Novel approach to the synthesis of omeprazole: An antipeptic ulcer agent

Article abstract of DOI:10.1080/00397910903341171

A novel approach for the synthesis of omeprazole, a potent antiulcer drug, is described. The synthetic procedure involved the formation of an ester of the 5-methoxy thiobenzimidazole followed by coupling of the ester with the Grignard reagent of 2-chloromethyl-4-methoxy-3,5-dimethyl-pyridine. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397910903341171

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Novel Approach to the Synthesis of
Omeprazole: An Antipeptic Ulcer Agent
Dinesh S. Bhalerao a , Golla China Mala Kondaiah a , Namrata
Dwivedi a , Ravi Kumar Mylavarappu a , Lekkala Amarnath Reddy a ,
Arnab Roy a , Gudimalla Nagaraju a , Padi Pratap Reddy a , Apurba
Bhattacharya a & Rakeshwar Bandichhor a
a Center of Excellence, Dr. Reddy's Laboratories Ltd., Bachupally,
Qutubullapur, India
Available online: 13 Sep 2010
To cite this article: Dinesh S. Bhalerao, Golla China Mala Kondaiah, Namrata Dwivedi, Ravi Kumar
Mylavarappu, Lekkala Amarnath Reddy, Arnab Roy, Gudimalla Nagaraju, Padi Pratap Reddy, Apurba
Bhattacharya & Rakeshwar Bandichhor (2010): Novel Approach to the Synthesis of Omeprazole: An
Antipeptic Ulcer Agent, Synthetic Communications: An International Journal for Rapid Communication
of Synthetic Organic Chemistry, 40:20, 2983-2987
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Synthetic Communications1, 40: 2983–2987, 2010
Copyright # Dr. Reddy’s Laboratories Ltd.
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910903341171
NOVEL APPROACH TO THE SYNTHESIS OF
OMEPRAZOLE: AN ANTIPEPTIC ULCER AGENT
Dinesh S. Bhalerao, Golla China Mala Kondaiah,
Namrata Dwivedi, Ravi Kumar Mylavarappu,
Lekkala Amarnath Reddy, Arnab Roy, Gudimalla Nagaraju,
Padi Pratap Reddy, Apurba Bhattacharya, and
Rakeshwar Bandichhor
Center of Excellence, Dr. Reddy’s Laboratories Ltd., Bachupally,
Qutubullapur, India
A novel approach for the synthesis of omeprazole, a potent antiulcer drug, is described. The
synthetic procedure involved the formation of an ester of the 5-methoxy thiobenzimidazole
followed by coupling of the ester with the Grignard reagent of 2-chloromethyl-4-methoxy-
3,5-dimethyl-pyridine.
Keywords: Esterification; Grignard reagent; oxidation; peptic ulcer
INTRODUCTION
Tricoordinated sulfur compounds and sulfoxides have attracted researchers for
the past few decades.[1] Many biologically active molecules[2] have stereogenic sulfur
and sulfenyl atoms in their structure.[3] Prominent examples are the sulfenyl-
substituted benzimidazoles, which are proton pump inhibitors (PPI),[4] a powerful
class of antiulcer agents.[5] The leading member of this family, omeprazole 1, was
the world’s best-selling drug in 1997. The enantiomerically pure isomer esomeprazole
(2) was introduced into the market later and was the seventh-best-selling drug in
2003. Omeprazole 1 had been previously synthesized by a linear reaction sequence
involving the nucleophilic substitution reaction between 5-methoxy thiobenzimida-
zole 7 and 2-chloromethyl-4-methoxy-3,5-dimethyl-pyridine 8, resulting in pyrmeta-
zole, which was subjected to oxidation with peroxides such as m-chloroperbenzoic
[6]
acid (m-CPBA) or H2O2 to furnish the omeprazole 1. A major drawback of this
methodology was the incomplete oxidation of pyrmetazole as well as overoxidation
to sulfone and formation of sulfone N-oxide.
Herein, we report a novel convergent approach to the synthesis of omeprazole,
comprising an ester and unprecedented Grignard fragments. This methodology
Received June 13, 2009.
Address correspondence to Rakeshwar Bandichhor, Center of Excellence, Innovation Plaza, IPDO,
Research and Development, Dr. Reddy’s Laboratories Ltd., Survey Nos. 42, 45, 46, and 54, Bachupally,
Qutubullapur, R. R. Dist.-500073, AP, India. E-mail: rakeshwarb@drreddys.com
2983

