Synthesis of 4-((1H-benzo[d]imidazol-2-yl)oxy)-3-methylpicolinic acid, a key related substance of Rabeprazole sodium

Article abstract of DOI:10.1016/j.tetlet.2020.152105

4-((1H-benzo[d]imidazol-2-yl)oxy)-3-methylpicolinic acid (11) is a key related substance of Rabeprazole sodium. In this article, this key related substance is synthesized by using 3-methylpicolinonitrile as a starting material via a five-step processes. By converting 3-methylpicolinonitrile to 4-hydroxy-3-methylpicolinonitrile (13), the preparation of TM becomes practical. This work provides a guarantee for quality standard establishment of Rabeprazole sodium.

Full text of DOI:10.1016/j.tetlet.2020.152105

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Synthesis of 4-((1H-benzo[d]imidazol-2-yl)oxy)-3-methylpicolinic acid, a key
related substance of Rabeprazole sodium
Xiaoyan He, Yan Chang, Xuefei Bao, Zi'ao Liu, Guoliang Chen, Xiuhong Lu
PII:
S0040-4039(20)30556-6
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https://doi.org/10.1016/j.tetlet.2020.152105
TETL 152105
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Tetrahedron Letters
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1 June 2020
Please cite this article as: He, X., Chang, Y., Bao, X., Liu, Z., Chen, G., Lu, X., Synthesis of 4-((1H-
benzo[d]imidazol-2-yl)oxy)-3-methylpicolinic acid, a key related substance of Rabeprazole sodium, Tetrahedron
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Synthesis of 4-((1H-benzo[d]imidazol-2-yl)oxy)-3-methylpicolinic acid，a key
related substance of Rabeprazole sodium
Xiaoyan He a,b, Yan Chang a,b, Xuefei Baoc, Zi’ao Liuc, Guoliang Chen*c, Xiuhong Lu*a,b
a Shanghai Key Laboratory of Molecular Imaging, Shanghai University of Medicine and Health Sciences, Shanghai 201318, P. R. China.
bSchool of pharmacy, Shanghai University of Medicine and Health Sciences, Shanghai 201318, P. R. China.
c Key Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, P.R. China.
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
4-((1H-benzo[d]imidazol-2-yl)oxy)-3-methylpicolinic acid (11) is a key related substance of
Rabeprazole sodium. In this article, this key related substance is synthesized by using 3-
methylpicolinonitrile as a starting material via a five-step processes. By converting 3-
methylpicolinonitrile to 4-hydroxy-3-methylpicolinonitrile (13), the preparation of TM becomes
practical. This work provides a guarantee for quality standard establishment of Rabeprazole
sodium.
Available online
Keywords:
Rabeprazole sodium
related substance
2009 Elsevier Ltd. All rights reserved.
4-hydroxy-3-methylpicolinonitrile
Rabeprazole impurity
1. Introduction
substances family.
Several kinds of impurities are produced during the production
and preparation processes of Rabeprazole sodium azole active
pharmaceutical ingredient (API). Therefore, it is of pivotal
importance to study and control the amount of impurities to ensure
the efficacy of Rabeprazole sodium. The synthesis of related
substances is a very meaningful work in API production.2 Eleven
kinds of impurities (Figure 1)3-5 have been reported up to date,
including: 1H-Benzoimidazol-2-ol (1), 1H-Benzoimidazol-2-
ylamine (2), 1H- Benzoimidazole-2-thiol (3), 2-(4-Methoxy-3-
methyl-pyridin-2-ylmethanesulfinyl)-1H-benzoimidazole (4), 2-
(4-Chloro-3-methyl-pyridin-2-ylmethanesulfinyl)-1H-
Rabeprazole sodium, [2-[[4-(3-methoxypropoxy)-3-methyl-2-
pyridyl]methyl-sulfinyl]benzimidazol-1-yl] (Figure 1), is an
effective proton pump inhibitor to treat acid-related diseases. It
was discovered by Eisai and commercialized in 1998. Rabeprazole
sodium exhibited identical therapeutic effects in duodenal and
gastric ulcers as omeprazole according to clinical research, while
it performed better in symptom improvements and showed fewer
side effects. It is a new and promising proton inhibitor.1
H
N
H
N
H
N
N
OH
NH2
SH
O
N
N
N
S
N
H
O
N
O
1
3
4
2
benzoimidazole (5), 2-(4-Methoxy-3-methyl-pyridin-2-ylmethyl-
sulfanyl)-1H-benzoimidazole (6), 2-[4-(3-Methoxy-propoxy)-3-
methyl-pyridin-2-ylmethylsulfanyl]-1H-benzoimidazole (7), 2-[4-
(3-Methoxy-propoxy)-3-methyl-1-oxy-pyridin-2-
N
N
N
O
O
N
S
Cl
N
S
N
H
S
H
H
N
N
O
N
ylmethanesulfinyl]-1H-benzoimidazole (8), 2-[4-(3-Methoxy-
propoxy)-3-methyl-pyridin-2-ylmethanesulfonyl]-1H-
benzoimidazole (9), 1-(1H-Benzoimidazol-2-yl)-3-methyl-4-oxo-
1,4-dihydro-pyridine-2-carboxylic acid (10) and 4-(1H-
7
5
6
N
N
O
O
O
O
O
N
N
S
S
H
H
O
N+
O
N
-O
8
Benzoimidazol-2-yloxy)-3-methyl-pyridine-2-carboxylic
acid
9
(11).
