Synthesis and X-ray analysis of 7-bromoarbidol, an impurity standard of arbidol

Article abstract of DOI:10.1002/jhet.625

For the first time, synthesis and X-ray analysis of 7-bromoarbidol hydrochloride is reported. The latter is a proven impurity of Arbidol which is an antiviral drug marketed in Russia and China.

Full text of DOI:10.1002/jhet.625

724
Synthesis and X-Ray Analysis of 7-Bromoarbidol, an Impurity
Standard of Arbidol
Vol 48
a
Zenta Tetere, Viktors Kumpiꢀns, Sergey Belyakov, Daina Zica¯ne,
b
a
ˇ a
and Ma¯ris Turksa*
aFaculty of Material Science and Applied Chemistry, Riga Technical University, Riga LV-1007,
Latvia
bLatvian Institute of Organic Synthesis, Riga LV-1006, Latvia
*E-mail: maris_turks@ktf.rtu.lv
Received June 10, 2010
DOI 10.1002/jhet.625
Published online 15 March 2011 in Wiley Online Library (wileyonlinelibrary.com).
For the first time, synthesis and X-ray analysis of 7-bromoarbidol hydrochloride is reported. The
latter is a proven impurity of Arbidol which is an antiviral drug marketed in Russia and China.
J. Heterocyclic Chem., 48, 724 (2011).
INTRODUCTION
virus, rhinovirus, coxsackie virus, and adenovirus [11–
13]. It has been marketed in Russia in 1993 and in
China in 2006 [12]. Further derivatives of arbidol have
been investigated as anti-hepatitis B drug-like substances
[14]. Earlier studies have shown also certain antimeta-
static effects of the latter [15].
The indole scaffold has proved to be very useful in
the terms of medicinal chemistry [1,2]. To name but a
few, indole derivatives are potent anti-HIV [3,4] and
antimicrobial agents [5], they also posses activity
against human cytomegalovirus [6]. On the other hand,
since the use of Tyrian purple (6,60-dibromoindigo), the
mankind has shown a certain interest in the use of bro-
moindole derivatives. Indeed, there is a plethora of natu-
rally occurring biologically active bromoindole deriva-
tives, most of them arising from differently brominated
tryptophans [7]. In the recent years, synthetic agent arbi-
dol (1) has emerged as a representative broad spectrum
antiviral medicament from the group of bromoindoles
(Fig. 1). According to one of the hypotheses it acts as
an interferon inducer [8], whereas other studies suggest
that it blocks viral fusion [9,10]. Regardless of the mode
of action arbidol is successfully used to treat viral infec-
tions caused by influenza A virus, respiratory syncytial
RESULTS AND DISCUSSIONS
The registration package of arbidol documents 7-bro-
moarbidol (2) (Fig. 1) as one of the main process-
derived impurities of pharmaceutically active ingredient
[16]. Correspondingly, the precise content of this impu-
rity has to be analyzed by appropriate impurity standard
which in this case consists of 7-bromoarbidol hydro-
chloride as the pharmaceutically active form of the
above mentioned drug is also a hydrochloride salt. To
the best of our knowledge, the synthesis of 7-bromoarbi-
dol or its hydrogen chloride salt has not been described.
C
V
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Synthesis and X-ray Analysis of 7-Bromoarbidol, an Impurity Standard of Arbidol
725
nOe effects of H-C(4) versus protons of 5-O-acetyl
group and methylene function of 3-ethoxycarbonyl moi-
ety. On the contrary, H-C(7) of 4c showed characteristic
nOe with H3C-N(1). It was found that a washing of the
crude reaction mixture containing all three indentified
products 4a–c (Table 1, entry 3) with ethyl acetate
increased the content of 4b up to 84%. Further crystalli-
zation of the mixture enriched with 4b from acetonitrile
gave an access to pure 4b in 28% isolated yield.
Figure 1. Structures of arbidol and 7-bromoarbidol.
