subꢀ
stance was obtained with 99.9% purity (HPLC data).
Antihypertensive and hemorheological activity of
pꢀtyrosol 1 was studied in spontaneously hypertensive rats
(SHRs). After a twoꢀweek course of agent 1 administraꢀ
tion in dose 50 mg kg–1 to SHRs), the arterial pressure did
not confidently changed as compared to the control
(Table 4). The highest hypotensive effect was observed in
animals administered with a combination of pꢀtyrosol 1
and captopril, which was reflected in the pronounced deꢀ
crease in the systolic and diastolic arterial pressure as
compared to the control by 33 and 38%, respectively
(р < 0.05). The coꢀadministration of agent 1 and captopril
showed a confidently lower level of diastolic arterial presꢀ
sure as compared to the group of rats obtaining only captoꢀ
pril. Therefore, pꢀtyrosol 1 is capable of enhancing the
antihypertensive effect of captopril.
The studies of red blood cell (RBC) aggregation in the
stream showed that in the control group of rats, the critiꢀ
cal time of erythrocytes was 11.7 0.3 s (see Table 5 and
Experimental). In animals administered with captopril for
two weeks, this index was confidently lower as compared
to control by 20%, that indicated the enhancement of the
RBC aggregation. After administration of pꢀtyrosol 1 for
two weeks, the critical time did not change significantly.
A coꢀadministration of captopril and agent 1, the critical
time was confidently higher than in rats which received
only captopril.
Entry Т/C
Product composition (%)
2a
2b
2c
2d
1
2
3
4
–10
0
15
25
43
32
22
—
13
12
10
5
44
47
50
70
—
9
18
25
Table 3. Hydrogenation of 2a
Entry
C2a
Catalyst : 2a
T/C
t/h Yield of 3
(wt.%) /g (g of substrate)–1
(%)
1
2
3
4
5
6
12
12
12
12
15
10
0.2
0.2
0.2
0.5
0.2
0.2
20
40
60
40
40
40
5.5
3.0
2.5
3.0
6.0
6.0
96
96
90
96
65
50
catalyst can be reused in the next hydrogenation cycles.
The experimental results (Table 3) indicate that the reacꢀ
tion outcome is sensitive to the concentration of 2a. An
increase in the concentration of the starting compound
to 5—10 wt.% leads to a noticeable decrease in the yield of
the target compound 3. It is unreasonable to increase
the amount of the catalyst, since this has no any considerꢀ
able effect on the reaction proceeding. Hydrogenation
at room temperature increases the reaction time, whereas
an increase in the temperature to 60 C leads to the deꢀ
crease in the yield. The addition of TsOH•H2O to the
reaction mixture considerably simplified the isolation of
the product. Upon cooling to 0 C, compound 3 crysꢀ
tallizes as a tosylate, which can be isolated by simple
filtration.
The studies of RBC aggregation under stationary conꢀ
ditions showed that the aggregation index values in the
control group and in animals administered with captopril
or pꢀtyrosol 1 did not confidently differ (see Table 5). In
the group of rats, which received captopril together with
pꢀtyrosol 1, the aggregation index was by 20% confidently
lower then in the control group, which indicated weakenꢀ
ing of RBC aggregation. Therefore, pꢀtyrosol 1 adminisꢀ
tered together with captopril removed the negative effect
of the latter on the erythrocyte aggregation processes.
Table 4. Antihypertensive activity of pꢀtyrosol in SHRs
Agent
Before administration
of agent
After course administration
of agent
SAP
DAP
SAP
DAP
Control
pꢀTyrosol
Captopril
pꢀTyrosol + Captopril
211 5
228 10
225 7
223 6
179 6
188 10
176 7
179 5
226 8
189 6
196 8
157 7a
118 12a,b
236 8
191 8a
152 14a
Note. Each group included six animals. SAP is the systolic arterial pressure, DAP is the diastolic arterial
pressure.
a Confident differences compared to control (р < 0.05).
b Confident differences compared to captopril (р < 0.05).

pꢀTyrosol: synthesis and activities
Russ.Chem.Bull., Int.Ed., Vol. 64, No. 9, September, 2015 2213
Table 5. Influence of pꢀtyrosol on RBC aggregation in SHRs
(t, 2 H, CH2, J = 6.6 Hz); 4.82 (t, 2 H, CH2, J = 6.6 Hz); 7.58
(d, 2 H, Ar, J = 8.5 Hz); 8.15 (d, 2 H, Ar, J = 8.5 Hz). 13C NMR
(acetoneꢀd6), : 32.7; 73.1; 123.5; 128.3; 130.7; 145.2.
