Synthesis and characterization of one impurity in esomeprazole, an antiulcerative drug

Article abstract of DOI:10.1007/s11696-019-00918-3

During drug synthesis, control of impurities is very important to get high-qualified drugs. A number of studies have devoted to synthesize the impurities and study the structures to support the method of purification. In this paper, we first synthesize one impurity in esomeprazole, rel-2-[[(3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-6-methoxy-1H-benzimidazole, with readily available raw materials, simple operation procedures and relatively mild reaction. Besides, we characterized its structure by MS, IR, ¹H-NMR and HPLC analyses. The purity of target compound is as high as 99.58%, which can be used as the reference substance of the impurities of esomeprazole.

Full text of DOI:10.1007/s11696-019-00918-3

Chemical Papers
https://doi.org/10.1007/s11696-019-00918-3
ORIGINAL PAPER
Synthesis and characterization of one impurity in esomeprazole,
an antiulcerative drug
Zhen‑Tao Liu1 · Xia Meng1 · Shi‑Min Fang1 · Li‑Zhen Wang2 · Zhen‑Zheng Wang1 · Geng Yang1 ·
Hong‑Dong Duan1 · Ai‑You Hao3
Received: 18 January 2019 / Accepted: 28 August 2019
© Institute of Chemistry, Slovak Academy of Sciences 2019
Abstract
During drug synthesis, control of impurities is very important to get high-qualifed drugs. A number of studies have devoted
to synthesize the impurities and study the structures to support the method of purifcation. In this paper, we frst synthesize
one impurity in esomeprazole, rel-2-[[(3,5-dimethyl-2-pyridinyl)methyl]sulfnyl]-6-methoxy-1H-benzimidazole, with readily
available raw materials, simple operation procedures and relatively mild reaction. Besides, we characterized its structure by
MS, IR, 1H-NMR and HPLC analyses. The purity of target compound is as high as 99.58%, which can be used as the refer-
ence substance of the impurities of esomeprazole.
Keywords Characterization · Esomeprazole · Impurity · Synthesis
Introduction
Romano 2012). Additionally, esomeprazole can cure pep-
tic ulcer rapidly by inhibiting the secretion of gastric acid
(Sugano et al., 2012) and efectively scavenging Helicobac-
ter pylori (Cheng et al. 2014).
Esomeprazole, the S-isomer of omeprazole (Vakil et al.
2001), is the frst single optical isomer proton pump inhibi-
tor in the clinics (Thitiphuree and Talley 2000). Esome-
prazole is a weak alkaline wall cell proton pump H/K-ATP
enzyme-specifc and non-competitive inhibitor (Andersson
et al. 2001), which acts on gastric parietal cells to prevent
gastric acid formation and reduce gastric acid secretion by
inhibiting H/K- activity (Tonini et al. 2001). At present,
esomeprazole is widely used to treat gastro-oesophageal
refux diseases (Sugimoto and Furuta 2012) and other acid-
related diseases (Tang and Wu 2013), due to its strong acid
inhibition, high specifcity and long duration (Cardile and
Because of the limitation of production technology, some
impurities are extremely difcult to be completely removed
(Manimaran and Stahly 1993), which will afect the stabil-
ity and efcacy of the drug or even hurt the health with-
out therapeutic efects (Stawny et al. 2016). As for esome-
prazole, always containing many impurities, the control
requirements for impurities are very strict (Reddy 2013). Of
note, we are interested in one specifc impurity, 5-methoxy-
2-[(3,5-dimethylpyridin-2-yl)methylsulfnyl]-1H-benzimida-
zole (compound 1), which has a similar chemical structure
with esomeprazole and is hard to be removed thoroughly.
Therefore, this article aimed at developing efcient synthe-
sis process of this impurity, and laying a foundation for the
detection and control of esomeprazole impurities. The main
synthetic routes are as follows (Fig. 1).
Electronic supplementary material The online version of this
article (https://doi.org/10.1007/s11696-019-00918-3) contains
supplementary material, which is available to authorized users.