OH
N
O
H
N
N
N
O
O
N-
Na+
S
Compounds 1, 2 and 3 are commercially available. Synthesis
of 4, 5 and 6 was reported by Pingili in 20054. Compound 7 is a
synthetic intermediate of Rabeprazole. Reddy published the
synthetic methods of 8 and 9 recently. 6 The compound 10 can be
N
O
N
H
O
COOH
O
N
N
Rabeprazole sodium
10
11
Figure 1 The structure of Rabeprazole sodium and its related

2
Tetrahedron Letters
Scheme 1 Retrosynthesis of compound 11.
obtained according to the synthesis of Omeprazole related
substances under the phosphoric acid buffer salt condition.7 The
synthesis of compound 11 has been only reported by He et al.,8 but
they employed a tedious synthetic procedure and started from a
rare and expensive raw material (Figure 2).
O
N
O
O
N
N
N
HNO3
H2O2
HO
CN
H2SO4
CN
O2N
CN
OH-
CN
O
N
Previous Work
N
O2N
OH
COOH
2 steps
H
N
5 steps
Cl
N
HO
N
Scheme 2 Nitrification route.
O
N
This Work
CN
O
N
N
N
conditional hydrolysis
POCl3
N
2 steps
N
CN
N
3 steps
COOH
HO
CN
Cl
CN
CN
H
N
O
N
OH
Figure 2 Comparison of current work and previous work.
Scheme 3 Synthesis of 4-hydroxy-3-methyl-pyridine-2-carbonitrile.
The production of 11 through a convenient and reliable method
is of great value for the establishment of the quality control method
of Rabeprazole sodium. In this paper, we will introduce a method
of building compound 11 through a 5 steps procedure by using an
easily available starting material (Figure 2).
The chlorination reaction of 3-methylpicolinonitrile by POCl3
affording
6-chloro-3-methyl-picolinonitrile
attracted
our
attention,11-13 but the production of 4-chloro-3-methyl-
picolinonitrile has not been reported. We anticipated that if the
conditions were controlled carefully, 4-chloro-3-methyl-
picolinonitrile would be obtained under this condition. Therefore,
the chlorination of 3-methylpicolinonitrile followed by conditional
hydrolyzation synthetic route was adopted to prepared 4-hydroxy-
3-methyl-picolinonitrile. In line with our expectations, 3-methyl-
1-oxy-pyridine-2-carbonitrile was chlorinated by phosphorus
oxychloride at 80 C resulting in 4-chloro-3-methyl-picolinonitrile
in the yield of 30% (Scheme 3). 68% of the product was 6-chloro-
3-methyl-pyridine-2-carbonitrile owning to the steric hinderance
of methyl group on position 3.
Results and Discussion
There are two strategies to synthesis 11 by breaking the ether
bond in the middle of the structure according to retrosynthesis as
shown in Scheme 1. Pathway A: 2-hydroxy-benzoimidazole-1-
carboxylic acid tert-butyl ester reacts with 4-chloro-3-methyl-
pyridine-2-carbonitrile through a coupling reaction. Pathway B: a
coupling reaction between 2-chloro-benzoimidazole-1-carboxylic
acid tert-butyl ester and 4-hydroxy-3-methyl- pyridine-2-
carbonitrile is another possible way. The strategy A was
abandoned, due to the tautomerism of the double bond of the
starting material 2-hydroxy-benzo-imidazole-1-carboxylic acid
tert-butyl ester, which led to the difficulty in isolation and
identification of two possible products.
