Synthesis and physicochemical properties of 8-bromo-7-[2-hydroxy-3-(4-tert- butyl)phenoxypropyl-1]-3-methylxanthine derivatives

Article abstract of DOI:10.1007/s10600-014-0998-5

A simple preparative synthetic method for previously undescribed 8-bromo-7-[2-hydroxy-3-(4-tertbutyl) phenoxypropyl-1]-3-methylxanthine derivatives, potential biologically active compounds and convenient synthons for further synthetic investigations, was developed. The spectral properties of the synthesized compounds were studied.

Full text of DOI:10.1007/s10600-014-0998-5

Chemistry of Natural Compounds, Vol. 50, No. 3, July, 2014 [Russian original No. 3, May–June, 2014]
SYNTHESIS AND PHYSICOCHEMICAL PROPERTIES OF
8-BROMO-7-[2-HYDROXY-3-(4-tert-BUTYL)PHENOXYPROPYL-1]
-3-METHYLXANTHINE DERIVATIVES
1*
2
1
N. I. Romanenko, M. V. Nazarenko, D. G. Ivanchenko,
1
1
A. Yu. Cherchesova, and E. V. Aleksandrova
A simple preparative synthetic method for previously undescribed 8-bromo-7-[2-hydroxy-3-(4-tert-
butyl)phenoxypropyl-1]-3-methylxanthine derivatives, potential biologically active compounds and convenient
synthons for further synthetic investigations, was developed. The spectral properties of the synthesized
compounds were studied.
Keywords: xanthine, synthesis, PMR spectroscopy.
The development of natural products chemistry is directly related to the search for biologically active compounds, on
the basis of which many new drugs with various pharmacological activities can be discovered. In this respect, xanthine
derivatives are extremely interesting because they occur in various plants and animals. Therefore, their metabolism has been
elaborated during the course of evolution. Mankind has used drinks such as tea, coffee, and cocoa throughout history.
The principal active principles of these are xanthine alkaloids (caffeine, theophylline, theobromine). Both natural and synthetic
xanthine derivatives are used as drugs in medical practice [1–3].
H C
3
CH
3
CH
3
O
21
H C
22
3
N
21
H C
CH
3
22
OH
3
CH
CH
3
3
NH
R
23
17
CH
3
3, 4
15
23
17
15
13
3: R = NH
4: R = CH
11
2
3
O
19
O
13
7
N
11
1
HN
7
NH
19
O
5
7
N
OH
OH
3
24
N
O
N
N
Br
Br
9
X
2
27
CH
3
26
1
5, 6
10
21
H C
22
21
H C
5: X = CH
6: X = O
3
22
2
CH
3
3
CH
3
CH
3
CH
23
3
17
15
23
17
15
13
O
11
13
19
O
7
N
11
19
4
O
7
N
5
HN
N
3
OH
1
OH
8
N
11
13
O
S
O
N
O
7
18
10
NH
24
CH
O
3
CH
3
O
24
19
25
9
17
15
25
CH
3
OH
CH
OH
3
7
9
8
20
Scheme 1
1) Zaporozhe State Medical University, Ukraine, 69035, Zaporozhe, Prosp. Mayakovskogo, 26; 2) S. I. Georgievskii
Crimea State Medical University, Russia, 95006, Simferopolꢀ, Bulꢀvar Lenina, 5/7, e-mail: ivanchenkodima@yandex.ru.
Translated from Khimiya Prirodnykh Soedinenii, No. 3, May–June, 2014, pp. 442–444. Original article submitted March 6,
2014.
©
0009-3130/14/5003-0511 2014 Springer Science+Business Media New York
511