* Hong-Dong Duan
hdduan67@163.com
1
School of Chemistry and Pharmaceutical Engineering, Qilu
Experimental
University of Technology (Shandong Academy of Sciences),
Jinan 250353, China
All reagents and solvents were purchased from common
commercial suppliers and were used without further purif-
cation. The melting point was measured by micro-melting
point meter WRS-2. The IR spectra were recorded on a
2
Biology Institute, Qilu University of Technology (Shandong
Academy of Sciences), Jinan 250014, China
3
School of Chemistry and Chemical Engineering, Shandong
University, Jinan 250012, China
Vol.:(0123456789)
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Fig. 1 The synthetic route of compound 1
TENSOR-IR spectrometer. The NMR spectra were recorded
in CDCl3 solution or DMSO solution on an AVANCE II
400 MHz. Agilent 1260 was used to determine product
purity. High-resolution mass spectrometry is obtained by
MTQ III q-TOF.
Synthesis
of 5‑methoxy‑2‑[(3,5‑dimethylpyridin‑2‑yl)
methylsulfnyl]‑1H‑benzimidazole (compound 1)
2,3,5-Trimethylpyridine (6.06 g, 0.050 mol) was added into
acetic acid solution (14.0 mL), and the mixture was stirred
and mixed evenly, heated to 98–100 ℃. Then hydrogen per-
oxide (9.70 g, 30%) was slowly dropped into the solution,
after which, the reaction mixture was heated and refuxed
for 1.0 h, and the reaction progress was detected by TLC
(ethyl acetate as unfolding agent). After the reaction, the
reaction solution was concentrated. The mixture was evap-
orated under reduced pressure to remove acetic acid until
no liquid is vaporized. Subsequently, H2O (10.0 mL) and
dichloromethane (15.0 mL) were added to concentrated
solution and then the pH of the solution was adjusted to
9.0 with sodium hydroxide solution. The water layer was
extracted with dichloromethane (2×25.0 mL); the organic
layers were combined and dried over anhydrous magne-
sium sulfate, fltered, and concentrated in vacuo to aford
2,3,5-trimethylpyridine-N-oxide (compound 2) as a white
solid at 81% yield (5.58 g). m.p.: 42.4–43.8 ℃, IR (KBr):
3949.1, 2831.5, 1625.9, 949.0 (Fig. 2), 1H NMR (400 MHz,
CDCl3) δ 8.02 (s, 1H), 6.88 (s, 1H), 2.47 (s, 3H), 2.29 (s,
3H), 2.23 (s, 3H) (Fig. 3). [1H NMR (400 MHz, CDCl3):
d=8.21 (s, H), 7.16 (s, H), 2.53 (s, 3H), 2.38 (s, 3H), 2.32
(s, 3H)] (Getter et al. 2015).
Fig. 2 FT-IR of compound 2
to 70.0–75.0℃ . TLC (unfolding agent—ethyl
acetate:ethanol = 2:1) was used to detect the completion
of the reaction. After the reaction, the reaction solution
was concentrated. Then the product was dissolved with
methanol (35.0 mL), and the sodium hydroxide (20.0 ml,
2.20 g of sodium hydroxide) solution was added to the
solution. The reaction mixture was refuxed. TLC (unfold-
ing agent—ethyl acetate:ethanol = 2:1) was used to detect
the completion of the reaction. After the TLC detection
reaction is completed and concentrated, dichloromethane
is added to separate the liquid. The organic layers were
combined and dried over anhydrous magnesium sulfate,
fltered, concentrated in vacuum to aford 3,5-dimethyl-
2-hydroxymethylpyridine (compound 3) as a yellow
sticky liquid. IR(KBr): 3394.7, 2922.1, 1573.9 (Fig. 4),
1H NMR (400 MHz, CDCl3) δ 8.22 (s, 1H), 7.29 (s, 1H),
4.65 (s, 2H), 2.31 (s, 3H), 2.18 (s, 3H) (Fig. 5). [1H NMR
Compound 2 (1.37 g, 0.010 mol) was added to ace-
tic anhydride (12.0 mL); the mixture was heated
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Fig. 3 1H NMR of compound 2
2-chloromethyl-3,5-dimethylpyridine hydrochloride (com-
pound 4) as a yellow solid at 45% overall yield (0.70 g).