The identification of these two products was confirmed by 1H-
NMR. The chemical shifts of three protons in 3-methyl-pyridine-
2-carbonitrile are 7.43 ppm, 7.69 ppm and 8.55 ppm with respects
to position 5, 4 and 6 in the pyridine ring (Figure S1). Therefore,
the spectrum with chemical shifts 8.45 ppm and 7.53 ppm in the
aromatic region was assigned to target product 4-chloro-3-methyl-
pyridine-2-carbonitrile (Figure S5). The peaks of hydrogens in the
pyridine ring of the side product, 6-chloro-3-methyl-pyridine-2-
carbonitrile, appeared on 7.65 ppm and 7.46 ppm (Figure S7).
The synthesis of 2-chloro-benzo- imidazole-1-carboxylic acid
tert-butyl ester, an intermediate in pathway B, has been reported
in the literatures.9 While, the synthesis of the other key
intermediate, 4-hydroxy-3-methylpicolinonitrile has not been
reported so far to the best of our knowledge. Veerareddy et al.
published a synthesis method of 4-chloro-3-methyl-picolinonitrile
(14),10 which involved the usage of the highly toxic reagent
trimethylsilyl cyanide and ethyl chloroformate, but the idea of
nitration was used as our reference. We adapted the synthetic route
and 3-methylpicolinonitrile was tried as a starting material to
prepare 4-hydroxy-3-methylpicolinonitrile (Scheme 2). 3-methyl-
picolinonitrile was oxidized by hydrogen peroxide to generate 3-
methyl-1-oxy-pyridine-2-carbonitrile, followed by a nitrification
Hydrolysis of 4-chloro-3-methyl-pyridine-2-carbonitrile was
carefully carried out under strict condition to ensure the selectively
hydrolyze the chlorine but not cyan group. We optimized the
conditions to 3 mol/L sulfuric acid aqueous solution and ethanol
to react 48 hours at 85 C.
Cupric iodide was confirmed to be an effective catalyst for the
Ullman coupling reaction of 2-chloro- benzoimidazole-1-
carboxylic
acid
tert-butyl
ester
and
4-hydroxy-3-
methylpicolinonitrile. The application of Suzuki reaction
conditions (palladium catalyst) failed to afford the desired product.
The final step was the selective hydrolysis of the 4-((1H-
benzo[d]imidazol-2-yl)oxy)-3-methylpicolinonitrile, to avoid
production of the amide by-product.
reaction
to
produce
3-methyl-4-nitro-1-oxy-pyridine-2-
carbonitrile. Unfortunately, the following hydrolysis reaction
under the alkaline condition failed to afford the target compound.
A decyanation product, 3-methyl-4-nitro-pyridine 1-oxide, was
isolated (Scheme 2). Reduction of the nitro group to an amino
group followed by hydroxylation through a Sandmeyer reaction
was also confirmed to be infeasible.
main product
68%
Cl
N
CN
ii
i
N
N
O
15
CN
OH
N
CN
Cl
CN
73%
H
N
N
30%
iii
89%
iv
N
O
65%
CN
+
N
Cl
CN
N
N
CN
N
OH
14
13
12
Boc
N
N
N
N
N
COOH
H
A
v
N
N
O
COOH
N
O
CN
46%
O
H
N
H
N
N
+
12
11
HO
CN
11
N
Cl
Boc
Scheme 4 i: H2O2, HAc, H2O, 90 C, 20 h; ii: POCl3, 80 C, 4 h; iii: 3
mol/L H2SO4, EtOH, 85 C, 48 h; iv: CuI, K2CO3, tert-butyl-2-chloro-
B

References and notes
1H-benzo[d]imidazole-1-carboxylate, DMF, 110 C, 20 h; v: 30%
NaOH, EtOH, 80 C, 4 h.
Conclusions
1.
2.
Carswel, C. I.; Goa, K. L. Drugs, 2001, 61, 2327–2356.