With tribromide 4b in hand, we continued the synthesis
by the standard procedures described for the synthesis of
arbidol. To this end, an alkylation of thiophenol by 4b in
methanolic solution in the presence of potassium hydroxide
proceeded with concurrent deacetylation to provide 5 in an
excellent yield. The final step in the sequence involves
Mannich reaction. Different experimental procedures are
known to assemble the carbon skeleton of arbidol. One of
them uses the mixture of acetic acid, formaline, and dime-
thylamine [17]. However, this method resulted in the re-
covery of unchanged starting material when applied to the
7-bromoderivative 5. This fact can be explained by the
poor solubility of starting material 5 in the reaction me-
dium. It appeared that the best choice for the introduction
of the dimethylaminomethyl group is the use of formalde-
hyde bisdimethylaminoaminal [18]. The latter reacted with
5 in dioxane solution under reflux to provide 7-bromoarbi-
dol in the form of its free base 6 in 65% yield. The base 6
was transformed into its hydrogen chloride salt 2 by treat-
ing with acetone/hydrochloric acid mixture. The molecular
structure of final product 2 was unambiguously proved by
single crystal X-ray analysis. It is interesting to note that
the above mentioned crystals exist in the form of methanol
solvate. ORTEP [19] representation in Scheme 2 shows the
asymmetric unit of the crystal structure of salt 2 methanol
solvate. There is the intermolecular hydrogen bond system
in this structure. The amine hydrogen atom H25 takes part
in the bifurcated hydrogen bond of NHꢁꢁꢁO type with car-
bonyl and methanol oxygens (O20 and O1m). The parame-
Hence, we describe here for the first time the synthesis
and structural analysis of the main pharmaceutical impu-
rity of arbidol, 1-[6,7-dibromo-3-(ethoxycarbonyl)-5-
hydroxy-1-methyl-2-phenyl-thio-methyl)-1H-indol-4-yl]-
N,N-dimethylmethanaminium chloride (2).
The synthesis of 2 starts from indole derivative 3
which in its turn is obtained by standard Nenitzescu pro-
tocol combining benzoquinone and 3-methylamino-but-
2-enoic acid ethyl ester. The 5-hydroxy intermediate is
acetylated to give derivative 3. The latter is the key in-
termediate in the synthesis of arbidol (1) [17].
With indole derivative 3 in hand, we turned to elabo-
ration of bromination conditions (Scheme 1). Solvents
other than halogen-containing ones (e.g., AcOH) led to
complete degradation. On the other hand, dichlorome-
thane proved to be too low-boiling for the desired trans-
formation. Thus, bromination of 3 with 2.2 equivalents
of bromine in 1,2-dichloroethane at 75ꢀC for 2 h pro-
vided arbidol precursor 4a in 84% [conversion by high-
performance liquid chromatography (HPLC)] along with
overbrominated products 4b and 4c, both in 2% (conver-
sion by HPLC) (Table 1.; entry 1). First, we proceeded
to isolate the dibromo derivative 4a to brominate it fur-
ther by a step-wise protocol. This approach was not suc-
cessful because of low solubility of the above mentioned
material. Hence, the molar excess of bromine was
increased up to 3.3 and 4.2 equivalents, respectively
(Table 1; entries 2, 3, respectively). As a result, content
of the required tribromo derivative 4b in the reaction
mixture increased up to 39%. Further increase of excess
of bromine lead to formation of tetrabrominated prod-
ucts and increased level of degradation. The structure of
4b was distinguished from that of 4c by measurement of
˚
ters of this bond are N25ꢁꢁꢁO20 ¼ 2.739(3) A, H25ꢁꢁꢁO20
ꢀ
˚
¼ 2.17 A, N25–H25ꢁꢁꢁO20 ¼ 116 ; N25ꢁꢁꢁO1m ¼ 2.861(3)
ꢀ
˚
˚
A, H25ꢁꢁꢁO1m ¼ 2.06 A, and N25–H25ꢁꢁꢁO1m ¼ 140 .