m.p.: 106.0–106.6℃, IR (KBr): 2996.2, 1621.5, 675.1
(Fig. 6), 1H NMR (400 MHz, CDCl3) δ 8.40 (s, 1H), 8.02
(s, 1H), 5.15 (s, 2H), 2.62 (s, 3H), 2.55 (s, 3H) (Fig. 7). 13
C
NMR (101 MHz, DMSO) δ 147.75 (s), 146.86 (s), 140.05
(s), 137.81 (s), 136.88 (s), 17.95 (s), 17.15 (s) (Fig. 8). m/z
[M+H]+ calcd for: C8H10ClN: 156.0580, found: 156.0581
(Fig. 9).
Compound 4 (2.88 g, 0.015 mol) and 2-mercapto-5-meth-
oxy benzimidazole (2.70 g, 0.015 mol) were dissolved in
methanol solution (18.0 mL), then the sodium hydrox-
ide solution (10.00 g, 2.50 g of sodium hydroxide) was
dropped to mixture, and the reaction mixture was heated
to 55.0–60.0 ℃. Detection of reaction progress by TLC
(unfolding agent—dichloromethane:ethyl acetate = 2:1).
After the reaction is completed, the white solid impurities
are removed by fltration. Concentrate the fltrate until no
liquid is removed. Then dichloromethane (15.0 mL) and
H2O (15.0 mL) were added, the pH value was adjusted
to 7 with acetic acid (15%). The mixture was stirred for
10 min and then extracted with dichloromethane and water.
The dichloromethane (25.0 mL) was added to the aqueous
phase, and the organic phase was merged after two extrac-
tions, the organic layers were dried over anhydrous mag-
nesium sulfate, fltered, concentrated in vacuum to aford
2-[(3, 5-dimethyl-2-pyridinyl) methylthio)]-5-methoxy-
1H-benzimidazole (compound 5) as a white solid (3.90 g,
yield 87%): m.p.: 53.7–59.5 ℃, IR (KBr): 3949.1, 2831.5,
Fig. 4 FT-IR of compound 3
(400 MHz,CDCl3): d = 8.12 (s, H), 7.20 (s, H), 4.57 (s,
2H), 2.22 (s, 3H), 2.11 (s, 3H)] (Getter et al. 2015).
Compound 3 from the previous step was diluted by
dichloromethane (20.0 mL), the solution was cooled to −5
to 0 ℃. Then SOCl2 (4.0 mL) which was diluted by dichlo-
romethane was dropped into the mixture solution. After the
drop was fnished, the reaction is held for 1 h and quenched
by isopropanol. The dichloromethane was removed by the
rotary evaporator until no liquid is distilled out, and the
residual liquid turned into brown sticky grease. Then the
acetonitrile was used to remove the liquid again by a rotary
evaporator, and fnally the yellow solid was obtained. The
resulting residue was recrystallized in toluene to aford
1
1625.9, 949.0 (Fig. 10), H NMR (400 MHz, DMSO) δ
12.48 (s, 1H), 8.20 (s, 1H), 7.43 (d, J=8.7 Hz, 1H), 7.11 (d,
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Fig. 5 1H NMR of compound 3
were detected with potassium iodide–starch test paper, and
then 20.0 mL distilled water was added into the solution.