Lee Y. H.; Viji M.; Lee E.; Jo H.; Yoo K.; Sim J.; Lee S.; Lee K.;
Lee H.; Jung J-K. Tetrahedron Letters, 2017, 58, 2614–2617.
European Pharmacopoeia 8.7, 2016, 5808.
Pingili, R. R.; Jambula, M. R.; Ganta, M. R.; Ghanta M. R.; Sajja,
E., Sundaram, V., Boluggdu, V. B. Die Pharmazie, 2005, 60, 814.
Raju, T.; Kumar, S.; Rao, I.; Rao, N. Asian J Pharm Clin Res, 2013,
6, Suppl 4, 43.
Reddy, G. M.; Mukkanti, K.; Bhaskar, B. V.; Reddy P. P.; Synthetic
Communications, 2009, 39(2), 278-290.
Rok, G.; Andrej, B.; Andrej, K. EP 2189456 A1, 2010; Chem.
Abstr. 2010, 152, 600738.
In summary,
a novel method of producing 4-(1H-
3.
4.
benzoimidazol-2-yloxy)-3-methyl-pyridine-2-carboxylic acid was
established in this work (Scheme 4), applying 3-methyl- pyridine-
2-carbonitrile as a starting material and followed by oxidation,
chlorination, hydrolyzation, Ullman reaction and hydrolyzation. It
provides an economic, environment friendly, and easy-to-operate
way to produce the reference compound for the industrial
manufacture of Rabeprazole sodium. Through this method, the
synthesis of 4-hydroxy-3-methyl-picolinonitrile was reported for
the first time.
5.
6.
7.
8.
He, X.; Hu, Y. Zh.; Zhang, Ch.; Liu, C.; Cui, X. L. Faming Zhuanli
Shenqing CN 107663192 A, 2018; Chem. Abstr. 2018, 168,
232784.
9.
Ogino, Y.; Ohtake, N.; Nagae, Y.; Matsuda, K.; Moriya, M.; Suga,
T.; Ishikawa, M.; Kanesaka, M.; Mitobe, Y.; Ito, J.; Kanno, T.;
Ishihara, A.; Iwaasa, H.; Ohe, T.; Kanatani, A.; Fukami, T.
Bioorganic & Medicinal Chemistry Letters, 2008, 18, 5010.
Acknowledgments
We gratefully acknowledge the National Natural Science
Foundation of China (No. 81971016; 81601173; 81830052),
Construction project of Shanghai Key Laboratory of Molecular
Imaging (18DZ2260400) and Shanghai Municipal Education
Commission (Class II Plateau Disciplinary Construction Program
of Medical Technology of SUMHS, 2018-2020) for financial
support.
10. Veerareddy, A., Surendrareddy, G., Dubey, P. K. Journal of
Heterocyclic Chemistry, 2011, 48, 961.
11. Kuduk S. D.; Liverton N.;ꢀLuo Y. WO2016095205 A1, 2016;
Chem. Abstr. 2016, 165, 101084.
12. Kuduk S. D.; Liverton N.; Luo Y. WO2016100156 A1, 2016;
Chem. Abstr. 2016, 165, 101085.
13. Michelle M.;ꢀGabriela D. A.; Grimm J. B.; Maccoss R. N.; Romeo
E.; Tony S.; Catherine W.; Kevin. W. WO2009155156 A1, 2009;
Chem. Abstr. 2009, 152, 75035.
Supplementary Material
Experimental details and structure identification data can be
found in supplementary material in the online version, at http://
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Synthesis of 4-((1H-benzo[d]imidazol-2-yl)
oxy)-3-methylpicolinic acid，a key related
substance of Rabeprazole sodium
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Xiaoyan He a,b, Yan Chang a,b, Xuefei Baoc, Zi’ao Liuc, Guoliang Chen*c, Xiuhong Lu*a,b
Previous Work
Si
N
O
N
OH
COOH
H
N
N
5 steps
Cl
Cl
N
HO
O
N
N
2 steps
This Work
Boc
N
CN
N
CN
N
Cl
3 steps
COOH
N
H
N
HO
N
2 steps
O
N
A key related substance for Rabeprazole sodium
This method provides an economic,
environment friendly, and easy-to-
operate way
Title compound is important in the
process control of Rabeprazole sodium
API
Synthesis of 4-hydroxy-3-methyl-
picolinonitrile was reported for the first
time
The synthetic route of title compound is
rarely reported