2984
D. S. BHALERAO ET AL.
Figure 1. Structures of proton pump inhibitors.
provides a generalized entry to various prazoles, which have similar kinds of
molecular architecture (1–6), as shown in Fig. 1.
RESULT AND DISCUSSION
The ester component was prepared according to the literature procedure by the
treatment of 7 with various alcohols in the presence of 30% aq. H2O2,[7] and the
results are summarized in Table 1. Simple alcohols such as methyl, ethyl, and benzyl
alcohols formed the corresponding esters (Table 1), whereas the chiral alcohols such
as menthol and diacetonide glucose failed to result in the respective chiral esters.
Table 1. Formation of ester of 5-methoxythiobenzimidazole
Entry
H2O2 eq.
Conditions
Yield (%) of 9a–e
1
2
3
4
5
5.0
5.0
1.5
5.0
5.0
Methanol, ꢀ10 ꢁC
35
42
75
—
—
Ethanol, ꢀ10 ꢁC
Benzyl alcohol, ꢀ10 ꢁC
Menthol, ꢀ10 ꢁC
Diacetonide glucose, ꢀ10 ꢁC

SYNTHESIS OF OMEPRAZOLE
2985
Figure 2. Structure of side products 10, 11, and 13.
We anticipate that the bulky nature of the alcohol plays a pivotal role in the
ester formation. In this reaction, the major by-product formed with MeOH, EtOH,
and BnOH was the benzimidaziole 10, whereas with menthol and diacetonide
glucose, compound 11 was the only product formed, as shown in Fig. 2. The
synthesis of the Grignard fragment was a difficult task. The conventional method
of generating the Grignard reagent using magnesium turnings and organic halides
was not possible in this instance because of the formation of benzylic and allylic
radicals, which are susceptible to migration from metal surface, yielding Wurtz
coupled products.[8] Moreover, the synthesis of polyfunctional Grignard reagents
was a problem because the insertion of magnesium metal to aryl (or heteroaryl)
halides bearing electron-withdrawing groups is inhibited by the presence of these
functional groups either inside or outside of the aromatic ring. These problems were
addressed by utilizing the magnesium–anthracene complex in tetrahydrofuran
(THF).[9] The 1:1 orange-colored crystalline magnesium–anthracene complex was
prepared by activating magnesium with a catalytic amount of ethyl bromide,
followed by addition of anthracene in THF at 40 ꢁC under an inert atmosphere.
2-Chloromethyl-4-methoxy-3,5-dimethyl-pyridine was added to this magnesium–
anthracene complex, furnishing the pyridyl Grignard reagent 12 as shown in
Scheme 1. The ester fragment 9b was added to the Grignard reagent 12 at 0 ꢁC to
furnish omeprazole 1 in moderate yield (Scheme 2). Along with the required product,
dimer 13 of the 2-chloromethyl-4-methoxy-3,5-dimethyl-pyridine and some
unreacted starting material were recovered.
1
The H NMR, IR, and mass spectra of the synthesized compound 1 were in
complete agreement with the reported values. In summary, we have described a
novel synthesis for omeprazole 1 using Grignard reagent and sulfinic ester.
Scheme 1. Preparation of Grignard reagent 12.
Scheme 2. Synthesis of omeprazole 1.