Agent
Aggregation
index
Critical
time/s
2ꢀ(4ꢀAminophenyl)ethanol (3). 2ꢀ(4ꢀNitrophenyl)ethyl nitrꢀ
ate (2a) (2 g, 9.4 mmol), isopropyl alcohol (100 mL), and 5%
Pd/C (Acros) (0.4 g) were placed into the reactor equipped with
a hydrogen supply system and a stirring device. After evacuaꢀ
tion, the reactor was sequentially purged with nitrogen and hyꢀ
drogen and filled with hydrogen. The stirring turned on and the
reaction mixture was heated to 40 C. In the course of the reacꢀ
tion, the reactor was regularly purged with hydrogen. The proꢀ
cess was monitored by TLC (Et2O—hexane, 1 : 1). After 3 h, the
catalyst was separated, the solvent was evaporated, a precipitate
formed was recrystallized from isopropyl alcohol to obtain comꢀ
pound 3 (1.23 g, 95.7%). M.p. 107—109 C. Found (%): C, 70.12;
H, 8.25; N, 10.30; O, 11.59. C8H11NO. Calculated (%): C, 70.03;
H, 8.10; N, 10.21; O, 11.66. 1H NMR (DMSOꢀd6), : 2.54 (t, 2 H,
CH2, J = 6.6 Hz); 3.48 (t, 2 H, CH2, J = 6.6 Hz); 4.50 (s, 1 H,
OH); 4.80 (s, 2 H, NH2); 6.47 (d, 2 H, Ar, J = 8.5 Hz); 6.85 (d, 2 H,
Ar, J = 8.5 Hz). 13C NMR (DMSOꢀd6), : 38.9; 63.3; 114.4;
127.3; 129.7; 147.3.
Control
pꢀTyrosol
Captopril
pꢀTyrosol + Captopril
26.26 1.02
24.13 2.05
25.77 2.96
21.18 1.13a
11.7 0.3
11.8 2.3
9.4 0.6a
13.1 1.3b
Note. Each group included six animals.
a Confident differences compared to control (р < 0.05).
b Confident differences compared to captopril (р < 0.05).
Table 6. Influence of pꢀtyrosol on RBC deformability (elongaꢀ
tion index) in SHRs at varying shear stress
Agent
Shear stress/Pa
7
10
20
Control
0.427 0.003
0.431 0.007
0.437 0.003
0.427 0.008
0.460 0.003
0.463 0.007
0.469 0.003
0.463 0.006
0.507 0.002
0.510 0.009
0.512 0.002
0.509 0.004
2ꢀ(4ꢀAminophenyl)ethanol tosylate (3•TsOH). 2ꢀ(4ꢀNitroꢀ
phenyl)ethyl nitrate (2a) (2 g, 9.4 mmol), isopropyl alcohol
(100 mL), TsOH•H2O (1.9 g, 10 mmol), and 5% Pd/C (0.4 g)
were placed into the reactor equipped with a hydrogen supply
system and a stirring device. After evacuation, the reactor was
sequentially purged with nitrogen and hydrogen and filled with
hydrogen. The stirring turned on and the reaction mixture was
heated to 40 C. In the course of the reaction, the reactor was
regularly purged with hydrogen. The process was monitored by
TLC (Et2O—hexane, 1 : 1). After 3 h, the catalyst was separated,
the reaction mixture was cooled to 5 C, a precipitate formed
was recrystallized from isopropyl alcohol to obtain 2ꢀ(4ꢀaminoꢀ
phenyl)ethanol tosylate (3•TsOH) (2.75 g, 95%). Found (%):
C, 60.12; H, 6.27; N, 4.20; O, 21.59. C15H19NO4S. Calculated (%):
pꢀTyrosol
Captopril
pꢀTyrosol +
+ Captopril
Note. Each group included six animals.
The course administration of captopril, compound 1,
and captopril together with compound 1 to SHRs showed
that the RBC elongation index did not confidently differ
within entire range of the shear stress studied, both beꢀ
tween the groups and in comparison with control animals
(Table 6). The data obtained indicate the absence of the
influence of compounds under study on the RBC deformꢀ
ability in rats with spontaneous arterial hypertension.
1
C, 58.25; H, 6.15; N, 4.35; O, 20.71. H NMR (D2O), : 2.13
(s, 3 H, CH3); 2.64 (t, 2 H, CH2, J = 6.6 Hz); 3.60 (t, 2 H, CH2,
J = 6.6 Hz); 6.82—7.32 (m, 8 H, 2 Ar); 7.43 (br.s, 2 H, NH,
OH). 13C NMR (D2O), : 20.4; 37.2; 62.09; 122.8; 125.3; 127.9;
129.3; 130.5; 131.9; 140.2; 142.4.
Experimental
pꢀTyrosol (1). Tosylate 3 (1.13 g, 3.65 mmol) was added to
a solution of pꢀtoluenesulfonic acid monohydrate (1.39 g,
7.3 mmol) in water (7 mL) with stirring. After the dissolution of
salt 3, the mixture was cooled to 0 C, followed by the addition of
a solution of NaNO2 (0.28 g, 4 mmol) in water (1.6 mL). The
reaction mixture was stirred for 0.5 h at 0 C, then a 2% aqueous
solution of TsOH•H2O (22 mL) was added, and the mixture was
heated at 60 C for 1 h. The product was extracted with diethyl
ether (3×30 mL), the solvent was evaporated. pꢀTyrosol 1 (0.24 g,
46.6%) was obtained after recrystallization from water with charꢀ
coal. M.p. 91—93 C. Found (%): C, 70.02; H, 7.26; O, 23.08.