Then the pH value of the solution was adjusted to 7 with
potassium carbonate solution. The mixture was stirred for
10 min and then the liquid was separated. The dichlorometh-
ane layer was extracted with water (2×25.0 mL). Then the
organic layers were combined with being dried over anhy-
drous magnesium sulfate and fltered. The dichloromethane
in the fltrate is removed by a rotary evaporator. After 5–7 h
at −5 to 0 ℃, the crude product is recrystallized by metha-
nol (5–8 mL) to get 2-(3,5-dimethyl-2-pyridinyl)methyl-
sulfnyl-5-methoxy-1H-benzimidazole (compound 1) as a
white solid in (2.61 g, yield 83%): m.p.: 166.1–166.5 ℃, IR
(KBr): 2989.6, 1625.9, 964.4 (Fig. 14), 1H NMR (400 MHz,
DMSO) δ 13.45 (s, 1H), 8.19 (s, 1H), 7.55 (d, J =7.8 Hz,
1H), 7.45 (s, 1H), 7.09 (s, 1H), 6.96–6.86 (m, 1H), 4.75 (d,
J = 12.0 Hz, 1H), 4.67 (d, J = 12.0 Hz, 1H), 3.81 (s, 3H),
2.28 (s, 3H), 2.25 (s, 3H) (Fig. 15), m/z [M+H]+ calcd for:
C16H17N3O2S: 316.1120, found: 316.1107 (Fig. 16). 13C
NMR (101 MHz, DMSO) δ 147.60 (s), 147.36 (s), 139.04
(s), 133.32 (s), 132.81 (s), 60.21 (s), 55.98 (s), 18.56 (s),
17.90 (s) (Fig. 17).
Fig. 6 FT-IR of compound 4
J=1.8 Hz, 1H), 6.92 (d, J=2.1 Hz, 1H), 6.78 (t, J=6.3 Hz,
1H), 4.68 (s, 1H), 4.65 (s, 1H), 3.80 (s, 3H), 2.38 (s, 3H),
2.28 (s, 3H) (Figure 11). 13C NMR (101 MHz, DMSO) δ
151.89 (s), 147.09 (s), 139.01 (s), 132.46 (s), 131.51 (s),
56.52 (s), 55.91 (s), 36.59 (s), 18.36 (s), 17.86 (s) (Fig. 12),
m/z [M + H]+ calcd for: C16H17N3OS: 300.1171, found:
300.1172 (Fig. 13).
Results and discussion
3-Chloroperoxybenzoic acid, diluted by dichloromethane,
was dropped into a mixture of dichloromethane (20.0 mL)
and compound 5 (2.99 g, 0.010 mol) under low tempera-
ture (− 5 to 0 ℃). The reaction process was monitored by
TLC (unfolding agent—dichloromethane:methyl tert butyl
ether = 2:1). When the reaction is almost complete, stop
dropping m-chloroperoxybenzoic acid. Peroxides in solution
The synthesis of compound 2 and 3 mainly refers to the
work of Tamar Gatter et al. Compound 3 was synthesized
using the Boekelheide rearrangement (Boekelheide and Linn
1954). And a modifcation of the procedure reported has
been carried out as per Ellervik and Magnusson (2010). We
made some modifcations by their experiments.
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Fig. 7 1H NMR of compound 4
Fig. 8 13C NMR of compound 4
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Fig. 9 Mass spectrometry of
compound 4
compound 2 was prepared by adding hydrogen peroxide at
one time, and the yield was 57%. In this paper, the method of
dropping hydrogen peroxide can not only shorten the reac-
tion time, but also increase the yield. The yield can reach
92.1%. Next, compound 2 reacted with acetic anhydride and
needed to be purifed by using silica gel column before the
next reaction could take place. In this paper, compound 2
can be further reacted without purifcation. This simplifes
the operation process and saves time.
The preparation of compounds 4, 5 and 1 has not been
reported in the literature. In this paper, the target products
can be prepared by simple experimental methods, and the
repeatability of the experiment has been guaranteed. The
general process of the experiment is as follows:
During the preparation, 2, 3, 5-trimethylpyridine was
frst oxidized to give 2,3,5-trimethylpyridine-N-oxide (com-
pound 2) by H2O2 in acetic acid solution. Then compound
2 was reacted with acetic anhydride to obtain 3,5-dimethyl-
2-hydroxymethylpyridine (compound 3) via rearrangement
and hydrolysis, which was further converted to the key
intermediate 2-chloromethyl-3, 5-dimethylpyridine hydro-
chloride (compound 4) by reacting with thionyl chloride.