TABLE 1. PMR Spectra of Synthesized 2–9 (ꢁ, ppm)
NÍ
(1Í, s)
ÎÍ
(1Í, d)
N7ÑÍ2ÑÍÑÍ2
(5Í, m)
Í3-10
(3Í, s)
3Í-21–23
(9Í, s)
Compound
Íarom. (2Í, d)
Others
11.24
7.25 (Í-15, 19);
6.80 (Í-16, 18)
7.25 (Í-15, 19);
6.77 (Í-16, 18)
7.25 (Í-15, 19);
6.78 (3Í, m, Í-16,
18 + NH)
5.47
5.42
5.42
4.42–3.89
(Í-11–13)
4.40–3.80 (7Í, m,
Í-11–13 + NH2)
4.20–3.80
3.30
3.30
3.28
1.23
1.25
1.22
2
3
4
10.68;
7.90
10.59
2.87 (3Í, d, Í-24)
(Í-11–13)
10.87
10.93
7.25 (Í-15, 19);
6.78 (Í-16, 18)
5.42
5.44
4.40 (1Í, m, Í-12);
4.11 (2Í, d, Í-11);
3.85 (2Í, d, Í-13)
3.29
3.29
1.22
1.22
3.25 (2Í, m, Í-24);
3.02 (2Í, m, Í-27);
1.56 (6Í, m, Í-25,
26, 28)
3.64 (4Í, m, Í-24, 27);
3.31 (2Í, m, Í-25);
3.05 (2Í, m, Í-26)
4.03 (2Í, s, Í-24)
5
6
7.24 (Í-15, 19);
6.78 (Í-16, 18)
4.40 (1Í, m, Í-12);
4.15 (2Í, d, Í-11);
3.89 (2Í, d, Í-13)
11.09
10.66
7.26 (Í-15, 19);
6.80 (Í-16, 18)
7.26 (3Í, d, Í-15,
19 + Ñ8NH);
13.1 (1Í, br.s); 4.40–3.84 (Í-11–13)
5.44
3.30
3.23
1.20
1.20
7
8
5.50
4.25–3.80
(7Í, m, Í-11–13, 24)
6.80 (Í-16, 18)
7.25 (Í-15, 19);
6.85 (Í-16, 18)
11.00
–
5.80 (1Í, m, Í-2);
4.52–4.12
(4Í, m, Í-3, 10)
3.28
1.21
9
We developed methods for synthesizing previously undescribed 7-(2-hydroxypropyl-1)xanthine derivatives, studied
their physicochemical properties, and assessed the potential for further discovery of new biologically active compounds in this
series in order to continue our research [4–6] taking into account the results of others [7–9].
Thus, the reaction of 8-bromo-3-methylxanthine (1) [10] with 4-tert-butylphenoxymethyloxirane in propanol-1 in
the presence of Et N synthesized 8-bromo-7-[2-hydroxy-3-(4-tert-butyl)phenoxypropyl-1]-3-methylxanthine (2) (Scheme 1).
3
The presence of the Br atom in 2 enabled xanthine to be extensively modified by introducing various substituents in
the 8-position. Heating 2 with an excess of hydrazine, methylamine, or secondary heterocyclic amines in aqueous dioxane
formed the corresponding 8-hydrazino- (3) and amino-substituted (4–6) 7-[2-hydroxy-3-(4-tert-butyl)phenoxypropyl-1]-
3-methylxanthine derivatives. Reaction of 2 with sodium thioglycolate or glycine also occurred in aqueous dioxane. This
reaction was possible in the presence of NaHCO (NaOH can be used) in analogy with the literature [11] in order to increase
3
the nucleophilicity of the S and N atoms and to destroy the glycine betaine (Scheme 1). Refluxing 2 with an excess of Et N in
3
dioxane caused intramolecular cyclization into 8-methyl-2-(4-tert-butylphenoxymethyl)-2,3-dihydro-1,3-oxazolo[2,3-f]xanthine
(9), a heterocyclic system for which the chemical and biological properties are practically unstudied.
PMR spectroscopy (Table 1) proved unambiguously the structures of synthesized 2–9. The presence of the substituent
in the 7-position in the spectrum of starting 2 was confirmed by two doublets for aromatic protons at 7.25 and 6.8 ppm.
The tert-butyl protons were found at strong field as a strong singlet at 1.23 ppm (9H); the propyl methylene and methine
protons, as a multiplet at 4.42–3.89 ppm (5H). This was due to the chiral C atom. The alcohol proton resonated as a doublet
at 5.47 ppm (1H). The uracil part of 2 was characterized by two singlets at 11.24 (1H) and 3.30 ppm (3H) that were due to
resonance of the NH– and CH – groups, respectively. Practically analogous uracil proton resonances of the molecule and
3
substituent in the 7-position were found in PMR spectra of other 8-substituted xanthines (3–8) (Table 1). The PMR spectrum
of the 8-hydrazino derivative (3) showed the C NH proton as a singlet at 7.9 ppm (1H). The amine protons were found in
8
the region of the propyl resonance. The PMR spectrum of 8-methylaminoxanthine (4) had the NH proton resonance at
6.78 ppm. It was overlapped by the aromatic proton resonances. The methyl protons formed a doublet at 2.87 ppm (3H).
The PMR spectrum of thioacid (7) exhibited methylene proton resonances at 4.03 ppm (2H). The hydroxyl protons of
the alcohol and carboxylic groups were recorded as weak broad singlets at 13.0 and 5.44 ppm because of rapid exchange.
The PMR spectrum of the amino acid (8) contained glycine methylene proton resonances in the region of the propyl proton
resonances at 4.25–3.8 ppm (7H). The proton of the secondary amine in the 8-position resonated at 7.26 ppm. The OH and
COOH protons were not detected in the spectrum of 8 because of exchange processes. The PMR spectrum of oxazolinoxanthine
(9) showed the methine proton in the 2-position as a multiplet at 5.8 ppm (1H). The methylene protons formed a 4H multiplet in
the range 4.52–4.12 ppm. Proton resonances of other groups fully confirmed the structures of the synthesized compounds (Table 1).
512

TABLE 2. Physicochemical Properties of Synthesized 2–9
Compound
Empirical formula
Yield, %
Compound
Empirical formula
Yield, %
mp, ꢂÑ
mp, ꢂÑ
214–215
236–237
181–182
185–186
C19H23BrN4O4
C19H26N6O4
C20H27N5O4
C24H33N5O4
61.1
97.5
90.0
78.0
201–202
193–194
209–210
279–280
C23H31N5O5
C21H26N4O6S
C21H27N5O6
C19H22N4O4
74.6
82.6
92.3
67.8
2
3
4
5
6
7
8
9
Practically all synthesized compounds could be used as synthons for further structural modifications of the uracil part
and also to prepare various functionalized derivatives of substituents in the 8-position.
EXPERIMENTAL
Melting points were determined in open capillaries on a PTP apparatus (M). Elemental analyses were performed on
an Elementar Vario L cube instrument. NMR spectra were recorded in DMSO-d with TMS internal standard on a Bruker SF-400
6
spectrometer (operating frequency 400 MHz). Mass spectra were recorded on a Varian 1200L instrument with electron-
impact ionization (70 eV) and direct sample introduction. Analytical data of all compounds agreed with those calculated.
Tables 1 and 2 present the physicochemical properties of the synthesized compounds.
Synthesis of 8-Bromo-7-[2-hydroxy-3-(4-tert-butyl)phenoxypropyl-1]-3-methylxanthine (2). A suspension of 1
(49.0 g, 0.2 mol), epoxide (49.4 g, 0.24 mol), and Et N (3 mL) in propanol-1 (150 mL) was refluxed for 3 h and filtered hot.
3
The filtrate was cooled, diluted to 1 L with H O, left for 24 h, and treated with NH OH (5 mL, 25%). The precipitate was
2
4
filtered off, washed well with H O and propanol-2 (50%), and crystallized from aqueous dioxane.
2
Synthesis of 8-Hydrazino-7-[2-hydroxy-3-(4-tert-butyl)phenoxypropyl-1]-3-methylxanthine (3). A mixture of
2 (4.5 g, 0.01 mol), hydrazine hydrate (5 mL, 0.1 mol), H O (30 mL), and dioxane (30 mL) was heated to boiling and rapidly
2
formed a solution. A voluminous precipitate formed 5 min after the start of boiling. Boiling was continued for 30 min. The
solution was cooled. The precipitate was filtered off, washed with H O, and crystallized from aqueous dioxane.
2
Synthesis of 7-[2-Hydroxy-3-(4-tert-butyl)phenoxypropyl-1]-3-methyl-8-methylaminoxanthine (4). A solution
of 2 (2.25 g, 5 mmol) and methylamine (10 mL, 40%) in H O (10 mL) and dioxane (20 mL) was refluxed for 1.5 h and filtered
2
hot. The filtrate was cooled and treated with H O (50 mL). The precipitate was filtered off, washed with H O, and crystallized
2
2
from aqueous dioxane.
8-Aminoxanthines 5 and 6 were synthesized analogously.
Synthesis of 7-[2-Hydroxy-3-(4-tert-butyl)phenoxypropyl-1]-3-methylxanthinyl-8-thioaceticAcid (7). Asolution
of 2 (4.5 g, 0.01 mol), sodium thioglycolate (2.28 g, 0.02 mol), and NaHCO (1.68 g, 0.02 mol) in H O (30 mL) and dioxane
3
2
(40 mL) was refluxed for 3 h, cooled, treated with H O (100 mL), left for 24 h, and filtered. The filtrate was treated with conc.
2
HCl to pH 2. The precipitate of the acid was filtered off, washed with H O, and purified by reprecipitation from aqueous
2
NaHCO solution.
3
Synthesis of 7-[2-Hydroxy-3-(4-tert-butyl)phenoxypropyl-1]-3-methylxanthinyl-8-aminoacetic Acid (8).
A solution of 2 (2.25 g, 5 mmol), glycine (1.13 g, 15 mmol), and NaHCO (1.26 g, 15 mmol) in H O (20 mL) and dioxane
3
2
(15 mL) was refluxed for 2 h, cooled, diluted with H O to 100 mL, and filtered. The filtrate was acidified with conc. HCl to
2
pH 2. The precipitate was filtered off, washed with H O, and purified by reprecipitation from aqueous NaHCO solution.
2
3
Synthesis of 8-Methyl-2-(4-tert-butylphenoxymethyl)-2,3-dihydro-1,3-oxazolo[2,3-f]xanthine (9). A solution of
2 (4.5 g, 0.01 mol) and Et N (5 mL) in dioxane (40 mL) was refluxed for 3 h and cooled. The precipitate of trimethylammonium
3
bromide was filtered off. The filtrate was diluted with H O to 100 mL. The precipitate of 9 was filtered off, washed with H O,
2
2
and crystallized from aqueous dioxane.
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