C8H10O2. Calculated (%): C, 69.53; H, 7.31; O, 23.16. 1H NMR
(DMSOꢀd6), : 2.62 (t, 2 H, CH2, J = 7.8 Hz); 3.54 (t, 2 H,
CH2, J = 7.8 Hz); 4.57 (s, 1 H, OH); 6.68 (d, 2 H, Ar, J = 7.5 Hz);
7.01 (d, 2 H, Ar, J = 7.5 Hz); 9.11 (s, 1 H, OH). 13C NMR
(DMSOꢀd6), : 38.8; 63.1; 115.4; 129.9; 130.2; 156.0.
Elemental analysis of compounds was performed on
a FlashEATM 1112 elemental analyzer. NMR spectra of prodꢀ
ucts were recorded on a BrukerAvance III NanoBayꢀ400 spectroꢀ
meter. HPLC analysis of products was carried out using an Agiꢀ
lent 1200 liquid chromatograph.
2ꢀ(4ꢀNitrophenyl)ethyl nitrate (2a). A mixture of 98% nitric
acid (120 g) and water (8 mL) was cooled to –10 C. 2ꢀPhenyleꢀ
thanol (Acros) (12.2 g, 0.1 mol) was added in portions to the
nitration mixture, maintaining temperature below –10 C. After
the addition of 2ꢀphenylethanol was completed, the reaction
mixture was allowed to stand for 30 min at 0 C and poured into
water (300 mL). The organic phase was separated, the aqueous
layer was extracted with chloroform (2×30 mL). The extracts
were combined with the organic phase, the solvent was evapoꢀ
rated. The residue was cooled to –18 C for crystallization of 2a.
Compound 2a (8.9 g, 42%) was obtained after recrystallization
from isopropyl alcohol. M.p. 54—56 C. Found (%): C, 45.32;
H, 3.75; N, 13.30; O, 37.63. C8H8N2O5. Calculated (%): C, 45.28;
H, 3.81; N, 13.23; O, 37.70. 1H NMR (acetoneꢀd6), : 3.22
Studies of antihypertensive and hemorheological activity. Studies
of antihypertensive and hemorheological activity of 1 were carꢀ
ried out in the E. D. Gol´dberg Institute of Pharmacology and
Regenerative Medicine. The experiments were performed
on 24 200—250ꢀg spontaneously hypertensive rats obtained

2214
Russ.Chem.Bull., Int.Ed., Vol. 64, No. 9, September, 2015
Sysolyatin et al.
from the vivarium of the Institute of Bioorganic Chemistry of the
Russian Academy of Sciences (Pushchino). The tested substancꢀ
es were administered to rats intragastrically in a 1% starch mucus
daily during two weeks. The first group included the control
animals, which obtained 1% starch mucus, the second group
included animals, which obtained pꢀtyrosol 1 in the 50 mg kg–1
daily dose, in the third group were animals obtaining captopril in
the 20 mg kg–1 dose. Animals in the forth group were adminisꢀ
tered with a combination of pꢀtyrosol 1 (50 mg kg–1) and captoꢀ
pril (20 mg kg–1). The samples of blood for the studies of RBC
aggregation and deformability were taken under ether anesthesia
from the common carotid artery. As an anticoagulant was used
a 3.8% solution of sodium citrate in the 1 : 9 v/v ratio with blood.
Systolic and diastolic arterial pressure in awake rats was deꢀ
termined using an NIBP200A system of nonꢀinvasive blood presꢀ
sure measurement for small animals (Biopac Systems, Inc.,
USA). Data recording and processing were performed using an
AcqKnowledge 4.2 for MP150 computer program. Before the
start of the studies, the rats were several times placed in a holdꢀ
ing chamber to adapt them to the experimental procedures. Sysꢀ
tolic and diastolic arterial pressure was measured at a constant
ambient temperature (34 C), for which a special block for warmꢀ
ingꢀup the animals was used. Red blood cell aggregation and
deformability were determined on a RheoscanꢀAnD 300 analyzꢀ
er (Rheo Meditech. Inc., Republic of Korea). Red blood cell
aggregation activity was assessed under the stationary conditions
based on the aggregation index23 and under the flow conditions
based on the critical time.24 RBC deformability was assessed
using ektacytometry in the 7—20 Pa shear stress range. Elongaꢀ
tion index was used as the cell deformability parameter.25
6. D. Vasour, G. Corona, J. P. Spencer, Arch. Biochem. Bioꢀ
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This work was partially financially supported by the
Russian Science Foundation (Project No. 14ꢀ25ꢀ00017).
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Received April 15, 2015