Fig. 10 FT-IR of compound 5
In their work, the preparation of compound 2 is as fol-
lows: To a stirred solution of commercially available
2,3,5-collidine, AcOH and 30% aq. H2O2 solution were
added. The mixture was heated at 80℃ for 6 h. In their work,
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Fig. 11 1H NMR of compound
5
Fig. 12 13C NMR of compound
5
The reaction of compound 4 with 2-mercapto-5-methoxy-
1H-benzimidazole via nucleophilic substitution in the pres-
ence of methanol formed 2-[(3, 5-dimethyl-2-pyridinyl)
methylthio)]-5-methoxy-1H-benzimidazole (compound 5).
Finally, rel-2-[[(3,5-dimethyl-2-pyridinyl)methyl]sulfnyl]-
6-methoxy-1H-benzimidazole (compound 1) was obtained
by the oxidation of compound 5 with m-chloroperbenzoic
acid.
indicates that compounds 2, 3 have been prepared. At the
same time, compounds 4, 5, 1 which did not have relevant
data in the literature were detected by nuclear magnetic
resonance, Fourier infrared analysis and high-resolution
mass spectrometry. Through the analysis of the data, it is
confrmed that the related compounds have been prepared.
Characterization data of compound 2: compound 2 was
characterized by FT-IR; the FT-IR spectroscopy shows C–H
stretching vibration peaks at 3049.4 cm−1, methyl peak at
2962.6 cm−1, aromatic ring stretching vibration peaks
The data of compounds 2, 3 detected by NMR and FTIR
are consistent with the data reported in the literature, which
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Fig. 13 Mass spectrometry of
compound 5
(skeleton bands) at 1577.7 cm−1 and out-of-plane bending
vibration peaks of aromatic hydrogen at 756.1 cm−1 (Fig. 2).
vibration peaks of aromatic hydrogen at 773.0 cm−1 (Fig. 6).
The 1H NMR displayed six protons at δ 2.55 and 2.62 ppm
corresponding to two methyl groups; δ 8.02 and 8.40 ppm
corresponding to two tertiary hydrogen groups; δ 5.15 ppm
corresponding to methylene (Fig. 7). In the 13C NMR,
the peak at 136.88–147.75 ppm is the carbon atom on the
pyridine ring, and the peaks at 17.15 and 19.95 ppm are
two primary carbons (Fig. 8). It can be seen from the high-
resolution spectra that the molecule with mass fraction of
156.0581 is consistent with the theoretical calculation of
compound 4. The theoretical value of compound 4 [M+H]+
is 156.0580 (Fig. 9).
1
The H NMR displayed nine protons at δ 2.23, 2.29 and
2.47 ppm corresponding to three methyl groups; δ 6.88 and
8.02 ppm corresponding to two tertiary hydrogen groups
(Fig. 3).
Characterization data of compound 3: the FT-IR spec-
troscopy shows that C–H stretching vibration peaks at
3000.9 cm−1, aromatic ring stretching vibration peaks (skel-
eton bands) at 1573.9 cm−1, out-of-plane bending vibration
peaks of aromatic hydrogen at 777.3 cm−1 and O–H peaks
at 3394.7 cm−1 (Fig. 3). The 1H NMR displayed 6 protons at
δ 2.18 and 2.31 ppm corresponding to two methyl groups; δ
7.29 and 8.22 ppm corresponding to two tertiary hydrogen
groups; δ 4.65 ppm corresponding to one methylene group;
δ 8.22 ppm corresponding to one methylene group (Fig. 7).
Characterization data of compound 4: compound 4 was
characterized by FT-IR, the FT-IR spectroscopy shows that
the absorption peak of –CH2Cl can be seen at 675.1 cm−1.
