Organic Process Research & Development 2009, 13, 804–806
Technical Notes
An Improved Synthesis of Antiulcerative Drug: Tenatoprazole
Somaiah Sripathi,† Ramachandra Reddy Bojja,† Venugopal Reddy Karnati,*,‡ V. V. N. K. V. Prasada Raju,§ and
Mayur D. Khunt§
Department of Research and DeVelopment, Srini Pharmaceuticals Ltd., Plot No. 10, Type-C, Road No. 8, Film Nagar, Jubilee
Hills, Hyderabad-500033, Andhra Pradesh, India, Department of Chemistry, Osmania UniVersity, Tarnaka, Hyderabad-
500007, Andhra Pradesh, India and Research and DeVelopment, Integrated Product DeVelopment Organization, InnoVation
Plaza, Dr. Reddy’s Laboratories Ltd., Bachupally, Qutubullapur, R. R. Dist. 500 072, Andhra Pradesh, India
Abstract:
gastric acid pump with a stoichiometry of 2.6 nmol mg-1 of
the enzyme in vitro. In vivo, maximum binding of tenatoprazole
was 2.9 nmol mg-1 of the enzyme at 2 h after intravenous (IV)
administration.9,10
An efficient, cost-effective and multikilogram-scale process for the
synthesis of tenatoprazole 1, an antiulcerative drug, is described.
The key steps in this synthesis involve the coupling of 2-mercapto-
5-methoxyimidazo[4,5-b]pyridine 2 with 2-chloromethyl-4-meth-
oxy-3,5-dimethyl pyridine hydrochloride 3 to yield 4 and its
subsequent oxidation with m-CPBA to produce sulfoxide 1. The
process has been scaled up for the multikilogram-scale of com-
pound 1 with an overall yield of 72%. The new process requires
no purification process and affords the target compound 1 with
99.8% purity by HPLC.
As outlined in Scheme 1, the existing process of tenatopra-
zole 1 involves two steps.11 Synthesis of target compound 1
commences with the coupling of 2-mercapto-5-methoxyimi-
dazo[4,5-b]pyridine 2 with 2-chloromethyl-4-methoxy-3,5-
dimethyl pyridine hydrochloride 3 in the presence of potassium
hydroxide affords 4 with 73% yield in ethanol and chloroform.
Although this condensation reaction was very good, it requires
high solvent volumes for the reaction, which was not a better
choice at large-scale production. The oxidation of the penulti-
mate sulfide intermediate 4 with m-CPBA in chloroform (100
vol) afforded 1 in moderate yields with the potential impurities
such as sulfone 6, N-oxide 7, sulfone N-oxide 8, and sulfide 4.
Removal of these impurities from the product is very difficult.
By keeping these compelling factors we thought to develop an
improved process, which could circumvent most of the above-
mentioned problems.
Introduction
Tenatoprazole is a novel imidazopyridine derivative and has
an imidazopyridine ring in place of the benzimidazole moiety
found in other proton pump inhibitors.1 It is activated more
slowly than other proton pump inhibitor, but its inhibition is
resistant to reversal.2 Tenatoprazole has an extended plasma
half-life in comparison with those of all other proton pump
inhibitors; this makes it more potent in the treatment of nocturnal
acid breakthrough than esomeprazole, one of the most popular
proton pump inhibitors.3,4
Tenatoprazole belongs to the class of covalent proton pump
inhibitors (PPIs), which is converted to the active sulfenamide
or sulfenic acid by acid in the secretory canaliculus of the
stimulated parietal cell of the stomach.5,6 This active species
binds to luminally accessible cysteines of the gastric H+,K+-
ATPase, resulting in disulfide formation and acid secretion
inhibition.7,8 Tenatoprazole binds at the catalytic subunit of the
Results and Discussion
In our development efforts we needed to set up an efficient
process for the impurity-free synthesis of tenatoprazole, 1. The
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* To whom correspondence should be addressed. Telephone: +91 9490783736.
E-mail: drkvr_ou@yahoo.com; kvgr1951@rediffmail.com.
† Srini Pharmaceuticals Ltd.
‡ Osmania University.
§ Dr. Reddy’s Laboratory Ltd.
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Vol. 13, No. 4, 2009 / Organic Process Research & Development
10.1021/op800173u CCC: $40.75 2009 American Chemical Society
Published on Web 11/12/2008