Phenol hydrogen atom H28 forms the hydrogen bond with
˚
chlorine anion: O28ꢁꢁꢁCl31 ¼ 3.041(2) A, H28ꢁꢁꢁCl31 ¼
Scheme 1. Bromination of indole derivative 3.
Journal of Heterocyclic Chemistry
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Z. Tetere, V. Kumpiꢀns, S. Belyakov, D. Zica¯ne, and M. Turks
726
Vol 48
Table 1
light and/or I2 camera. HPLC conditions: column Merck
LiChrospher 60 RP-select 5 lm, 4 ꢂ 125 mm. Eluent A: 0.01
M KH2PO4 buffer solution with pH 4.60/MeOH ¼ 94/6. Elu-
ent B: MeOH. Gradient From 65% B to 95% B in 15 min.,
flow rate 1 mL/min., DAD detector: 220 nm.
Bromination of indole derivative 3.
Product distribution
(HPLC)
Reaction conditionsa
5-Acetoxy-6,7-dibromo-2-bromomethyl-1-methyl-1H-indole-
3-carboxylic acid ethyl ester (4b). A solution of Br2 (5.16 mL,
16 g, 100 mmol, 4.2 equiv.) in 1,2-dichloroethane (25 mL) was
added to a stirred suspension of 4a (6.73 g, 24.4 mmol, 4.1
equiv) in 1,2-dichloroethane (60 mL) within 4 h at reflux tem-
perature of solvent (ꢃ þ85ꢀC). The resulting reaction mixture
was heated at reflux for 0.5 h, cooled to ambient temperature
and solvent was evaporated under reduced pressure. The result-
ing solid material was suspended in EtOAc (100 mL) and fil-
tered. The filter cake was rinsed with MeOH (2 ꢂ 10 mL) and
dried in the air. Technical product 4b (HPLC purity 84%) was
obtained as a beige amorphous powder 4.50 g. The latter was
crystallized from MeCN (390 mL) yielding 4b (3.53 g, 28%)
with HPLC purity 96.7% (tR ¼ 8.00 min.). M.p. 223–224ꢀC.
1H-NMR (600 MHz, CDCl3): 7.95 (s, 1H, H-C(4)), 5.10 (bs,
2H, BrCH2-C(2)), 4.48 (q, 2H, 3J ¼ 7.0 Hz, CH3CH2OC(O)-
C(3)), 4.18 (s, 3H, H3C-N(1)), 2.37 (s, 3H, H3CCOO-C(5)), 1.43
(t, 3H, 3J ¼ 7.0 Hz, CH3CH2OC(O)-C(3)). 13C-NMR (150
MHz, CDCl3): 169.1, 163.9, 144.1, 143.9, 133.4, 127.4, 118.0,
115.3, 108.0, 106.1, 60.5, 33.7, 20.9, 20.8, 14.4. IR (KBr): 3075,
2985, 2940, 2900, 1755, 1690, 1550, 1530, 1460, 1445, 1415,
1375, 1320, 1285, 1245, 1205, 1180, 1135, 1100, 1065, 1020,
1010, 970, 935, 905. Anal. Calcd for C15H14Br3NO4 (511,99) C
35.19, H 2.76, N 2.74; Found C 35.31, H 2.76, N 2.59.
Entry
equiv. of Br2
time, h
4a:4b:4c:Xb
1
2
3
2.2
3.3
4.2
2
3
4
84%:2%:2%:12%
53%:23%:4%:20%
20%:39%c:14%:26%
a Reactions were carried out in ClCH2CH2Cl at 85ꢀC.
b Sum of unidentified bromination products.
c 28% isolated yield of 4b.
ꢀ
˚
2.00 A, O28–H28ꢁꢁꢁCl31 ¼ 176 . In turn, the chlorine
anion takes part in the hydrogen bond with the methanol
˚
molecule; the length of this bond is equal 3.039(2) A
ꢀ
˚
(H1mꢁꢁꢁCl31 ¼ 2.13 A, O1m–H1mꢁꢁꢁCl31 ¼ 152 ). In the
crystal structure these bonds form the net, which is parallel
to the crystallographic plane (100).