At the same time, there are C–H stretching vibration peaks
at 3024.8 cm−1, aromatic ring stretching vibration peaks
(skeleton bands) at 1562.4 cm−1 and out-of-plane bending
Characterization data of compound 5: FT-IR spectros-
copy show that the absorption peak of –S– can be seen at
949.0 cm−1, C–H stretching vibration peaks at 3049.5 cm−1,
aromatic ring stretching vibration peaks (skeleton bands)
at 1489.0 cm−1, out-of-plane bending vibration peaks
of aromatic hydrogen at 761.9 cm−1, and methyl peak at
2947.2 cm−1 (Fig. 10). The 1H NMR displayed 6 protons at
δ 2.28 and 2.38 ppm corresponding to two methyl groups, δ
3.80 ppm corresponding to a methoxy group, δ 12.48 ppm
corresponding to N–H (Fig. 11). In the 13C NMR, the
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Fig. 14 FT-IR of compound 1
compound 5. The theoretical value of compound 4 [M+H]+
is 300.1171 (Fig. 13).
Characterization data of compound 1: compound 1 was
characterized by FT-IR; the FT-IR spectroscopy shows that
C–H stretching vibration peaks at 3049.5 cm−1, methyl peak
at 2989.6 cm−1, aromatic ring stretching vibration peaks
(skeleton bands) at 1510.3 cm−1 and out-of-plane bending
vibration peaks of aromatic hydrogen at 715.6 cm−1. A sharp
band could be observed at 964.4 cm−1 in the infrared spec-
tra, which was attributed to S=O stretching (Fig. 15). The
proton NMR spectra displayed six protons at δ 2.25 and
2.28 ppm corresponding to two methyl groups, δ 3.81 ppm
corresponding to a methoxy group, δ 13.45 ppm corre-
sponding to N–H, and δ 4.65~4.77 ppm corresponding to
methylene (Fig. 16). In the 13C NMR, the number of car-
bon atoms in the test results is consistent with the target
product (Fig. 17). It can be seen from the high-resolution
spectra that the molecule with mass fraction of 316.1107 is
consistent with the theoretical calculation of compound 5.
The theoretical value of compound 4 [M+H]+ is 316.1120
(Fig. 14). Based on the characterization data, it is possible
to determine that the target product has been synthesized. In
Fig. 15 1H NMR of compound 1
number of carbon atoms in the test results is consistent with
the target product (Fig. 12). It can be seen from the high-
resolution spectra that the molecule with mass fraction of
300.1172 is consistent with the theoretical calculation of
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Fig. 16 13C NMR of compound
1
Fig. 17 Mass spectrometry of
compound 1
this synthetic method, the purity of the target product was as
high as 99.58% (Fig. 18, Table 1).
5, all intermediate products did not have to be chro-
matographed, which could be directly used as the raw
material for the next step. Thus, the reaction time was
greatly reduced, and the production efciency was greatly
improved. Meanwhile, the synthetic method has the advan-
tages of readily available raw materials, simple operation
and mild reaction. Most important of all, the purity of
the target product obtained by this synthetic route is high
enough to supply kinds of research for detection and con-
trol of esomeprazole impurities.
Conclusion
A simple novel method to synthesize an impurity in
esomeprazole has been developed. All raw materials
used in the synthetic process were of low cost and easily
obtained. Furthermore, from raw materials to compound
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Fig. 18 HPLC of compound 1
Table 1 Data analysis of HPLC
Peak#
4
Retention time [min]
10.514
Type
BB
Peak width [min]
0.2072
Peak area [mAU*s]
1.32697e4
Peak height [mAU]
997.70233
Peak area %
99.5839
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Acknowledgements This work is supported by Natural Science Foun-
dation of Shandong Province (ZR2016EMM13), Natural Science Foun-
dation of Shandong Province (ZR2017LC005) and the Key Research
and Development Program of Shandong Province of China (Major Sci-
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