2986
D. S. BHALERAO ET AL.
CONCLUSION
We have successfully demonstrated an unprecedented coupling of sulfinic ester
(9b) and Grignard reagent (12) to synthesize omeprazole, which can be utilized for
synthesis of the other members of the prazole class of molecules. Efforts are under
way to synthesize chiral esters (e.g., entries 4 and 5; Table 1) in high yields, which
would result in an enamtiomercally pure isomer of not only esomeprazole but also
the other members of this type (Fig. 1).
EXPERIMENTAL
1H and 13C NMR spectra were recorded at 400 and 200 MHz respectively with
a Varian Gemini FT NMR spectrometer. The chemical shifts are reported in d ppm
relative to tetramethylsilane (TMS). The Fourier transform (FT)–IR spectra were
recorded using a Perkin-Elmer 16650 FT-IR spectrometer. Mass spectra (70 eV) were
recorded on a HP-5989A LC-MS spectrometer. The melting points were determined
by using the capillary method on a Polmon (model MP-96) melting-point apparatus
and are uncorrected. The solvents and reagents were used without further purifi-
cation. Optical rotations were measured with a Jasco DIP-370 digital polarimeter
at 25 ꢁC. A microwave reactor specifically designed for holding reactions at a set
temperature (Discover, CEM Corporation) was used. All reactions were performed
in flame-dried glassware under nitrogen. Tetrahydrofuran (THF) and Et2O were
dried and distilled from Na=benzophenone. Benzene and CH2Cl2 were dried and dis-
tilled from CaH2. Hexane and ethyl acetate were freshly distilled from CaH2.
Thin-layer chromatography (TLC) was performed on silica-gel 60 F254 precoated
plates (250-mm layers). All retention factors (Rf) are on silica-gel TLC plates unless
otherwise noted. TLC visualizations were performed with 5% phosphomolybdic acid
[0.2 M in 2.5% conc. H2SO4=EtOH (v=v)], I2 vapor, or ultraviolet (UV) light.
Commercial reagents were used without further purification unless specifically noted.
Column chromatography was performed using 100–700 times excess 32- to 64-mm
silica gel. Products separated by chromatography are specified in elution order. In
some cases, the yields of products containing residual amounts of solvent were cor-
rected for the solvent peak integration in 1H NMR spectra and specified individually
in the data sections. The purity of reaction products was estimated to be at least
90–95% by TLC and NMR analyses unless specified otherwise.
Synthesis of Omeprazole 1
Ethyl bromide (0.01 mL) was added to a stirred solution of Mg (1 g, 0.041 mol)
in THF (2 mL) and heated to 40–45 ꢁC. Anthracene (4 g) in THF (20 mL) was added
and stirred at 45–50 ꢁC after 6 h, resulting in an orange complex of [Mg(antrace-
ne)(THF)3]. The magnesium–antharacene complex was cooled between ꢀ5 and
0 ꢁC, followed by the addition of 8 (3.8 g, 0.028 mol), resulting in Grignard reagent
12. Ester fragment 9b (2.5 g, 0.010 mol) in THF (5 mL) was added, and the reaction
mixture was maintained for 1 h at this temeperature and allowed to stir to room tem-
perature for another 3 h. After completion of the reaction (TLC monitoring), THF
was distilled under reduced pressure to result in a crude oil. Water (30 mL) was

SYNTHESIS OF OMEPRAZOLE
2987
added, and the pH was adjusted between 12 and 13 using 10% aq. NaOH (7 mL).
Ethyl acetate (2 ꢂ 50 mL) was used to wash the aquoeus layer, and then the pH of
aqueous layer was adjusted between 7 and 8 by 3 N HCl solution. The product
was extracted from the aqueous layer with dichoromethane (2 ꢂ 50 mL). The dichlor-
omethane layer was dried over Na2SO4, filtered, and evaporated under reduced
pressure at 30–35 ꢁC to result in a oily compound. Acetone (2 mL) was added to it
to furnish a white solid omeprazole 1 (1.12 g, 30%).
ACKNOWLEDGMENTS
The authors are thankful to the management of the Dr. Reddy’s Laboratories
Ltd. for supporting this work and to Dr. R Vijay Anand for the discussions.
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