EXPERIMENTAL
General methods. Commercial reagents except bis-dime-
thylaminomethane were used without purification. The latter
was purified by fractional distillation (64. . .66ꢀC) under nitro-
gen atmosphere. Solvents were distilled before use. Column
chromatography was performed on silica gel (Rocc 0.040–
6,7-Dibromo-5-hydroxy-1-methyl-2-phenylsulfanylmethyl-
1H-indole-3-carboxylic acid ethyl ester 5. Thiophenol (0.60
mL, 5.85 mmol, 1.2 equiv.) was added to a stirred solution of
KOH (0.99 g, 83%, 14.7 mmol, 3.0 equiv.) in dry MeOH
˚
0.063 mm, 60 A). Thin-layer chromatography for reaction
monitoring: Merck silica gel 60 F254 plates; detection by UV
Scheme 2. Synthesis of 7-bromoarbidol (2).
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Synthesis and X-ray Analysis of 7-Bromoarbidol, an Impurity Standard of Arbidol
727
(30 mL) at þ20ꢀC. The resulting reaction mixture was stirred at
ambient temperature for 30 min. Then tribromide 4b (2.50 g,
4.88 mmol, 1.0 equiv.) as a solid substance was added at once to
a stirred solution of potassium phenylthiolate at 15ꢀC. The
resulting suspension was stirred at ambient temperature for 3 h.
The undissolved material consisting mainly of KBr was filtered
off, and the clear filtrate was mixed with a solution of glacial
acetic acid (1.5 mL) in water (6.0 mL). The resulting suspension
was stirred for 20 min. and filtered. The filter cake was washed
successively with water (40 mL) and hexanes (10 mL) and dried
under reduced pressure at þ50ꢀC. The crude product (2.35 g)
was dissolved in a refluxing mixture of ethanol (250 mL) and
CHCl3 (250 mL), filtered and evaporated under reduced pressure
until resting volume of 150 mL. After 14 h at ambient tempera-
ture it was filtered, washed on the filter with MeOH (2 ꢂ 5 mL),
and dried in the air. Yield 2.10 g, 86% with HPLC purity 97.0%
(tR ¼ 8.35 min). M.p. 225–226ꢀC.
(0.10 mL) at þ40ꢀC. The resulting suspension was left to
reach ambient temperature and stirred for 1 h. Then it was
evaporated under reduced pressure to provide quantitative
yield (53 mg) of pure hydrochloride salt 2. The latter was dis-
solved in a three component mixture (0.5 mL) consisting of
acetone:methanol:aq. conc. HCl in the ratio 15:2:0.16 at
þ40ꢀC. After two days at þ4ꢀC, the resulting crystals were
removed by filtration. Yield of X-ray quality crystals 31 mg,
55% (in the form of methanol solvate); HPLC purity 99.8%
(tR ¼ 7.35 min). M.p. 169ꢀC (DSC studies).
1H-NMR (300 MHz, DMSOd6): 9.79 (bs, 1H, HO-C(5)),
9.32 (bs, 1H, HN-CH2-C(4)), 7.39-7.27 (m, 5H, H-C(Ph)),
4.80 (s, 2H, (CH3)2N-CH2-C(4)), 4.73 (s, 2H, S-CH2-C(2)),
4.20 (q, 2H, 3J ¼ 7.0 Hz, CH3CH2OC(O)-C(3)), 4.04 (s, 3H,
H3C-N(1)), 3.19 (s, 3H, CH3OH), 2.71 (s, 6H, (CH3)2N-CH2-
C(4)), 1.23 (t, 3H, 3J ¼ 7.0 Hz, CH3CH2OC(O)-C(3)). 13C-
NMR (75.5 MHz, DMSOd6): 165.0, 149.6, 145.4, 134.1,
131.3, 130.7, 129.2, 127.6, 127.1, 116.5, 110.6, 109.7, 106.4,
70.0, 52.8, 48.7 (CH3OH) 42.4, 34.9, 29.7, 13.9. IR (KBr):
3385, 3060, 2960, 2930, 2835, 1700, 1580, 1550, 1480, 1410,
1380, 1330, 1225, 1165, 1130, 1100, 1035, 965. Anal. Calcd
for C22H25Br2ClN2O3SꢁCH3OH (624.81) C 44.21, H 4.68, N
4.48, S 5.13; Found C 44.44, H 4.70, N 4.42, S 5.51.
1H-NMR (300 MHz, DMSOd6): 10.25 (s, 1H, HO-C(5)),
7.66 (s, 1H, H-C(4)), 7.38-7.25 (m, 5H, H-C(Ph)), 4.76 (s, 2H,
SCH2-C(2)), 4.16 (q, 2H, 3J ¼ 7.2 Hz, CH3CH2OC(O)-C(3)),
3.96 (s, 3H, H3C-N(1)), 1.27 (t, 3H, 3J
¼
7.2 Hz,
CH3CH2OC(O)-C(3)). 13C-NMR (75.5 MHz, DMSOd6): 163.6,
150.3, 145.1, 134.0, 131.1, 129.0, 128.9, 128.0, 127.3, 112.0,
107.0, 105.2, 103.6, 59.5, 33.7, 28.4, 14.2. IR (KBr): 3240,
2990, 1640, 1610, 1523, 1470, 1415, 1390, 1340, 1295, 1250,
1230, 1200, 1140, 1100, 1070, 1025, 975, 930, 895. Anal.
Calcd for C19H17Br2NO3S (499.22) C 45.71, H 3.43, N 2.81, S
6.42 Found C 45.74, H 3.38, N 2.75, S 6.63.
X-ray diffraction analysis. Diffraction data were collected
at ꢄ100ꢀC on a Nonius KappaCCD diffractometer using
˚
graphite monochromated Mo-Ka radiation (k ¼ 0.71073 A).
The crystal structure was solved by direct methods and refined
by full-matrix least squares. Crystal data: monoclinic; a ¼
6,7-Dibromo-4-dimethylaminomethyl-5-hydroxy-1-methyl-
2-phenylsulfanyl-methyl-1H-indole-3-carboxylic acid ethyl
ester 6. Bis-dimethylaminomethane (0.5 mL, 3.67 mmol, 7.06
equiv.) was added to a sealable pressure flask containing sus-
pension of compound 5 (0.25 g, 0.52 mmol, 1.0 equiv.) in abs.
dioxane (6 mL). The resulting reaction mixture was sealed and
then it was stirred under reflux (bath temperature 105ꢀC) for 2
h. At the temperature of reflux, the reaction mixture became
clear. Then, it was cooled to ambient temperature and poured
onto crashed ice (50 g). The resulting yellowish precipitate
was filtered and dried in the air. The crude product 2 (0.21 g,
HPLC purity 89%) was purified by silica gel (8 g) column
chromatography using gradient elution by CHCl3 ! CHCl3/
THF (95/5). Fractions containing product were combined and
evaporated to dryness. The solid residue was reprecipitated
from MeOH/water system. Yield: 0.19 g, 65%; HPLC purity:
98.5% (tR ¼ 7.40 min.). M.p. 131–132ꢀC, Rf ¼ 0.33 (CHCl3/
THF ¼ 8/2).
˚
7.5220(2), b ¼ 11.4594(5), c ¼ 15.6335(4) A, a ¼ 72.287(2),
3
ꢀ
˚
b ¼ 84.821(2), c ¼ 79.128(1) ; V ¼ 1259.86(7) A , Z ¼ 2, l
¼ 3.439 mmꢄ1; space group is P1. The final R-factor is 0.038.
For further details, see crystallographic data deposited with the
Cambridge crystallographic data centre as supplementary pub-
lication number CCDC-780284. Copies of the data can be
obtained, free of charge, on application to CCDC, 12 Union
Road, Cambridge CB2 1EZ, UK.
Acknowledgments. Authors thank JSC Grindeks for donation of
ˇ
chemicals and Professor E. Liepiꢀns for valuable comments.
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Vol 48
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet