1-arylsulfonyl-2-(Pyridylmethylsulfinyl) benzimidazoles as new proton pump inhibitor prodrugs

Article abstract of DOI:10.3390/molecules14125247

New arylsulfonyl proton pump inhibitor (PPI) prodrug forms were synthesized. These prodrugs provided longer residence time of an effective PPI plasma concentration, resulting in better gastric acid inhibition.

Full text of DOI:10.3390/molecules14125247

Molecules 2009, 14, 5247-5280; doi:10.3390/molecules14125247
OPEN ACCESS
molecules
ISSN 1420-3049
www.mdpi.com/journal/molecules
Article
1-Arylsulfonyl-2-(Pyridylmethylsulfinyl) Benzimidazoles as New
Proton Pump Inhibitor Prodrugs
Jai Moo Shin 1,*, George Sachs 1,*, Young-moon Cho 1 and Michael Garst 2
1
Department of Physiology, David Geffen School of Medicine, University of California at Los
Angeles, and VA Greater Los Angeles Healthcare System, Los Angeles, CA 90073, USA;
E-Mail: ymkscho@yahoo.com (Y.M.C.)
2
Allergan, Inc. Irvine, California 92660, USA; E-Mail: garst_michael@allergan.com (M.G.)
* Authors to whom correspondence should be addressed; E-Mails: jaishin@ucla.edu (J.S.);
gsachs@ucla.edu (G.S.); Tel.: +1-310-478-3711, ext. 42053; Fax: +1-310-312-9478.
Received: 9 October 2009; in revised form: 8 December 2009 / Accepted: 14 December 2009 /
Published: 15 December 2009
Abstract: New arylsulfonyl proton pump inhibitor (PPI) prodrug forms were synthesized.
These prodrugs provided longer residence time of an effective PPI plasma concentration,
resulting in better gastric acid inhibition.
Keywords: proton pump inhibitor; prodrug; gastric acid secretion
1. Introduction
The first drug for inhibiting gastric acid secretion, introduced into clinical use in 1989, was
omeprazole (5-methoxy-2-(4-methoxy-3,5-dimethyl-pyridin-2-ylmethanesulfinyl)-1H-benzimidazole).
Later, lansoprazole (2-[3-methyl-4-(2,2,2-trifluoroethoxy)pyridin-2-ylmethanesulfinyl]-1H-benz-
imidazole), pantoprazole (5-difluoromethoxy-2-(3,4-dimethoxy-pyridin-2-ylmethanesulfinyl)-1H-
benzimidazole), rabeprazole (2-[4-(3-methoxy-propoxy)-3-methyl-pyridin-2-ylmethanesulfinyl]-1H-
benzimidazole sodium salt) and more recently the S-enantiomer of omeprazole were introduced. This
class of drugs, collectively known as proton pump inhibitors (PPIs), are now the mainstay of treatment
of all acid related diseases. All of these drugs inhibit the gastric H,K-ATPase by covalent binding and
therefore the duration of their effect is longer than expected from their levels in the blood [1,2].

Molecules 2009, 14
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Proton pump inhibitors are weak bases with a pKa1 between 3.8 and 4.5. This weak base pKa
enables proton pump inhibitors to accumulate only in the acidic space of the secretory canaliculus of
the stimulated parietal cell in the stomach. When gastric acid is secreted, the extracellular lumen of the
canaliculus achieves a pH ~ 1.0, thus predicting about a thousand fold accumulation in this space. This
acid space is the first important property that determines their therapeutic index and giving an elevated
concentration of PPI at the luminal surface of the pump enzyme. The second vital step is pH dependent
conversion from the accumulated PPI to an activated species that is a sulfenic acid and a sulfenamide.
These active forms are highly reactive thiophilic reagents that form disulfides with luminally
accessible cysteines of the H,K-ATPase, resulting in inhibition of the gastric acid secretion [1,3,4].
The effectiveness of PPIs may be ascribed to three factors: their ability to accumulate selectively in
the highly acidic space of the stimulated secretory canaliculus of the parietal cell due to the pKa of the
pyridine group of the PPIs, their acid-activated formation of the reactive species and the requirement
for acidic pH for a significant rate of activation. Even though a meal stimulates acid secretion and acid
secretion in turn activates PPIs, PPIs cannot inhibit all gastric acid pumps in vivo since at no time are
all acid pumps active and activity of the pumps is required for covalent inhibition by the PPIs. Only
about 70% of pumps are inhibited since PPIs have short half-lives and not all pump enzymes are
activated. The PPIs are rapidly metabolized by the liver with half-lives of about 60-90 min [5]. It takes
about three days to reach steady state inhibition of acid secretion since a balance is struck between
covalent inhibition of active pumps, subsequent stimulation of inactive pumps after the drug has been
eliminated from the blood and de novo synthesis of new pumps [6,7]. The gastric H,K-ATPase protein
has a half-life of about 54 h in the rat [8], thus about 20% new pumps are synthesized over a 24 h
period. On the assumption that about 70% of pumps are activated by breakfast and that the PPI is given
30-60 minutes before, it can be calculated that steady state inhibition on once-a-day dosage is about
66% of maximal acid output. Increasing the dose has virtually no effect once optimal dosage has been
reached, but increasing dose frequency has some effect so a morning dose and an evening dose before
meals results in about 80% inhibition of maximal acid output. This finding suggests that prolonging
PPI plasma concentration would achieve maximal inhibition of gastric acid secretion. This requirement
necessitated the design of novel prodrugs, 1-arylsulfonyl PPIs. There have been several attempts to
make prodrugs of the proton pump inhibitors. These studies variously described N-acyloxyalkyl
[9–11], N-carboxyalkyl [12], N-alkoxycarbonyloxyalkyl [12,13], N-alkoxycarbonyl [9], N-
(aminoethyl) [9], and N-alkoxyalkyl benzimidazole sulfoxides [9] as proton pump inhibitor prodrugs.
One of the modifications at the N1 position is a long alkyl group containing a phosphate moiety for
increasing aqueous solubility [11]. These prodrugs exhibited improved chemical stability in the solid
state and in aqueous solutions compared to PPIs, but had less activity than the corresponding parent
compounds having a free imidazole N-H group. This may be due to poor hydrolysis of the N-
substituent or formation of something other than the PPI, even though a study showed that N-
methylomeprazole forms the disulfide adduct in the presence of a thiol [14]. We found N-arylsulfonyl
benzimidazole provided rapid hydrolysis of the sulfonamide group by plasma proteins in vitro and in
vivo, releasing the parent drug. This property enabled a new prodrug form of PPI, 1-arylsulfonyl PPI.
The present study illustrates a further advance in the art of gastric acid inhibition. Prodrugs with
improved stability of the proton pump inhibitor type drugs are described. We report the suitability of
these compounds for use as proton pump inhibitor prodrugs, which possess improved efficacy in

Molecules 2009, 14
5249
therapy of acid related diseases due to prolongation of the presence of the parent proton pump
inhibitors in the body.
Figure 1. Proton pump inhibitors.
R1
O R2
S
R3
N
N
R4
N
M
1
R1
R2
R3
CH3O-
CF3CH2O-
R4
CH3
H
M
Omeprazole (1a)
Lansoprazole (1b)
Pantoprazole (1c)
Rabeprazole (1d)
CH3O-
H
CH3
CH3
Mg
H
CHF2O- CH3O- CH3O-
CH3 CH3OCH2CH2CH2O-
H
H
Na
Na
H
2. Results and Discussion
2.1. Synthesis of 1-arylsulfonyl-2-(2-pyridylmethylsulfinyl)benzimidazoles
The 1-arylsulfonyl-2-(2-pyridylmethylsulfinyl)benzimidazoles were prepared by the reaction of
arylsulfonyl chlorides with 2-(2-pyridylmethylsulfinyl)benzimidazoles (Scheme 1).
Scheme 1. General method for preparation of 1-arylsulfonyl-benzimidazole compounds.
N
R4
N
N
N
R1
S
O R2
R1
R4
N
R3
R5
SO2Cl
+
S
SO2
N
H
O R2
R3
R6
R5
R6
1
2
3
Compound 3 R1
R2
R3
R4
H
R5
R6
3a
3b
3c
3d
3e
3f
H
H
H
Me
Me
Me
Me
Me
Me
Me
MeOCH2CH2CH2O-
H
H
H
H
H
H
H
H
H
H
H
H
CF3CH2O
H
NH2CONH-
MeOCH2CH2CH2O-
H
NH2CONH-
5- MeO
6-MeO
5- MeO
6-MeO
MeO
MeO
MeO
MeO
MeO
MeO
MeO
MeO
Me
Me
Me
Me
H
H
H
NH2CONH-
3g
3h
3i
NH2CONH-
5- CF2HO MeO
Cl
Cl
6-CF2HO
5- MeO
6-MeO
MeO
Me
H
3j
Me
Me
PyNHCOCH2O-
PyNHCOCH2O-
3k
Me

Molecules 2009, 14
5250
Current PPIs have poor water solubility at neutral pH, so formulation of a suitable, intravenous
injectable formulation of PPI was not simple. Injectable PPI formulations require basic pH with a
special filtering device. Therefore, a simple i.v. injectable prodrug was designed by introducing a
carboxylate group at the arylsulfonyl group. This water-soluble prodrug was synthesized as shown in
Scheme 2.
Scheme 2. General method to prepare water-soluble 1-arylsulfonyl-benzimidazole compounds.
Compound R1
R2
R3
R4
H
H
H
H
H
H
H
R6 R7
R8
H
H
H
H
R9 R10
Y
Z
5a
6a
5b
6b
5c
6c
5d
H
H
H
H
H
H
H
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CF3CH2O-
CF3CH2O-
CF3CH2O-
CF3CH2O-
CF3CH2O-
CF3CH2O-
CH3O(CH2)
3O
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
CH3
H
CH3CH2 CH3
CH3CH2
H
H
H
CH3 CH3
CH3 CH3
H
H
H
CH3
H
H
CH3
6d
H
CH3
CH3O(CH2)
3O
H
H
H
H
H
H
5e
6e
5f
5-CH3O
CH3
CH3O-
CH3
CH3
CH3
CH3
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
CH3
CH3
CH3
CH3
H
H
H
H
5-CH3O
CH3
CH3O-
6-CH3O
CH3
CH3O-
6f
6-CH3O
CH3
CH3O-
5g
6g
5h
6h
5-CF2HO-
5-CF2HO-
5-CF2HO-
5-CF2HO-
CH3O-
CH3O-
CH3O-
CH3O-
CH3O-
CH3O-
H
CH3O-
H
CH3O-
H

Molecules 2009, 14
5251
Proton pump inhibitors are not soluble in aqueous solution at neutral pH and not stable enough to be
used in a solution of pH 7.4. In order to make an appropriate intravenous formulation, proton pump
inhibitors were converted to metal salts, and dissolved in a solution having high pH of approximately
9.5, therefore a special kit was required to dissolve these PPIs at the site where IV therapy was to be
performed. This suggests that a water-soluble and acid stable injectable form of PPI would be
advantageous. This property can be achieved by introducing a carboxylate group into the aryl moiety of
the sulfonyl substituent. The water soluble prodrug form of PPI was designed as shown in Schemes 3-5.
Scheme 3. General method to prepare water-soluble 1-(3-carboxybenzenesulfonyl)-
benzimidazole compounds.
N
R4
N
R7
C
S
R1
N
R3
R2
O
R6
R9
SO2Cl
R8
N
R1
R4
N
R7
SO2
R8
+
S
R6
N
H
O R2
R3
O
O
R9
C
O
1
O
Z
O2S
Z
Y
O2S
Y
7
8
N
R4
N
S
O R2
SO2
R1
O2
S
N
R3
NaHCO3
R7
+
R6
R9
CH3CN-H2O
Y
R8
Z
O-Na+
C
O
9
Compound R1
R2
R3
R4
H
H
H
H
CH3
CH3
CH3
CH3
R6 R7
R8 R9
Y
H
Z
NO2
8a
9a
8b
9b
8c
9c
8d
9d
8e
9e
8f
H
H
H
H
CH3 CF3CH2O-
CH3 CF3CH2O-
CH3 CF3CH2O-
CH3 CF3CH2O-
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
CH3
CH3
CH3
CH3
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
CH3O- CH3
CH3O-
H
H
H
H
H
H
5-MeO CH3 CH3O-
5-MeO CH3 CH3O-
6-MeO CH3 CH3O-
6-MeO CH3 CH3O-
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
CH3
CH3
CH3
CH3
CH3
CH3 CH3O(CH2)3O- H
CH3 CH3O(CH2)3O- H
CH3 CF3CH2O-
CH3 CF3CH2O-
CH3 CH3O(CH2)3O- H
CH3 CH3O(CH2)3O- H
H
H
9f
8g
9g

Molecules 2009, 14
5252
Scheme 4. General method to prepare water-soluble 1-arylsulfonyl-benzimidazole
compounds having di(carboxylate) groups.
Compound R1
R2
R3
R4
11a
11b
11c
12a
12b
12c
H
CH3
CH3
CH3
CH3
CH3
CH3
CF3CH2O-
CH3O-
CH3O-
CF3CH2O-
CH3O-
CH3O-
H
5-CH3O-
6-CH3O-
H
5-CH3O-
6-CH3O-
CH3
CH3
H
CH3
CH3

Molecules 2009, 14
5253
Scheme 5. General method to prepare water-soluble 1-arylsulfonyl-benzimidazole
compounds having a bis(carboxymethoxy) group.
Compound R1
R2
R3
R4
Y
15a
15b
15c
16a
16b
16c
H
CH3
CH3
CH3
CH3
CH3
CH3
CF3CH2O-
CH3O-
CH3O-
CF3CH2O-
CH3O-
CH3O-
H
H
5-CH3O-
6-CH3O-
H
5-CH3O-
6-CH3O-
CH3
CH3
H
CH3
CH3
CH3
CH3
H
CH3
CH3
These water-soluble prodrugs were stable at pH 7, which enables formulation in the pharmacy and
then distribution to different units in the hospital. PPIs are very unstable under acidic condition, so
PPIs were used as a basic metal salt form or formulated with basic materials, and furthermore, enteric
coating was required to protect the drugs from the acid of the stomach. However the arylsulfonyl-
prodrug form of PPIs overcomes the acid-instability. The prodrug was very stable under acidic
conditions and did not require the enteric coating. Also the prodrug significantly improved the shelf
life of the PPI. Furthermore, these carboxylates control absorption in the intestine, so plasma level of

Molecules 2009, 14
5254
PPI lasted much longer than PPI. Regiospecific derivatives of water-soluble proPPI were synthesized
[15,16] and Compound 6e was chosen for the clinical study [17].
2.2. Biology
PPIs are acid-activated prodrugs [1,18]. They are all membrane permeant weak bases with one pKa
(pKa1) at about 4.0, with the exception of rabeprazole that has this pKa at ~5.0. This pKa has two quite
distinct consequences. Firstly, it determines the ability of these drugs to accumulate selectively in the
highly acidic space of the parietal cell as compared to any other acidic space such as lysosomes or
distal renal tubular contents. There is no other membrane-enclosed space with a pH low enough to
accumulate the PPIs. Secondly, it contributes to the acid stability of the PPIs. If the pKa is too high, the
drug is relatively unstable at neutral pH. Following accumulation of the drug due to the protonated
pyridine, there is a second protonation on the imidazole N of the benzimidazole (pKa2), resulting in a
nucleophilic attack of the pyridine N on the 2C of the benzimidazole to form a planar tetracyclic
derivative that then forms a sulfenic acid that reacts with luminally exposed cysteines of the H,K-
ATPase [1].
However, 1-arylsulfonyl PPI prodrugs did not inhibit the gastric H,K-ATPase in an in vitro
experiment in the absence of the plasma or blood. Since the imidazole N of benzimidazole is blocked
by the arylsulfonyl group, acidity does not catalyze the intramolecular rearrangement to make the
active form. But this arylsulfonyl prodrug of PPI showed that these prodrugs can inhibit the H,K-
ATPase in the presence of plasma, because the arylsulfonyl group is easily cleaved in plasma or blood,
generating acid activatable PPIs. Many of 1-arylsulfonyl PPIs provided a t1/2 of between 1 min- 30 min
in the plasma. Generally speaking, hydrophilic 1-arylsulfonyl PPIs showed shorter half-lives than
hydrophobic 1-arylsulfonyl PPIs. In vivo, arylsulfonyl PPIs were detected at a much lower level than
the PPI products in the blood since the hydrolysis of arylsulfonyl PPI was very fast and absorption is
rate limiting. However, many of these arylsulfonyl PPIs resulted in a prolongation of the residence
time of the PPI in vivo, compared to PPI itself. This was frequently observed in carboxyarylsulfonyl
prodrugs and carboxamido-arylsulfonyl prodrugs (data not shown). A typical compound of 1-
arylsulfonyl PPI class of drug, compound 6e was shown to inhibit the H,K-ATPase only after
hydrolysis of the arylsulfonyl group in the plasma.
Hydrolysis of compound 6e in blood and inhibition of compound 6e
The gastric H+,K+-ATPase activity in the presence of compound 6e and omeprazole was measured
without pre-treatment of plasma or plasma fraction, or after plasma exposure. The compound was
ineffective against the ATPase without pretreatment and reacted rapidly after pre-incubation in plasma,
showing that the sulfonyl derivative is truly a prodrug converted to the active form by plasma
hydrolysis.

Molecules 2009, 14
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Table 1. Inhibition of H+,K+-ATPase by compound 6e without plasma or plasma fraction
pre-treatment or after pre-treatment of the plasma.
% Inhibition without
plasma pre-treatment plasma pre-treatment
% Inhibition after
Inhibitor
Inhibitor(µM)
Compound 6e
Compound 6e
Compound 6e
Compound 6e
Compound 6e
Omeprazole
Omeprazole
Omeprazole
5
10
20
50
100
5
-0.5 ± 3.6
0.1 ± 0.8
3.2 ± 7.4
5.3 ± 1.6
4.9 ± 0.4
68.0 ± 2.2
75.1 ± 6.5
89.5 ± 3.4
(n.d)*
37.2 ± 1.6
47.9 ± 1.8
79.0 ± 4.4
(n.d)
(n.d)
77.0 ± 4.6
87.6 ± 3.9
10
20
*(n.d): not determined.
Compound 6e, a sulfonamide derivative, the phenoxyacetic acid sodium salt derivative of
omeprazole, was chosen for clinical trials since this provided a candidate drug with several desirable
properties that can be predicted from its structure and pharmacokinetics. Since one of the benz-
imidazole nitrogens is substituted, the compound is acid stable, unlike any other PPIs and hence does
not require an enteric coating. Further, it is neutral pH stable, hence not requiring alkaline solutions for
stability in IV formulation, distribution or administration. It is slowly absorbed throughout the small
intestine, but then rapidly hydrolyzed in the blood to omeprazole and the sulfonic acid. It is not
genotoxic and no adverse events were found in either rats or dogs after dosing for 3 months at 1gm/kg
in rat and 500 mg/kg in dogs. Only trace quantities of the intact molecule are found in humans hence
its safety profile should resemble that of omeprazole.
The effect of various doses in man showed a linear dose relationship with no evidence for
saturation. Hence movement across the gut is by simple diffusion. The pharmacokinetic/
pharmacodynamic profile in human volunteers was investigated following administration of compound
6e [17]. This shows much longer residence time, above 50 ng/mL, compared to esomeprazole.
Compound 6e provides a great prolongation of the blood level of omeprazole and as found for
omeprazole shows increased bioavailability after five days dosing. But significantly, there is
prolongation of the residence time of omeprazole in the blood so that drug is present at effective levels
over 24 hours after five days administration in contrast to any currently used PPI. This leads to
considerable improvement in the profile of intragastric pH.
With esomeprazole, a period of high acidity in the morning and for about 6 h during the night, is
clearly sufficient to potentially cause damage and symptoms and prevent H. pylori from entering
growth phase. With once a day compound 6e, the pH is stably maintained at > 4.0. Averaging pH
values over 24 hours or at night shows the remarkable advantage of compound 6e not only at night but
also during the day [17].

Molecules 2009, 14
5256
3. Experimental
3.1. General
All reactions were carried out under an atmosphere of nitrogen. All commercial reagents were used
1
without further purification. NMR spectra were acquired using a Bruker 400 MHz spectrometer. H-
NMR data are reported in parts per million (δ) downfield from tetramethylsilane. The following
abbreviations are used: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), and br (broad).
Thin-layer chromatography (TLC) was performed using Merck silica gel 60 F254 0.2 mm alumina-
backed plates. Visualization was accomplished using ultraviolet light or one of the following stains:
anisaldehyde, phosphomolybdic acid, and potassium permanganate. Flash chromatography was carried
out using ICN Biomedicals silica gel 60 (230–400 mesh). Compound 6e was prepared by the method
as described in [15].
3.2. Preparation of arylsulfonyl chlorides
Many arylsulfonyl chlorides are commercially available and were used without further purification.
N-[4-(chlorosulfonyl)phenyl]urea was synthesized by a known method of Cremlyn et al. [19]. N-[(p-
chlorosulfonyl)phenyl]morpholine [20], 1,2-bis(carbamoylmethoxy)benzene [21], p-(dimethylamino)-
benzenesulfonyl chloride [22], 2-[p-(chlorosulfonyl)phenoxy]acetamide [23] were prepared as
previously described. Similarly, p-(dimethylamino)methylbenzenesulfonyl chloride,), (4-chloro-
sulfonylphenoxy)acetic acid methyl ester, and 2-[p-(chlorosulfonyl)phenoxy]-N-(2-pyridyl)acetamide
were synthesized by chlorosulfonylation of the corresponding aryl compounds using chlorosulfuric
acid.
3.2.1. Phenoxyacetic acid 2-(toluene-4-sulfonyl)ethyl ester
To a solution of phenoxyacetyl chloride (5.0 g) and triethylamine (3 g) in CH3CN (50 mL) was
added a solution of the alcohol (5.0 g) at 0 °C. After water was added, the reaction mixture was
extracted with CH2Cl2. The combined organic layers were washed with 1 N HCl solution and saturated
NaHCO3 solution, dried over MgSO4, and concentrated to give 8.0 g (97%) of the ester as light-yellow
solid. 1H-NMR (CDCl3) δ: 2.41 (s, 3 H), 3.47 (t, 2 H), 4.40 (s, 2 H), 4.53 (t, 2 H), 6.83 (d, 2 H), 7.01
(m, 1 H), 7.29 (d, 2 H), 7.36 (d, 2 H), 7.81 (d, 2 H).
3.2.2. (4-Chlorosulfonylphenoxy)acetic acid 2-(toluene-4-sulfonyl)ethyl ester
To a mixture of phenoxyacetic acid 2-(toluene-4-sulfonyl)ethyl ester (3.0 g) and CH2Cl2 (1 mL)
was added dropwise chlorosulfuric acid (3.0 mL, 5.2 g, 5.0 eq.) with ice bath cooling. After the
addition was complete, the ice bath was removed. The stirring was continued at room temperature for
3 h. The thick syrupy mixture was poured onto the crushed ice with vigorous stirring. The white
precipitates were collected by filtering, washed with methanol and cold benzene, and dried under high
1
vacuum overnight to yield 3.4 g (87%) of the title compound as white powder. H-NMR (CDCl3)
δ: 2.44 (s, 3 H), 2.47 (t, 2 H), 4.59 (t, 2 H), 4.63 (s, 2 H), 7.03 (d, 2 H), 7.40 (d, 2 H), 7.80 (d, 2 H),
7.98 (d, 2 H).

Molecules 2009, 14
5257
3.2.3. Phenoxy-2-butyric acid 2-(p-toluenesulfonyl)ethyl ester
To the mixture of phenoxy-2-butyric acid (2.51 g, 13.8 mmol), 2-(p-toluenesulfonyl)ethanol (2.8 g,
13.8 mmol), and p-dimethyaminopyridine (0.5 g) in THF (50 mL) was added N,N’-dicyclohexyl-
carbodiimide (3.14 g, 15.2 mmol, 1.1 eq) in THF (15 mL) at 0 °C. The mixture was stirred overnight at
room temperature. After the white solid was removed by filtration, the filtrate was concentrated. The
resulting oil was purified by column chromatography (hexane-CH2Cl2 to CH2Cl2) to yield 4.1 g (82%)
of a clear oil. 1H-NMR (CDCl3) δ: 1.02 (t, 3 H), 1.86 (m, 2 H), 2.45 (s, 3 H), 3.40 (m, 2 H), 4.45 (m, 3
H), 6.82 (d, 2 H), 6.97 (t, 1 H), 7.26 (t, 2 H), 7.37 (d, 2 H), 7.77 (d, 2 H).
3.2.4. 4-Chlorosulfonylphenoxy-2-butyric acid 2-(p-toluenesulfonyl)ethyl ester
To a mixture of phenoxy-2-butyric acid 2-(p-toluenesulfonyl)ethyl ester (4.0 g, 11.0 mmol) and
CH2Cl2 (1 mL) was added dropwise chlorosulfuric acid (3.7 mL, 6.4 g, 5.0 eq.) with ice bath cooling.
After addition was complete, the ice bath was removed. The mixture was continued to stir at room
temperature for 3 h. The thick syrupy mixture was poured onto the crushed ice with vigorous stirring.
The gummy precipitates were observed. The mixture was extracted with CH2Cl2 (500 mL). The
organic layer was dried over MgSO4, and concentrated to yield 4.1 g (81%) of the thick yellow oil. 1H-
NMR (CDCl3) δ: 1.06 (t, 3 H), 1.97 (m, 2 H), 2.45 (2 s, 3 H), 3.41 (m, 2 H), 4.46 (m, 1 H), 4.63 (m,
2 H), 7.01 (dd, 2 H), 7.38 (d, 2 H), 7.78 (d, 2 H), 7.96 (dd, 2 H).
3.2.5. 3,5-Dimethylphenoxyacetic acid 2-(p-toluenesulfonyl)ethyl ester
The mixture of 3,5-dimethylphenoxyacetic acid (2.3 g, 12.6 mmol), 2-(p-toluenesulfonyl)ethanol
(2.3 g, 11.5 mmol), and p-toluenesulfonic acid hydrate (0.5 g) in toluene (100 mL) was refluxed with a
Dean-Stark trap for 4 h. After water (100 mL) was added, the mixture was extracted with CH2Cl2
(200 mL). The combined organic layers were washed with saturated NaHCO3 solution two times, dried
over MgSO4, and concentrated to give 4.4 g (97%) of yellowish thick oil. 1H-NMR (CDCl3) δ: 2.29 (s,
6 H), 2.42 (s, 3 H), 4.37 (s, 2 H), 4.53 (t, 2 H), 6.64 (s, 1 H), 7.36 (m, 2 H), 7.81 (d, 2 H).
3.2.6. 4-Chlorosulfonyl-3,5-dimethylphenoxyacetic acid 2-(p-toluenesulfonyl)ethyl ester
To the mixture of 3,5-dimethylphenoxyacetic acid 2-(p-toluenesulfonyl)ethyl ester (4.0 g,
11.0 mmol) and CH2Cl2 (1.5 mL) was added dropwise ClSO3H (3.7 mL) with cooling, and then the
mixture was stirred vigorously at 0 °C for 2 h. The thick oil was poured onto the crushed ice with
vigorous stirring. The mixture was extracted with CH2Cl2 (500 mL). The organic layer was dried over
MgSO4, and concentrated to give thick oil. Upon treatment with ether (2 mL) and hexane (2 mL), the
oil was solidified. The solid was dried under vacuum to give 4.7 g (94%) of off-white solid. 1H- NMR
(CDCl3) δ: 2.44 (s, 3 H), 2.73 (s, 6 H), 3.46 (t, 2 H), 4.57 (t, 2 H), 4.60 (s, 2 H), 6.80 (s, 2 H), 7.38 (d,
2 H), 7.80 (d, 2 H).

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3.2.7. 6-[2-(3,5-Dimethylphenoxy)acetylamino]hexanoic acid
After the mixture of the 3,5-dimethylphenoxyacetic acid (9.3 g, 51.6 mmol) and SOCl2 (11.3 mL,
18.5 g, 156 mmol, 3.0 eq) in benzene (10 mL) was refluxed for 2 h, the volatile materials were
removed by vacuum distillation to give the acid chloride, a light brown oil.Aa solution of the acid
chloride (prepared in the previous step) in CH3CN (100 mL) and a solution of NaHCO3 (6.5 g, 77.0
mmol, 1.5 eq) in H2O (80 mL) were both added dropwise with ice-bath cooling to a solution of 6-
amino-n-caproic acid (13.5 g, 103 mmol, 2.0 eq) and NaOH (4.2 g, 105 mmol) in H2O (100 mL) and
CH3CN (130 mL). The mixture was stirred vigorously overnight. After most of CH3CN was removed
under reduced pressure, the mixture was acidified with conc. HCl to pH 2 at room temperature. The
white precipitates were collected by filtration, washed with H2O followed by hexane, and dried under
1
high vacuum to yield 14.5 g (95%) of white solid. H-NMR (CDCl3) δ: 1.35 (m, 2 H), 1.56 (m, 2 H),
1.64 (m, 2 H), 2.29 (s, 6 H), 2.35 (m, 2 H), 3.34 (m, 2 H), 4.44 (s, 2 H), 6.47 (s, 2 H), 6.70 (s, 1 H).
3.2.8. 6-[2-(3,5-Dimethylphenoxy)acetylamino]hexanoic acid 2-(3-nitrobenzenesulfonyl)ethyl ester
A mixture of 6-[2-(3,5-dimethyl-phenoxy)acetylamino]hexanoic acid (3.0 g, 10.2 mmol), 2-(m-
nitrobenzenesulfonyl)ethanol (2.3 g, 10.0 mmol), and TsOH hydrate (0.5 g) in toluene (100 mL) was
refluxed overnight with a Dean-Stark trap. After water (100 mL) was added, the mixture was extracted
with CH2Cl2 (200 mL). The combined organic layers were washed with saturated NaHCO3 solution
two times, dried over anhydrous MgSO4, and concentrated. The oil was purified by column
chromatography (1% MeOH in CH2Cl2) to give 4.8 g (89%) of yellowish thick oil. 1H-NMR (CDCl3)
δ: 1.25 (m, 2 H), 1.51 (m, 4 H), 2.07 (t, 2 H), 2.27 (s, 6 H), 2.31 (m, 2 H), 3.53 (t, 2 H), 4.45 (m, 4 H),
6.53 (s, 2 H), 6.65 (s, 1 H), 7.82 (t, 1 H), 8.26 (d, 1 H), 8.52 (m, 1 H), 8.77 (s, 1 H).
3.2.9. 6-[2-(4-Chlorosulfonyl-3,5-dimethylphenoxy)acetylamino]hexanoic acid 2-(3-nitrobenzene-
sulfonyl)ethyl ester
To
a
cooled solution of 6-[2-(3,5-dimethyl-phenoxy)acetylamino]hexanoic acid 2-(3-
nitrobenzenesulfonyl)ethyl ester (4.6 g, 9.1 mmol) in CH2Cl2 (3 mL) was added dropwise ClSO3H (3
mL, 5 eq., 45.5 mmol)) at 0 °C. During the reaction, small aliquots of the reaction mixture was taken
out and treated with ice, extracted with ethyl acetate, and ethyl acetate layer was analyzed by thin layer
chromatography (TLC), which showed the reaction was completed after 30 min. The thick mixture
was poured onto the crushed ice with vigorous stirring, resulted in yellow gummy material in the
bottom of the flask. The mixture was extracted with CH2Cl2 (300 mL), and the organic layer was dried
1
over anhydrous MgSO4, and concentrated to give 2.2 g (40%) of white foam. H-NMR (CDCl3)
δ: 1.26 (m, 2 H), 1.50 (m, 4 H), 2.08 (t, 2 H), 2.73 (s, 6 H), 2.30 (m, 2 H), 3.52 (t, 2 H), 4.44 (t, 2 H),
4.63 (s, 2 H), 6.80 (s, 2 H), 7.82 (t, 1 H), 8.26 (d, 1 H), 8.52 (m, 1 H), 8.77 (s, 1 H).
3.2.10. 3-Chlorosulfonylbenzoic acid 2-(3-nitrobenzenesulfonyl)ethyl ester
To the solid 3-chlorosulfonylbenzoic acid (3.2 g, 14.4 mmol) was added solid PCl5 (3.0 g,
14.4 mmol) at room temperature with mixing. With heating to 70 °C, the mixture started to react to
give a brown liquid, which was heated for 2 h more. After the resulting POCl3 was removed by

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vacuum distillation, the brown oil was dissolved in CH3CN (15 mL) and then 2-(3-
nitrobenzenesulfonyl) ethanol (2.8 g, 12.0 mmol) was added. The mixture was heated to reflux
temperature for 36 h. After water (100 mL) was added, the mixture was extracted with CH2Cl2 (500
mL). The organic extract was dried over anhydrous MgSO4, and concentrated. The resulting oil was
purified by short column chromatography (eluent: CH2Cl2 to 1% MeOH in CH2Cl2) to give a brown
semisolid, which was solidified by treating with ether-EtOAc to yield 2.75 g (53%) of a white solid.
1H-NMR (DMSO-d6) δ: 4.08 (t, 2 H), 4.58 (t, 2 H), 7.33 (t, 1 H), 7.40 (d, 1 H), 7.77 (d, 1 H), 7.84 (m,
2 H), 8.32 (d, 1 H), 8.40 (d, 1 H), 8.56 (s, 1 H).
3.2.11. 5-Chlorosulfonyl-2-methoxybenzoic acid
2-Methoxybenzoic acid (5.0 g, 32.9 mmol) was warmed with chlorosulfuric acid (164 mmol,
5.0 eq., 19.1 g, 11.0 mmol) at 50 °C for 2 h. The brown thick liquid was poured on crushed ice with
vigorous stirring. The resulting white precipitates were filtered, washed with H2O, and dried under
1
high vacuum overnight to give 4.8 g (58%) of a white powder. H-NMR (DMSO-d6) δ: 3.77 (s, 3 H),
7.03 (d, 1 H), 7.65 (dd, 1 H), 7.84 (s, 1 H).
3.2.12. 2-(p-Toluenesulfonyl)ethyl 5-chlorosulfonyl-2-methoxybenzoate
The mixture of 2-methoxybenzoic acid (3.0 g, 12.0 mmol) and SOCl2 (6 mL) was heated to the
reflux temperature for 2 h. Then all of excess SOCl2 was distilled off. After the resulting oil was
dissolved in CH2Cl2 (20 mL), 2-(p-toluenesulfonyl)ethanol (2.0 g, 10 mmol) in CH2Cl2 (10 mL) was
added at room temperature. Then the mixture was heated to the reflux temperature for 3 h. After the
volatile materials were removed under reduced pressure, the resulting oil was purified by column
chromatography (silica gel, hexane: CH2Cl2 = 1:1 to CH2Cl2) to give 3.5 g (81%) of clear thick oil.
1H- NMR (CDCl3) δ: 2.51 (s, 3 H), 3.76 (t, 2 H), 4.17 (s, 3 H), 4.83 (t, 2 H), 7.29 (d, 1 H), 7.46 (m, 2
H), 7.97 (m, 2 H), 8.29 (dd, 1 H), 8.42 (d, 1 H).
3.2.13. 3-Chlorosulfonylbenzoic acid 2-(toluene-4-sulfonyl)ethyl ester
A heterogeneous mixture of 3-chlorosulfonyl benzoic acid (11.0 g, 50.0mmol) in SOCl2 (18 mL)
was refluxed for 3 h. Thereafter the excess of SOCl2 was removed, the residual brown oil was
dissolved in CH3CN (60 mL) and then 2-(p-tolylsulfonyl)ethanol (9.4 g, 47.0 mmol, 0.95 eq.) was
added. The mixture was heated to reflux temperature for 20 h. Thereafter the most of CH3CN was
removed, the resulting oil was purified by short column chromatography (silica gel, CH2Cl2) to give
light brown oil, which was dried further under vacuum to yield 19.1 g (95%) of a light brown solid.
1H-NMR (CDCl3) δ: 2.34 (s, 3 H), 3.61 (t, 2 H), 4.73 (t, 2 H), 7.29 (d, 2 H), 7.68 (t, 1 H), 7.81 (d, 2 H),
8.19 (m, 2 H), 8.43 (s, 1 H).
3.2.14. 3-(2-Methoxyphenyl)propionic acid 2-(toluene-4-sulfonyl)ethyl ester
A mixture of 3-(2-methoxyphenyl)propionic acid (5.0 g, 27.8 mmol), 2-(p-toluenesulfonyl)ethanol
(5.5 g, 27.8 mmol), and p-toluenesulfonic acid hydrate (0.5 g) in toluene (100 mL) was refluxed with a
Dean-Stark trap for 5 h. Then water was added and the mixture was extracted with CH2Cl2 (500 mL)

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The combined organic layers were washed with saturated NaHCO3 solution (2 × 200 mL), dried over
1
MgSO4, and concentrated to give the title compound (5.5 g, 88%) as a light brown liquid. H-NMR
(CDCl3) δ: 2.39 (m, 5 H), 2.79 (t, 2 H), 3.40 (t, 2 H), 3.81 (s, 3 H), 4.37 (t, 2 H), 6.87 (m, 2 H), 7.07
(m, 1 H), 7.17-7.35 (m, 3 H), 7.78 (d, 2 H).
3.2.15. 3-(5-Chlorosulfonyl-2-methoxyphenyl)propionic acid 2-(toluene-4-sulfonyl)ethyl ester
To a mixture of 3-(2-methoxyphenyl)propionic acid 2-(toluene-4-sulfonyl)ethyl ester (5.0 g, 13.8
mmol) and CH2Cl2 (5 mL) was added dropwise chlorosulfuric acid (8.0 g, 69.0 mmol, 5.0 eq) with ice-
bath cooling. The mixture was stirred at 0 °C for 30 min. The resulting thick oil was poured onto
crushed ice with vigorous stirring. The mixture was extracted with EtOAc (400 mL). The organic layer
was dried over MgSO4, and concentrated by evaporation to give a thick oil, which was purified by
column chromatography (CH2Cl2) to yield 3-(5-chlorosulfonyl-2-methoxyphenyl)propionic acid 2-
1
(toluene-4-sulfonyl)ethyl ester (4.7 g, 74%) as a light brown oil. H-NMR (CDCl3) δ: 2.40 (s, 3 H),
2.47 (t, 2 H), 2.89 (t, 2 H), 3.42 (t, 2 H), 3.94 (s, 3 H), 4.40 (t, 2 H), 6.98 (d, 1 H), 7.36 (d, 2 H), 7.75
(d, 1 H), 7.80 (d, 2 H), 7.91 (m, 1 H).
3.2.16. 3-Chlorosulfonyl-4-methylbenzoic acid 2-(p-tolylsulfonyl)ethyl ester
A heterogeneous mixture of 3-chlorosulfonyl-4-methylbenzoic acid (11.7 g, 50.0mmol) in SOCl2
(18 mL) was refluxed for 3 h. After the excess of SOCl2 was removed, the residual brown oil was
dissolved in CH3CN (50 mL), and then 2-(p-tolylsulfonyl) ethanol (9.4 g, 47.0 mmol, 0.95 eq.) was
added. The mixture was heated to reflux temperature for 24 h. Thereafter most of CH3CN was
removed, the resulting oil was purified by short column chromatography (CH2Cl2 to 1% MeOH in
CH2Cl2) to give a light brown oil, which solidified on standing. The solid was dried further under
vacuum to yield 19.5 g (99%) of 3-chlorosulfonyl-4-methylbenzoic acid 2-(p-tolylsulfonyl)ethyl ester.
1H-NMR (CDCl3) δ: 2.33 (s, 3 H), 2.84 (s, 3 H), 3.50 (t, 2 H), 4.70 (t, 2 H), 7.29 (d, 2 H), 7.46 (d, 1
H), 7.79 (d, 2 H), 8.03 (d, 1 H), 8.42 (s, 1 H).
3.2.17. 5-Chlorosulfonyl-2-[2-(toluene-4-sulfonyl)-ethoxycarbonylmethoxy]-benzoic acid 2-(toluene-
4-sulfonyl)ethyl ester (10)
A mixture of 2-(carboxymethoxy)-5-chlorosulfonyl-benzoic acid (4.0 g, 13.5 mmol) and thionyl
chloride (10 mL) was heated to reflux temperature for 2 h, and then the excess thionyl chloride was
distilled off. The residual oil was dissolved in CH3CN (15 mL) and 2-(tolylsulfonyl)ethanol (5.0 g,
25.0 mmol) was added. The mixture was heated to reflux temperature for 40 h, then allowed to cool
and water was added. The mixture was extracted with EtOAc (400 mL) and the organic layer was
1
washed with 1 N NaHCO3, dried, and concentrated to yield 7.7 g (93%) of a brown foam. H-NMR
(DMSO-d6) δ 2.44 (m, 6 H), 3.46 (t, 2 H), 3.59 (t, 2 H), 4.57 (t, 2 H), 4.64 (t, 2 H), 4.76 (s, 2 H), 7.30
(d, 1 H), 8.07 (d, 1 H), 8.28 (s, 1 H).

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3.2.18. [2-(2-Benzenesulfonyl-ethoxycarbonylmethoxy)-phenoxy]acetic acid 2-benzenesulfonyl-ethyl
ester (13)
A mixture of 1,2-phenylenedioxydiacetic acid (available from Aldrich, 3.0 g, 13.3 mmol),
2-(phenylsulfonyl) ethanol (5.0 g, 26.5 mmol), and p-TsOH·H2O (0.5 g) in benzene (100 mL) was
heated overnight to reflux temperature with a Dean-Stark trap. Thereafter the mixture was concentrated
by evaporation under reduced pressure, water was added and the mixture was extracted with CH2Cl2
(500 mL). The combined organic layers were washed with saturated NaHCO3 solution (300 mL) and
water (300 mL), dried, and concentrated under reduced pressure. The resulting residual oil was
purified by short path column chromatography (silica gel, CH2Cl2) to give the compound 13 (7.4 g,
99%) as a light brown oil. 1H-NMR (CDCl3) δ 3.48 (t, 4 H), 4.48 (s, 4 H), 4.53 (t, 4 H), 6.80 (t, 2 H),
6.95 (m, 2 H), 7.57 (m, 4 H), 7.64 (m, 2 H), 7.92 (m, 4 H).
3.2.19. [2-(2-Benzenesulfonyl-ethoxycarbonylmethoxy)-4-chlorosulfonyl-phenoxy]-acetic acid 2-
benzenesulfonyl-ethyl ester (14)
To a solution of [2-(2-benzenesulfonyl-ethoxycarbonylmethoxy)-phenoxy]acetic acid 2-benzene-
sulfonyl-ethyl ester (7.4 g, 13.2 mmol) in CH2Cl2 (10 mL) was added dropwise ClSO3H (5.0 mL, 8.8
g, 75.8 mmol, 5.7 eq) at 0 °C with vigorous stirring. The mixture was stirred at 0 °C for 1.5 h. and then
poured onto crushed ice with vigorous stirring, resulting in a thick mass. This was extracted with
CH2Cl2 (500 mL). The organic layer was dried over anhydrous MgSO4, and concentrated under
reduced pressure. The residual oil was dried under vacuum overnight to give the title compound (8.0 g,
92%) as an off-white foam. 1H-NMR (CDCl3) δ 3.48 (m, 4 H), 4.57 (m, 6 H), 4.69 (s, 2 H), 6.96 (d, 1
H), 7.39 (s, 1 H), 7.59 (m, 4 H), 7.67 (m, 3 H), 7.92 (m, 4 H).
3.2.20. {2-[2-(Toluene-4-sulfonyl)-ethoxycarbonylmethoxy]-phenoxy}-acetic acid 2-(toluene-4-
sulfonyl)ethyl ester
1,2-Phenylenedioxydiacetic acid (5 g, 22.1 mmole) and 2-(p-tolylsulfonyl)ethanol (8.8 g,
44.2 mmole) were added to toluene (100 mL). Catalytic amounts of p-toluenesulfonic acid hydrate
(0.5 g) were added and the reaction mixture was refluxed with removal of water, using a Dean-Stark
trap. After 6 h of reflux, the toluene was distilled off. The residual material was dissolved in
dichloromethane (250 mL) and washed with water (200 mL), and 6 N sodium bicarbonate solution
(150 mL). The dichloromethane layer was dried over anhydrous magnesium sulfate, and concentrated
1
under reduced pressure to yield 13 g (99%) of the title compound. H-NMR (CDCl3) δ 2.46 (s, 6 H),
3.46 (t, 4 H), 4.52 (m, 8 H), 6.80 (m, 2 H), 6.94 (m, 2 H), 7.35 (d, 4 H), 7.78 (d, 4 H).
3.2.21. {4-Chlorosulfonyl-2-[2-(toluene-4-sulfonyl)-ethoxycarbonylmethoxy]-phenoxy}-acetic acid 2-
(toluene-4-sulfonyl)ethyl ester
{2-[2-(Toluene-4-sulfonyl)-ethoxycarbonylmethoxy]-phenoxy}-acetic acid 2-(toluene-4-sulfonyl)-
ethyl ester (13 g, 22 mmole) was added to dichloromethane (30 mL), and cooled in an ice bath.
Chlorosulfuric acid (10 mL) was slowly added, and the mixture was stirred at 0 °C for 2 h, then at
room temperature for 1 h. Thereafter it was poured into crushed ice (200 g) with stirring. The

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precipitates were extracted with dichloromethane (600 mL). The dichloromethane layer was dried over
anhydrous magnesium sulfate and concentrated, the residue was dried in vacuo to yield 17.3 g of {4-
chlorosulfonyl-2-[2-(toluene-4-sulfonyl)-ethoxycarbonylmethoxy]-phenoxy}-acetic acid 2-(toluene-4-
1
sulfonyl)ethyl ester. H-NMR (CDCl3) δ 2.43 (2 s, 6 H), 3.46 (m, 4 H), 4.56 (m, 4 H), 4.59 (s, 2 H),
4.71 (s, 2 H), 6.97 (d, 1 H), 7.41 (m, 5 H), 7.67 (d, 1 H), 7.79 (m, 4 H).
3.2.22. Methyl 2-[4-(chlorosulfonyl)phenoxy]acetate
Methyl phenoxyacetate (99.9 g, 0.6 mol) was added dropwise to chlorosulfuric acid (279.6 g,
159.5 mL, 2.4 mol) at –5 °C at such a rate to maintain internal temperature between 0 to –5 °C (the
addition took about 60 min). Some solid formed during this addition. The cooling bath was removed
and the reaction mixture was stirred at room temperature for an additional 1.5 h. The reaction mixture
was poured into a vigorously stirring mixture of dichloromethane (900 mL) and methanol (100 mL) at
0 °C. After 15 min the cooling bath was removed and the resulting mixture was stirred at room
temperature for 1 h. The resulting mixture was washed with ice cold water (2 × 250 mL). The
combined aqueous layers were back extracted with dichloromethane (1 × 250 mL). The combined
organic layers were washed with brine (1 × 200 mL), dried over anhydrous magnesium sulfate (15 g)
and concentrated under reduced pressure to give 132 g (83%) of the title compound as a white solid.
1H-NMR (CDCl3) δ 8.2-7.2 (AB, 4H), 4.95 (s, 2H), 3.95 (s, 3H).
3.3. General procedure of synthesis of 1-arylsulfonyl-2-(2-pyridylmethylsulfinyl)benzimidazoles 3
Compounds 3 were prepared by the reaction of arylsulfonyl chloride with 2-(2-
pyridylmethylsulfinyl)benzimidazole in the presence of base. In a typical run, 1-benzenesulfonyl-2-
[[[(4-(3-methoxypropoxy)-3-methyl-2-pyridyl]methyl]sulfinyl]-1H-benzimidazole (3a) was prepared
as follows: benzenesulfonyl chloride (94 mg) was added to 2-[[[4-(3-methoxypropoxy)-3-methyl-2-
pyridyl]methyl]sulfinyl]-1H-benzimidazole sodium salt (191 mg) in dichloromethane (15 mL) and
triethylamine (0.1 mL). The reaction mixture was stirred at room temperature overnight. The reaction
mixture was washed with water (10 mL). The organic layer was dried over anhydrous magnesium
sulfate, and evaporated. Residual material was crystallized from acetonitrile-ethyl ether. 210 mg of the
title product was obtained. mp 126-128 °C; 1H-NMR (CDCl3) δ: 1.97-2.09 (m, 2H), 2.27 (s, 3H), 3.34
(s, 3H), 3.52-3.57 (t, 3H), 4.05-4.10 (t, 3H), 4.81-5.03 (q, AB, 2H), 6.66 (d, 1H), 7.38-7.53 (m, 4H),
7.61-7.65 (t, 1H), 7.80 (d, 1H), 8.00 (d, 1H), 8.11-8.16 (m, 3H).
Omeprazole (1a) and pantoprazole (1c) provided an isomeric mixture of 1-arylsulfonyl products in
the reaction with arylsulfonyl chloride, since the N1 position and N3 positions of the benzimidazole
ring can both react with chloride. For example, omeprazole (1a) reacts with benzenesulfonyl chloride
to
give
a
mixture
of
1-benzenesulfonyl-5-methoxy-2-[(3,5-dimethyl-4-methoxy-2-
pyridyl)methylsulfinyl]-1H-benzimidazole (3d) and 1-benzensulfonyl-6-methoxy-2-[(3,5-dimethyl-4-
methoxy-2-pyridyl)methylsulfinyl]-1H-benzimidazole (3e) as follows: 5-methoxy-2-[(3,5-dimethyl-4-
methoxy-2-pyridyl)methylsulfinyl]-1H-benzimidazole (172 mg, 0.5 mmole) was dissolved in
dichloromethane (20 mL) and triethylamine (0.140 mL). The solution was cooled to 0-4 °C in an ice
bucket. Benzenesulfonyl chloride (96 mg, 0.55 mmole) was slowly added and stirred at 0-4 °C with
thin layer chromatography monitoring (developing solvent system: 10:1 chloroform-methanol and 1:1

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acetonitrile-chloroform). After the reaction was complete, the organic layer was washed with an
aqueous solution composed of 0.1 M NaCl, and 0.1 M sodium phosphate, pH 8.5 (10 mL). The organic
layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The
residual material was crystallized from dichloromethane-ethyl ether-heptane to provide 127 mg of
product. mp 87-89 °C (decomposition). Heptane was introduced to the remaining organic layer to
provide a second crop of product (104 mg). After combining the solids, 231 mg of the product (yield
95%) was obtained. The product was a mixture of 1-benzensulfonyl-5-methoxy-2-[(3,5-dimethyl-4-
methoxy-2-pyridyl)methylsulfinyl]-1H-benz-imidazole (3d) and 1-benzene-sulfonyl-6-methoxy-2-[(3,5-
dimethyl-4-methoxy-2-pyridyl)-methylsulfinyl]-1H-benzimidazole (3e) (3:2 ratio). 1H-NMR (CDCl3) δ:
8.10-8.15 (m, 3H), 7.45-7.80 (m, 5H), 7.0-7.1 (m, 1H), 4.8-5.0 (2q, 2AB total 2H), 3.83 and 3.92 (2s,
total 3H), 3.75 (s, 3H), 2.31(s, 3H), 2.23 (s, 3H).
N-(4-{[2-({[3-Methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl}sulfinyl)benzimidazol-1-yl]sulfonyl}-
phenyl)urea (3b): 67% yield; mp 115 °C (decomposition); 1H-NMR (CDCl3) δ: 2.25 (s, 3H), 4.37-4.42
(q, 2H), 4.6-4.85 (q, AB, 2H), 6.67 (d, 1H), 7.35-7.42 (m, 2H), 7.61-7.75 (m, 3H), 7.89-8.05 (m, 2H),
8.27-8.38 (m, 2H).
N-(4-{[2-({[4-(3-Methoxypropoxy)-3-methyl-2-pyridyl]methyl}sulfinyl)benzimidazol-1-yl]sulfonyl}-
phenyl)urea (3c): 74% yield, 1H-NMR (CDCl3) δ: 2.03-2.07 (m, 2H), 2.18 (s, 3H), 3.34 (s, 3H), 3.52-
3.54 (t, 2H), 4.05-4.08 (t, 2H), 4.76-5.00 (q, AB, 2H), 5.50-5.61 (br, -NH2), 6.69 (d, 1H), 7.33-7.37
(m, 3H), 7.51 (d, 1H), 7.65 (d, 1H), 7.81 (d, 2H), 7.98 (d, 1H), 8.17 (d, 1H), 8.97 (s, -NH-).
N-[4-[[5-Methoxy-2-[[(3,5-dimethyl-4-methoxy-2-pyridyl)methyl]sulfinyl]benzimidazol-1-yl]sulfonyl]-
phenyl]urea (3f) and N-[4-[[6-methoxy-2-[[(3,5-dimethyl-4-methoxy-2-pyridyl)methyl]-sulfinyl]-
benzimidazol-1-yl]sulfonyl]phenyl]urea (3g) (4:3 ratio): yield 86%; mp 154-158 °C (decomposition);
1H-NMR (CDCl3) δ: 2.19 (s, 3H), 2.20 and 2.21 (2s, total 3H), 3.69 and 3.70 (2s, total 3H), 3.76 and
3.89 (2s, total 3H), 4.75-4.94 (q, AB, 2H), 5.6-5.7 (br, NH2), 6.95-7.08 (d, 1H), 7.05 (s, 1H), 7.43-7.86
(m, 5H), 8.12 (s, 1H), 9.0 (br, NH).
1-(4-Chlorobenzenesulfonyl)-5-difluoromethoxy-2-[(3,4-dimethoxy-2-pyridyl)methyl-sulfinyl]-1H-
benzimidazole (3h) and 1-(4-chlorobenzenesulfonyl)-6-difluoromethoxy-2-[(3,4-di-methoxy-2-
1
pyridyl)methylsulfinyl]-1H-benzimidazole (3i) (5:4 ratio): yield 74.5%; mp 82-83 °C; H- NMR
(CDCl3) δ: 8.05-8.15 (m, 2H), 8.0 (d, 1H), 7.78-7.81 (m, 1H), 7.45-7.6 (m, 2H), 7.2-7.3 (m, 1H), 6.80-
6.81 (d, 1H), 6.5-6.6 (d, 1H), 4.9-5.0 (q, 2H), 3.93 (s, 3H).
2-{4-[(5-Methoxy-2-{[(3,5-dimethyl-4-methoxy-2-pyridyl)methyl]sulfinyl}benzimidazol-1-yl)sulfonyl]-
phenoxy}-N-(2-pyridyl)acetamide (3j) and 2-{4-[(6-methoxy-2-{[(3,5-dimethyl-4-methoxy-2-pyridyl)-
methyl]sulfinyl}benzimidazol-1-yl)sulfonyl]phenoxy}-N-(2-pyridyl)acetamide (3k) (2:1 ratio): yield
87%; mp 76-80 °C; 1H-NMR (CDCl3) δ: 2.21 and 2.23 (2s, total 3H), 2.32 (s, 3H), 3.74 and 3.75 (2s,
total 3H), 3.83 and 3.93 (2s, total 3H), 4.65 (s, 2H), 4.83-4.92 (q, AB, 2H), 6.99-7.11 (m, 5H), 7.46 (d,
1H), 7.68-7.88 (m, 2H), 8.75 (br, NH).

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2-(4-{[2-({[3-Methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl}sulfinyl)benzimidazol-1-yl]sulfonyl}-
1
phenoxy)-N-(2-pyridyl)acetamide (3l): yield 94%; mp 78-81 °C; H-NMR (CDCl3) δ: 2.31 (s, 3H),
4.34-4.40 (q, 2H), 4.71 (s, 2H), 4.84-5.05 (q, AB, 2H), 6.62 (d, 1H), 7.09 (d, 2H), 7.29-7.47 (m, 2H),
7.62-7.80 (m, 2H), 7.98 (d, 1H), 8.11 (d, 2H), 8.20-8.29 (m, 4H), 8.92 (br, NH).
2-{4-[(5-(Difluoromethoxy)-2-{[(3,4-dimethoxy-2-pyridyl)methyl]sulfinyl}benzimidazol-1-yl)sulfonyl]-
phenoxy}-N-(2-pyridyl)acetamide (3m) and 2-{4-[(6-(difluoromethoxy)-2-{[(3,4-dimethoxy-2-pyridyl)-
methyl]sulfinyl}benzimidazol-1-yl)sulfonyl]phenoxy}-N-(2-pyridyl)acetamide (3n) (2:1 ratio by NMR):
yield 88%; mp 95-101 °C; 1H-NMR (CDCl3) δ: 3.90 (s, 3H), 3.93 (s, 3H), 4.67 (s, 2H), 4.85-5.00 (2q,
2AB, 2H; s like, 1H), 6.52-6.80 (m, 2H), 7.08 (m, 3H), 7.29-7.40 (d, 1H), 7.58-7.80 (m, 2H), 7.97-8.16
(m, 3H), 8.22 (d, 1H), 8.30 (d, 1H), 8.82 (br, NH).
1-[4-[3-(Morpholin-4-yl)
propoxy]
benzenesulfonyl]-5-methoxy-2-[[(3,5-dimethyl-4-methoxy-2-
pyridyl)methyl]sulfinyl]-1H-benzimidazole (3o) and 1-[4-[3-(morpholin-4-yl) propoxy] benzene-
sulfonyl]-6-methoxy-2-[[(3,5-dimethyl-4-methoxy-2-pyridyl)methyl]sulfinyl]-1H-benz-imidazole (3p)
1
(1:1 ratio): yield 87%; mp 98-102 °C (decomposition); H-NMR (CDCl3) δ: 1.97-2.05 (m, 2H), 2.09
(s, 3H), 2.20 (s, 3H) 3.05-3.15 (m, 6H), 3.58 (s, 3H), 3.65-3.80 (m, 4H), 3.81 & 3.92 (2s, total 3H),
3.82-3.95 (t, 2H), 4.73-4.94 (q, AB, 2H), 6.89-6.91 (d, 2H), 7.4-7.6 (m, 3H), 7.79-8.0 (m, 2H), 8.17
(s, 1H).
1-[(4-Dimethylaminomethyl)benzenesulfonyl]-5-methoxy-2-[(3,5-dimethyl-4-methoxy-2-pyridyl)-
methylsulfinyl]-1H-benzimidazole (3q) and 1-[(4-dimethylaminomethyl)benzenesulfonyl]-6-methoxy-2-
1
[(3,5-dimethyl-4-methoxy-2-pyridyl)methylsulfinyl]-1H-benzimidazole (3r) (1:1 ratio): yield 89%; H-
NMR (CDCl3) δ: 2.22 (s, 3H), 2.26 (s, 3H), 3.00 (s, 6H), 3.73 (s, 3H), 3.80 and 3.91 (s, s; 5-methoxy
and 6-methoxy), 4.77-4.99 (q, 2H), 6.54-6.60 (m, 2H), 6.93-8.21 (m, 6H).
1-[(N,N-Dimethylamino)benzene-4-sulfonyl]-5-methoxy-2-[[(3,5-dimethyl-4-methoxy-2-pyridyl)-
methyl]sulfinyl]-1H-benzimidazole (3s) and 1-[(N,N-dimethylamino)benzene-4-sulfonyl]-6-methoxy-2-
[[(3,5-dimethyl-4-methoxy-2-pyridyl)methyl]sulfinyl]-1H-benzimidazole (3t) (1:1 ratio): yield 87%;
mp 92-96 °C; 1H-NMR (CDCl3) δ: 2.24 (s, 3H), 2.30 (s, 3H), 3.02 (s, 3H), 3.03 (s, 3H), 3.75 (s, 3H),
3.83 & 3.92 (2s, total 3H), 4.77-4.94 (2q, AB and A’B’, total 2H), 6.57-6.61 (m, 2H), 6.96-7.07 (m,
1H), 7.48 & 7.68 (2d, total 1H), 7.85-7.90 (m, 3H), 8.22 (s, 1H).
2-(4-{[2-({[4-(3-Methoxypropoxy)-3-methyl-2-pyridyl]methyl}sulfinyl)benzimidazol-1-yl]sulfonyl}-
phenoxy)-N-(2-pyridyl)acetamide (3u): yield 88%; mp 78-81 °C (decomposition);1H-NMR (CDCl3) δ:
2.00-2.10 (m, 2H), 2.27 (s, 3H), 3.35 (s, 3H), 3.52-3.57 (t, 2H), 4.06-4.10 (t, 2H), 4.64 (s, 2H), 4.83-
5.02 (q, AB, 2H), 6.67 (d, 1H), 7.07-7.10 (m, 3H), 7.32-7.49 (m, 3H), 7.70-7.82 (m, 2H), 7.99 (d, 1H),
8.14-8.30 (m, 4H), 8.77 (br, NH).
1-[4-(Morpholin-4-yl)phenylsulfonyl]-2-[[[4-(3-methoxypropoxy)-3-methyl-2-pyridyl]methyl]sulfinyl]-
1H-benzimidazole (3v): yield 78%; mp 93-96 °C (decomposition); 1H-NMR (CDCl3) δ: 2.02-2.06 (m,

Molecules 2009, 14
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2H), 2.26 (s, 3H), 3.2-3.3 (m, 4H), 3.35 (s, 3H), 3.50-3.53 (t, 2H), 3.75-3.80 (m, 4H), 4.04-4.08 (t, 2H),
4.71-4.79 (q, AB, 2H), 6.71 (d, 1H), 7.26-7.5 (m, 4H), 7.8-8.1 (m, 2H), 8.27 (d, 1H).
1-[{2-(Morpholin-4-yl)ethoxy}phenyl-4-sulfonyl]-2-[[[(4-(3-methoxypropoxy)-3-methyl-2-pyridyl]-
1
methyl]sulfinyl]-1H-benzimidazole (3w): yield 77%, H-NMR (CDCl3) δ: 2.05-2.10 (m, 2H), 2.27 (s,
3H), 2.56 (m, 4H), 2.79-2.82 (t, 2H), 3.35 (s, 3H), 3.53-3.56 (t, 2H), 3.69-3.72 (m, 4H), 4.07-4.10 (t,
2H), 4.12-4.15 (t, 2H), 4.81-4.99 (q, AB, 2H), 6.68 (d, 1H), 6.95 (d, 2H), 7.36-7.46 (m, 2H), 7.81 (d,
1H), 7.99 (d, 1H), 8.06 (d, 2H), 8.21 (d, 1H).
2-{4-[(5-Methoxy-2-{[(3,5-dimethyl-4-methoxy-2-pyridyl)methyl]sulfinyl}benzimidazol-1-yl)sulfonyl]-
phenoxy}acetamide (3x) and 2-{4-[(6-methoxy-2-{[(3,5-dimethyl-4-methoxy-2-pyridyl)methyl]-
sulfinyl}benzimidazol-1-yl)sulfonyl]phenoxy}acetamide (3y) (3:2 ratio of 5-methoxy/6-methoxy
1
compounds): yield 92%; mp 159-161 °C (decomposition); H-NMR (CDCl3) δ: 2.13 (s, 3H), 2.25 (s,
3H), 3.69 (s, 3H), 3.78 and 3.88 (2s, total 3H), 4.56 (s, 2H), 4.82-5.04 (2q, AB, 2H), 7.05-7.18 (m,
3H), 7.34-7.40 (m, 1H), 7.60-7.90 (m, 2H), 8.12-8.18 (m, 2H).
2-(4-{[2-({[3-Methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl}sulfinyl)benzimidazol-1-yl]sulfonyl}-
1
phenoxy)acetamide (3z): yield 96%; mp 162-166 °C (decomposition); H-NMR (CDCl3) δ: 2.21 (s,
3H), 4.55 (s, 2H), 4.86-5.15 (q, 2H and q, 2H) 6.99 (d, 1H), 7.16 (d, 2H), 7.39-7.58 (m, 2H), 7.79 (d,
1H), 7.97-8.03 (m, 2H), 8.17 (d, 2H).
2-(4-{[2-({[4-(3-Methoxypropoxy)-3-methyl-2-pyridyl]methyl}sulfinyl)benzimidazol-1-yl]sulfonyl}-
phenoxy)acetamide (3aa): yield 92%; mp 148-153 °C (decomposition); 1H-NMR (CDCl3) δ: 1.93-1.97
(m, 2H), 2.18 (s, 3H), 3.35 (s, 3H), 3.46 (t, 2H), 4.06 (t, 2H), 4.56 (s, 2H), 4.83-5.13 (q, AB, 2H), 6.85
(d, 1H), 7.16 (d, 2H), 7.41-7.60 (m, 2H), 7.79 (d, 1H), 7.89 (d, 1H), 8.00-8.02 (d, 1H), 8.16-8.18
(d, 2H).
1-[{2-(Morpholin-4-yl)ethoxy}phenyl-4-sulfonyl]-2-[(3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl)-
1
methylsulfinyl]-1H-benzimidazole (3ab): yield 82%; H-NMR (CDCl3) δ: 2.33 (s, 3H), 2.50-2.52 (m,
4H), 2.78-2.81 (t, 2H), 3.70-3.74 (m, 4H), 4.12-4.15 (t, 2H), 4.84-5.02 (q, AB, 2H), 6.63 (d, 1H), 6.96
(d, 2H), 7.38-7.49 (m, 2H), 7.81 (d, 1H), 7.99 (d, 1H), 8.04 (d, 2H), 8.26 (d, 1H).
1-[[2-{2-(Morpholin-4-yl)ethoxy}ethoxy]phenyl-4-sulfonyl]-2-[(3-methyl-4-(2,2,2-trifluoroethoxy)-2-
1
pyridyl)methylsulfinyl]-1H-benzimidazole (3ac): yield 76%; H-NMR (CDCl3) δ: 2.30 (s, 3H), 2.48
(m, 4H), 2.58 (t, 2H), 3.64-3.77 (m, 8H), 4.10 (t, 2H), 4.34-4.40 (q, 2H), 4.81-5.01 (q, AB, 2H), 6.62
(d, 1H), 6.94 (d, 2H), 7.35-7.47 (m, 2H), 7.78 (d, 1H), 7.96 (d, 1H), 8.02 (d, 2H), 8.22 (d, 1H).
1-[[2-{2-(Morpholin-4-yl)ethoxy}ethoxy]phenyl-4-sulfonyl]-2-[[[(4-(3-methoxypropoxy)-3-methyl-2-
1
pyridyl]methyl]sulfinyl]-1H-benzimidazole (3ad): yield 56%; H-NMR (CDCl3) δ: 1.99-2.03 (m, 2H),
2.21 (s, 3H), 2.46 (t, 2H), 2.55 (t, 2H), 2.67 (t, 2H), 3.29 (s, 3H), 3.48-3.53 (m, 2H), 3.64-3.68 (m, 6H),
3.73-3.74 (m, 2H), 4.02-4.07 (m, 4H), 4.74-4,97 (q, AB, 2H), 6.62 (d, 1H), 6.89-6.92 (d, 2H), 7.31-
7.42 (m, 2H), 7.75 (d, 1H), 7.93 (d, 1H), 8.02 (d, 2H), 8.13 (d, 1H).

Molecules 2009, 14
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N-(Carbamoylmethyl)-2-{4-[(5-methoxy-2-{[(3,5-dimethyl-4-methoxy-2-pyridyl)methyl]sulfinyl}benz-
imidazol-1-yl)sulfonyl]phenoxy}acetamide (3ae) and N-(carbamoylmethyl)-2-{4-[(6-methoxy-2-{[(3,5-
dimethyl-4-methoxy-2-pyridyl)methyl]sulfinyl}benzimidazol-1-yl)sulfonyl]phenoxy}acetamide
(3af)
(1:1 ratio): yield 73%; 1H-NMR (DMSO-d6) δ: 2.14 (s, 3H), 2.25 (s, 3H), 3.34 (br, -NH, -NH2), 3.66
(d, 2H), 3.70 (s, 3H), 3.88 (s, 3H), 4.67 (s, 2H), 4.81-5.08 (q, AB, 2H), 7.05-7.22 (m, 3H), 7.35 (s, 1H),
7.89 (dd, 1H), 8.14-8.18 (m, 2H), 8.32 (s, 1H).
N-(Carbamoylmethyl)-2-(4-{[2-({[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl}sulfinyl)benz-
1
imidazol-1-yl]sulfonyl}phenoxy)acetamide (3ag): yield 79%; H-NMR (DMSO-d6) δ: 2.23 (s, 3H),
3.36 (br, -NH2, -NH), 3.66 (d, 2H), 4.67 (s, 2H), 4.84-5.17 (m, 2H and q, AB, 2H), 6.99-8.35 (m, 10H,
aromatic H).
N-(Carbamoylmethyl)-2-(4-{[2-({[4-(3-methoxypropoxy)-3-methyl-2-pyridyl]methyl}sulfinyl)benz-
1
imidazol-1-yl]sulfonyl}phenoxy)acetamide (3ah): yield 72%; H-NMR (DMSO-d6) δ: 1.94-1.97 (m,
2H), 2.19 (s, 3H), 3.22 (s, 3H), 3.46 (t, 2H), 3.67 (d, 2H), 4.06 (t, 2H), 4.68 (s, 2H), 4.84-5.14 (q, AB,
2H), 6.85 (d, 1H), 7.21 (d, 2H), 7.42-7.55 (m, 2H), 7.80 (d, 1H), 7.91 (d, 1H), 8.02 (d, 1H), 8.18 (d,
2H).
{4-[5-Methoxy-2-(4-methoxy-3,5-dimethyl-2-pyridinyl)methylsulfinyl
benzimidazole-1-sulfonyl]
phenoxy}acetic acid methyl ester (3ai) and {4-[6-methoxy-2-(4-methoxy-3,5-dimethyl-2-
pyridinyl)methylsulfinyl benzimidazole-1-sulfonyl] phenoxy}acetic acid methyl ester (3aj) (1:1 of 5-
methoxy/6-methoxy isomer): yield 97%; 1H-NMR (CDCl3) δ: 2.24 (s, 3H), 2.27 (s, 3H), 3.77 (s, 6H),
3.81 and 3.90 (s, s; 5-methoxy and 6-methoxy), 4.63-4.65 (d, 2H), 4.86-5.05 (m, 2H), 6.92-8.18 (m, 8H).
2-(2-Carbamoylmethoxy-4-{2-[4-(3-methoxypropoxy)-3-methylpyridin-2-yl methylsulfinyl]benzimid-
1
azole-1-sulfonyl}phenoxy)acetamide (3ak): yield 79%; H-NMR (DMSO-d6) δ: 1.93-1.99 (m, 2H),
2.19 (s, 3H), 3.23 (s, 3H), 3.47 (t, 2H), 4.07 (t, 2H), 4.55 (s, 2H), 4.61 (s, 2H), 4.85-5.14 (q, 2H), 6.85-
8.03 (m, 9H), 7.5 (br, -NH2, 4H).
2-(2-Carbamoylmethoxy-4-{2-[3-methyl-4-(2,2,2-trifluoroethoxy)-pyridin-2-ylmethanesulfinyl]-benz-
1
imidazole-1-sulfonyl}-phenoxy)-acetamide (3al): yield 78%; H-NMR (DMSO-d6) δ: 2.23 (s, 3H),
4.55 (s, 2H), 4.61 (s, 2H), 4.88 (q, 2H), 4.90-5.15 (q, AB, 2H), 6.99 (d, 1H), 7.12 (d, 1H), 7.42-7.56 (m,
2H), 7.46 (s, NH2), 7.50 (s, NH2), 7.74 (s, 1H), 7.78-7.88 (m, 2H), 7.99-8.02 (m, 2H).
3.4. Synthesis of water-soluble 1-arylsulfonyl-2-(2-pyridylmethylsulfinyl)-benzimidazoles
3.4.1. (4-{2-[3-Methyl-4-(2,2,2-trifluoroethoxy)pyridin-2-ylmethanesulfinyl]-benzimidazole-1-
sulfonyl} phenoxy)acetic acid 2-(toluene-4-sulfonyl)ethyl ester (5a)
To a heterogeneous solution of lansoprazole (900 mg, 2.44 mmol) in CH2Cl2 (30 mL) was added
NaH (70 mg, 2.92 mmol) at room temperature, in which time the mixture became homogeneous. To
the clear reaction mixture was added (4-chlorosulfonyl-phenoxy)acetic acid 2-(toluene-4-
sulfonyl)ethyl ester (1.26 g, 2.92 mmol, 1.2 eq) as a powder. After the chlorosulfonate was dissolved
completely, solid NaHCO3 (about 1 g) was added to the mixture. After all the solvent was removed,

Molecules 2009, 14
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the oil was purified by column chromatography (silica gel, CH2Cl2 to 4% MeOH in CH2Cl2) to give
1
1.75 g (94%) of the desired product as off-white foam. H-NMR (CDCl3) δ: 2.24 (s, 3 H), 2.39 (s, 3
H), 3.46 (m, 2 H), 4.50-4.63 (m, 6 H), 5.15-5.27 (dd, 2 H), 6.97 (m, 3 H), 7.35 (d, 2 H), 7.41 (t, 1 H),
7.49 (t, 1 H), 7.76 (d, 2 H), 7.82 (d, 1 H), 7.99 (d, 1 H), 8.10 (d, 2 H), 8.37 (d, 1 H).
3.4.2. (4-{2-[3-Methyl-4-(2,2,2-trifluoroethoxy)-pyridin-2-ylmethanesulfinyl]-benzoimidazole-1-
sulfonyl}-phenoxy)acetic acid sodium salt (6a)
The ester (5a) (400 mg, 0.54 mmol) was dissolved in CH3CN (4 mL) and isopropanol (2 mL), and
then the solution of NaHCO3 (48 mg, 0.57 mmol, 1.1 eq) in H2O (3 mL) was added. The mixture was
heated to 70°C for 2 h. After all the volatile materials were removed under vacuum, the oil was re-
dissolved in EtOAc (30 mL), and then the mixture was filtered to remove the undissolved material.
The filtrate was concentrated and dried under vacuum to give off-white foam. The foam was washed
with ethyl ether (30 mL) to removed byproduct (vinyl toluene sulfone) to yield 300 mg of off-white
foam. 1H-NMR (DMSO-d6) δ: 2.18 (s, 3 H), 4.28 (s, 2 H), 4.88 (m, 3 H), 5.16 (d, 1 H), 7.01 (m, 3 H),
7.46 (m, 1 H), 7.54 (m, 1 H), 7.80 (d, 1 H), 8.00 (m, 2 H), 8.08 (d, 2 H).
3.4.3. 2-(4-{2-[3-Methyl-4-(2,2,2-trifluoroethoxy)-pyridin-2-ylmethanesulfinyl]-benzoimidazole-1-
sulfonyl}phenoxy)butyric acid 2-(toluene-4-sulfonyl)ethyl ester (5b)
To a heterogeneous mixture of lansoprazole (500 mg, 1.36 mmol) in CH2Cl2 (10 mL) was added
NaH (35 mg, 1.45 mmol) at room temperature, resulting in a clear solution. To this clear mixture was
added (4-chlorosulfonylphenoxy)acetic acid 2-(toluene-4-sulfonyl)ethyl ester (700 mg, 1.52 mmol,
1.12 eq) in CH2Cl2 (10 mL) at room temperature, and then the mixture was stirred for 2 h. After water
was added, the mixture was extracted with CH2Cl2 (70 mL), and the organic layers were dried, and
concentrated. The oil was purified by column chromatography (3% MeOH in CH2Cl2) to yield 1.0 g
(93%) of white foam. 1H-NMR (CDCl3) δ: 0.99 (m, 3 H), 1.89 (m, 2 H), 2.28 (s, 3 H), 2.42 (2 s, 3 H),
3.38 (m, 2 H), 4.43-4.53 (m, 5 H), 5.01 (m, 1 H), 5.14 (d, 1 H), 6.81 (m, 1 H), 6.92 (dd, 2 H), 7.33-7.50
(m, 4 H), 7.76 (m, 3 H), 8.00 (d, 1 H), 8.06 (d, 2 H), 8.29 (d, 1 H).
3.4.4. 2-(4-{2-[3-Methyl-4-(2,2,2-trifluoroethoxy)-pyridin-2-ylmethanesulfinyl]-benzimidazole-1-
sulfonyl}phenoxy)butyric acid sodium salt (6b)
The solution of the ester (5b) (400 mg, 0.50 mmol) and NaHCO3 (47 mg, 0.55 mmol, 1.1 eq) in
CH3CN-H2O (7 mL/3 mL) was heated to 70 °C for 3 h. After all the volatile materials were removed,
the gummy oil was dissolved in CH3CN (50 mL) and then the mixture was filtered to removed non-
dissolved solid. The filtrate was dried and then the yellow foam was treated with ether-EtOAc (5:1) to
precipitate the solid. The solid was again treated with CH3CN, and then filtered to give 180 mg (58%)
1
of a brown solid. H-NMR (DMSO-d6) δ: 0.88 (t, 3 H), 1.83 (m, 2 H), 2.20 (s, 3 H), 4.75 (m, 1 H),
4.84 (m, 3 H), 5.11 (m, 1 H), 6.96 (d, 1 H), 7.06 (d, 2 H), 7.42 (t, 1 H), 7.51 (t, 1 H), 7.77 (d, 1 H), 7.95
(m, 2 H), 8.10 (d, 2 H).

Molecules 2009, 14
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3.4.5. (3,5-Dimethyl-4-{2-[3-methyl-4-(2,2,2-trifluoroethoxy)-pyridin-2-ylmethanesulfinyl]-benz-
imidazole-1-sulfonyl}phenoxy)acetic acid 2-(toluene-4-sulfonyl)ethyl ester (5c)
To a heterogeneous mixture of lansoprazole (500 mg, 1.36 mmol) in CH2Cl2 (10 mL) was added
NaH (40 mg, 1.65 mmol) at room temperature, resulting in a clear solution. To this clear mixture was
added (4-chlorosulfonyl-phenoxy)acetic acid 2-(toluene-4-sulfonyl)ethyl ester (760 mg, 1.65 mmol,
1.2 eq) in CH2Cl2 (5 mL) at room temperature, and then the mixture was stirred for 4 h. After water
(15 mL) was added, the mixture was extracted with CH2Cl2 (20 mL), and the organic layers were dried,
and concentrated. The oil was purified by column chromatography (3% MeOH in CH2Cl2) to yield 700
mg (65%) of white foam. 1H-NMR (CDCl3) δ: 2.04 (s, 3 H), 2.43 (s, 3 H), 2.56 (s, 6 H), 3.44 (t, 2 H),
4.55 (m, 6 H), 4.92 (d, 1 H), 5.04 (d, 1 H), 6.71 (s, 2 H), 7.38 (m, 5 H), 7.77 (m, 3 H), 7.88 (d, 1 H),
8.33 (d, 1 H).
3.4.6. (3,5-Dimethyl-4-{2-[3-methyl-4-(2,2,2-trifluoroethoxy)-pyridin-2-ylmethanesulfinyl]-benz-
imidazole-1-sulfonyl}phenoxy)acetic acid sodium salt (6c)
The solution of the ester (5c) (400 mg, 0.50 mmol) and NaHCO3 (51 mg, 0.60 mmol, 1.2 eq) in
THF-H2O (6 mL/3 mL) was heated to 70 °C for 3 h. After all the volatile materials were removed, the
gummy oil was dissolved in THF (30 mL), and then the mixture was filtered to remove undissolved
solids. The filtrate was dried and then the yellow foam was treated with ether-EtOAc (5:1) to
precipitate the solid. The solid was again treated with CH3CN, and then filtered to give 230 mg (72%)
1
of a light yellow solid. H-NMR (DMSO-d6) δ: 2.12 (s, 3 H), 2.39 (s, 6 H), 4.20 (s, 2 H), 4.84 (m,
4 H), 6.72 (s, 2 H), 6.98 (d, 1 H), 7.46 (m, 3 H), 7.84 (d, 1 H), 8.04 (d, 1 H).
3.4.7. (4-{2-[4-(3-Methoxypropoxy)-3-methylpyridin-2-ylmethanesulfinyl]-benzoimidazole-1-sulfon-
yl}phenoxy)acetic acid 2-(toluene-4-sulfonyl)ethyl ester (5d)
To a solution of rabeprazole sodium salt (760 mg, 2.0 mmol) in CH2Cl2 (10 mL) was added (4-
chlorosulfonyl-phenoxy)acetic acid 2-(toluene-4-sulfonyl)ethyl ester (1.04 g, 2.4 mmol, 1.2 eq) as a
powder. After the ester was dissolved completely, solid NaHCO3 (~1 g) was added to the mixture. The
reaction mixture was stirred at room temperature for 3h. After all the solvent and the solid NaHCO3
were removed, the oil was purified by column chromatography (silica gel, CH2Cl2 to 3% MeOH in
CH2Cl2) to give 1.4 g (92%) of off-white foam. 1H-NMR (CDCl3) δ: 2.09 (m, 2 H), 2.26 (s, 3 H), 2.38
(s, 3 H), 3.35 (s, 3 H), 3.43 (t, 2 H), 3.55 (t, 2 H), 4.16 (t, 2 H), 4.50 (m, 4 H), 5.13 (dd, 2 H), 6.82 (m,
1 H), 6.95 (d, 2 H), 7.34 (d, 2 H), 7.40 (t, 1 H), 7.47 (t, 1 H), 7.76 (d, 2 H), 7.81 (d, 1 H), 7.99 (d, 1 H),
8.11 (d, 2 H), 8.26 (d, 1 H).
3.4.8. (4-{2-[4-(3-Methoxypropoxy)-3-methylpyridin-2-ylmethanesulfinyl]-benzimidazole-1-
sulfonyl}-phenoxy)-acetic acid sodium salt (6d)
The compound 5d ester (400 mg, 0.53 mmol) was dissolved in acetone (6 mL) and a solution of
NaHCO3 (50 mg, 0.597 mmol, 1.1 eq) in H2O (4 mL). The mixture was heated to 70°C for 2 h. After
all the volatile materials were removed under vacuum, the oil was re-dissolved in EtOAc-iPrOH (5:1,
30 mL), and then the mixture was filtered to remove the undissolved material. The filtrate was

Molecules 2009, 14
5269
concentrated and dried under vacuum to give off-white foam. The foam was washed with ethyl acetate
to removed byproduct (vinyl toluene sulfone) to yield 300 mg of off-white solid. 1H-NMR (DMSO-d6)
δ: 1.98 (m, 2 H), 2.20 (s, 3 H), 3.24 (s, 3 H), 3.48 (t, 2 H), 4.08 (t, 2 H), 4.27 (s, 3 H), 4.86 (d, 1 H),
5.12 (d, 1 H), 6.87 (d, 1 H), 7.02 (d, 2 H), 7.45 (t, 1 H), 7.54 (t, 1 H), 7.81 (d, 1 H), 7.93 (d, 1 H), 8.02
(d, 1 H), 8.09 (d, 2 H).
3.4.9. {4-[5-Methoxy-2-(4-methoxy-3,5-dimethylpyridin-2-ylmethanesulfinyl)-benzimidazole-1-
sulfon-yl]-phenoxy}acetic acid 2-(toluene-4-sulfonyl)-ethyl ester (5e) and {4-[5-methoxy-2-(4-
methoxy-3,5-dimethylpyridin-2-ylmethanesulfinyl)-benzimidazole-1-sulfonyl]-phenoxy}acetic acid 2-
(toluene-4-sulfonyl)-ethyl ester (5f)
To a heterogeneous solution of omeprazole (840 mg, 2.44 mmol) in CH2Cl2 (20 mL) was added
NaH (90 mg, 3.75 mmol, 1.5 eq) at room temperature, in which time the mixture became
homogeneous. To the clear reaction mixture was added (4-chlorosulfonyl-phenoxy)acetic acid 2-
(toluene-4-sulfonyl)ethyl ester (1.26 g, 2.92 mmol, 1.2 eq) as a powder. After the
chlorosulfonylphenoxy compound was dissolved completely, solid NaHCO3 (about 1 g) was added to
the mixture. The reaction mixture was further stirred for 2h. After all the solvent was removed, the oil
was purified by column chromatography (silica gel, CH2Cl2 to 4% MeOH in CH2Cl2) to give 1.6 g
(88%) of the product (1:1 ratio of 5-/6-methoxy isomers) as off-white foam. 1H-NMR (CDCl3) δ: 2.23
(s, 3 H), 2.29 (s, 3 H), 2.39 (s, 3 H), 3.43 (t, 2 H), 3.76 (s, 3 H), 3.82 and 3.89 (2 s, 3 H), 4.52 (m,4 H),
4.90 (m, 1 H), 4.99 (m, 1 H), 6.93 (dd, 2 H), 7.00 and 7.10 (2 m, 1 H), 7.24 and 7.43 (2 s, 1 H), 7.34
(d, 2 H), 7.67 and 7.84 (2 d, 1 H), 7.75 (d, 2 H), 8.06 (t, 2 H), 8.17 (s, 1 H).
3.4.10. {4-[5-Methoxy-2-(4-methoxy-3,5-dimethylpyridin-2-ylmethanesulfinyl)-benzimidazole-1-
sulfonyl]-phenoxy}-acetic acid sodium salt (6e) and {4-[6-methoxy-2-(4-methoxy-3,5-
dimethylpyridin-2-ylmethanesulfinyl)-benzimidazole-1-sulfonyl]-phenoxy}-acetic acid sodium salt (6f)
The mixture of the ester compound 5e and 5f (2.2 g, 2.97 mmol) was dissolved in CH3CN (20 mL),
and then a solution of NaHCO3 (250 mg, 2.97 mmol, 1.0 eq) in H2O (10 mL) was added. The mixture
was heated to 60°C for 3 h. Most of acetonitrile was evaporated under reduced pressure, and the
residual material (an aqueous layer) was extracted with ethyl acetate (50 mL) to remove by-product.
The aqueous layer was lyophilized, and dissolved in methylene chloride (200 mL). The extract was
filtered. The organic layer was dried under reduced pressure to yield 1.37 g (82%) of off-white solid
1
(1:1 ratio of compounds 6e and 6f). H-NMR (D2O) δ: 1.77 and 1.80 (s, 3 H), 1.83 (s, 3 H), 3.33 and
3.34 (s, 3 H), 3.51 and 3.54 (s, 3 H), 4.19 and 4.20 (s, 2 H), 4.54 (d, 1 H), 4.66 (d, 1 H), 6.70 (m, 3 H),
6.99 (m, 1 H), 7.32 (d, 1 H), 7.68 (m, 3 H).

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3.4.11. 4-[5-Difluoromethoxy-2-{(3,4-dimethoxypyridin-2-yl)-methanesulfinyl}-benzimidazole-1-
sulfonyl]phenoxyacetic acid 2-(toluene-4-sulfonyl)ethyl ester (5g) and 4-[6-difluoromethoxy-2-{(3,4-
dimethoxypyridin-2-yl)-methanesulfinyl}-benzimidazole-1-sulfonyl]phenoxyacetic acid 2-(toluene-4-
sulfonyl)ethyl ester (6g)
To
a
heterogeneous
solution
of
5-difluoromethoxy-2-[(3,4-dimethoxy-pyridin-2-yl)-
methanesulfinyl]-1H-benzimidazole sodium salt (4.3 g, 10.0 mmol) and Et3N (6 mL) in CH2Cl2
(50 mL) was added (4-chlorosulfonyl-phenoxy)acetic acid 2-(toluene-4-sulfonyl)ethyl ester (5.0 g,
11.5 mmol, 1.15 eq). Solid NaHCO3 (about 2 g) was added after the chlorosulfonyl ester had dissolved
completely in the reaction mixture. The reaction mixture was stirred for 2h. Thereafter the solvent was
removed by evaporation and the residual oil was purified by column chromatography (silica gel,
CH2Cl2 to 2% MeOH in CH2Cl2) to give 7.8 g (99%) of a mixture of the title compounds 5g and 6g
(1:1 ratio) as an off-white foam. 1H-NMR (CDCl3) δ: 2.40 (s, 3 H), 3.43 (m, 2 H), 3.90 (s, 3 H), 3.93
(s, 3 H), 4.52 (m, 4 H), 4.95 (dd, 2 H), 6.55 (t, J = 73.4, 5-OCHF2 or 6-OCHF2, 1/2 H), 6.59 (t,
J = 73.4, 5-OCHF2 or 6-OCHF2, 1/2 H), 6.78 (m, 1 H), 6.95 (dd, 2 H), 7.20-7.70 (m, 4 H), 7.77 (m, 3
H), 7.92-8.20 (m, 3 H).
3.4.12. 4-[5-Difluoromethoxy-2-{(3,4-dimethoxypyridin-2-yl)-methanesulfinyl}-benzimidazole-1-
sulfonyl]phenoxyacetic acid sodium salt (5h) and 4-[6-difluoromethoxy-2-{(3,4-dimethoxypyridin-2-
yl)-methanesulfinyl}-benzimidazole-1-sulfonyl]phenoxyacetic acid sodium salt (6h)
To
a
solution of
a
mixture of 4-[5-difluoromethoxy-2-{(3,4-dimethoxypyridin-2-yl)-
methanesulfinyl}-benzimidazole-1-sulfonyl]phenoxyacetic acid 2-(toluene-4-sulfonyl)ethyl ester (5g)
and 4-[6-difluoromethoxy-2-{(3,4-dimethoxypyridin-2-yl)-methanesulfinyl}-benzimidazole-1-sulfon-
yl]phenoxyacetic acid 2-(toluene-4-sulfonyl)ethyl ester (6g) (7.7 g, 9.9 mmol) in CH3CN (70 mL) was
added a solution of NaHCO3 (0.94 g, 11.1 mmol, 1.2 eq) in H2O (35 mL). The mixture was heated to
65°C for 5 h. Thereafter all the volatile materials were removed under vacuum, the mixture was
washed with EtOAc, and then the aqueous layer was lyophilized overnight. The solid was dissolved in
CH2Cl2, and then the mixture was filtered to remove the insoluble material. The filtrate was
concentrated and the resulting oil was dissolved in EtOAc (20 mL). Diethyl ether was added to the
mixture to precipitate a white solid. The precipitate was collected by filtration, washed with ether, and
dried under vacuum to yield 4.5 g (73%) of a mixture of the title compounds (1:1 ratio) as an off-white
solid. 1H-NMR (DMSO-d6) δ: 3.42 and 3.43 (2 s, 3 H), 3.57 (s, 3 H), 4.24 (s, 2 H), 4.66 (m, 2 H), 6.55
and 6.65 (t, J = 73.4, 5-OCHF2 or 6-OCHF2, 1/2 H), 6.69 (t, J = 73.4, 5-OCHF2 or 6-OCHF2, 1/2 H),,
6.75 (m, 3 H), 6.93 (m, 1 H), 7.19 and 7.37 (2 s, 1 H), 7.43 and 7.58 (2 d, 1 H), 7.70 (t, 2 H), 7.83
(d, 1 H).
3.4.13. 3-{2-[3-Methyl-4-(2,2,2-trifluoroethoxy)-pyridin-2-ylmethanesulfinyl]-benzimidazole-1-
sulfon-yl}benzoic acid 2-(3-nitro-benzenesulfonyl)ethyl ester (8a)
To a heterogeneous mixture of lansoprazole (600 mg, 1.62 mmol) in CH2Cl2 (10 mL) was added
NaH (45 mg, 1.95 mmol) at room temperature, resulting in a clear solution. To this clear mixture was

Molecules 2009, 14
5271
added 3-chlorosulfonyl-benzoic acid 2-(3-nitrobenzenesulfonyl) ethyl ester (845 mg, 1.95 mmol, 1.2
eq), in CH2Cl2 (15 mL) at room temperature, and then the mixture was stirred for 2 h. After water
(15 mL) was added, the mixture was extracted with CH2Cl2 (80 mL), and the organic layers were dried,
and concentrated. The oil was purified by column chromatography (3% MeOH in CH2Cl2) to yield 1.0
1
g (80%) of yellow foam. H-NMR (CDCl3) δ: 2.33 (s, 3 H), 3.73 (m, 2 H), 4.54 (m, 2 H), 4.75 (m, 2
H), 5.22 (dd, 2 H), 6.95 (m, 1 H), 7.43 (t, 1 H), 7.52 (t, 1 H), 7.62 (t, 1 H), 7.71 (t, 1 H), 7.80 (d, 1 H),
7.99 (d, 1 H), 8.11 (d, 1 H), 8.25 (m, 4 H), 8.55 (s, 1 H), 8.71 (s, 1 H).
3.4.14. 3-{2-[3-Methyl-4-(2,2,2-trifluoroethoxy)-pyridin-2-ylmethanesulfinyl]-benzimidazole-1-
sulfon-yl}benzoic acid sodium salt (9a)
The
solution
of
3-{2-[3-methyl-4-(2,2,2-trifluoroethoxy)-pyridin-2-ylmethanesulfinyl]-
benzimidazole-1-sulfonyl}-benzoic acid 2-(3-nitro-benzenesulfonyl)ethyl ester (900 mg, 1.17 mmol)
and NaHCO3 (118 mg, 1.41 mmol, 1.2 eq.) in THF-H2O (6 mL/3 mL) was heated to 70 °C for 20 min,
in which time the heterogeneous mixture became clear. After all the volatile materials were removed in
vacuo, the residual gummy material was dissolved in CH2Cl2 (90 mL) and then the mixture was
filtered to removed the solid. The filtrate was dried in vacuo, and then, the yellow foam was treated
with ether-EtOAc (5:1) to precipitate the solid. The solid was collected by filtration to give 630 mg
(94%) of a light brown solid. 1H-NMR (DMSO-d6) δ: 2.23 (s, 3 H), 4.86 (m, 3 H), 5.15 (d, 1 H), 6.99
(d, 1 H), 7.30 (m, 1 H), 7.47 (t, 1 H), 7.60 (m, 2 H), 7.81 (m, 1 H), 7.93 (d, 1 H), 8.00 (d, 1 H), 8.22 (m,
1 H), 8.58 (s, 1 H).
3.4.15. 2-Methoxy-5-{2-[3-methyl-4-(2,2,2-trifluoroethoxy)-pyridin-2-ylmethanesulfinyl]-benzimida-
zole-1-sulfonyl}benzoic acid 2-(toluene-4-sulfonyl)ethyl ester (8b)
To a clear solution of lansoprazole (740 mg, 2.0 mmol) and NaH (60 mg, 2.5 mmol) in CH2Cl2
(10 mL) was added 2-(p-toluenesulfonyl)ethyl 5-chlorosulfonyl-2-methoxybenzoate (1.0 g, 2.3 mmol).
Then the mixture was stirred at room temperature for 1.5 h. After water (20 mL) was added, the
mixture was extracted with CH2Cl2 (50 mL). The oil was purified by column chromatography (silica
1
gel, CH2Cl2 to 2% MeOH in CH2Cl2) to give 1.0 g (65%) of light yellow foam. H-NMR (CDCl3)
δ: 2.28 (s, 3 H), 2.31 (s, 3 H), 3.54 (m, 2 H), 3.92 (s, 3 H), 4.58 (m, 4 H), 5.22 (dd, 2 H), 6.95 (m, 1 H),
7.09 (d, 1 H), 7.22 (d, 2 H), 7.42 (t, 1 H), 7.51 (t, 1 H), 7.78 (m, 3 H), 8.03 (d, 1 H), 8.30 (dd, 1 H),
8.36 (dd, 1 H), 8.52 (d, 1 H).
3.4.16. 2-Methoxy-5-{2-[3-methyl-4-(2,2,2-trifluoroethoxy)-pyridin-2-ylmethanesulfinyl]benzimida-
zole-1-sulfonyl}-benzoic acid sodium salt (9b)
The mixture of compound 8b (400 mg, 0.52 mmol) and NaHCO3 (52 mg, 0.62 mmol, 1.2 eq) in
CH3CN (3 mL) – H2O (2 mL) – i-PrOH (1 mL) was heated to 70°C for 1.5 h. After all the volatile
materials were removed, the residual oil was dissolved in CH2Cl2-MeOH (10:1) (25 mL), and then the
mixture was filtered to remove the solid(s). The filtrate was concentrated. The oil was dissolved in
H2O (10 mL), and then the mixture was extracted with CH2Cl2 (2 × 10 mL) to remove the starting
material, lansoprazole and tolyl vinyl sulfone. The water layer was dried by freezing dry to yield

Molecules 2009, 14
5272
200 mg (65%) of light yellow solid. 1H-NMR (DMSO-d6) δ: 2.24 (s, 3 H), 3.78 (s, 3 H), 4.88 (m, 3 H),
5.14 (d, 1 H), 7.01 (d, 1 H), 7.14 (d, 1 H), 7.46 (d, 1 H), 7.55 (t, 1 H), 7.81 (d, 1 H), 7.88 (s, 1 H), 7.97
(d, 1 H), 8.02 (d, 1 H), 8.10 (d, 1 H).
3.4.17. 3-[5-Methoxy-2-(4-methoxy-3,5-dimethylpyridin-2-yl-methanesulfinyl)-benzimidazole-1-
sulfon-yl]-benzoic acid 2-(toluene-4-sulfonyl)ethyl ester (8c) and 3-[6-methoxy-2-(4-methoxy-3,5-
dimethylpyridin-2-yl-methanesulfinyl)-benzimidazole-1-sulfonyl]-benzoic acid 2-(toluene-4-sulfonyl)-
ethyl ester (8d)
To a heterogeneous mixture of 5-methoxy-2-(4-methoxy-3,5-dimethylpyridin-2-yl-methane-
sulfinyl)-1H-benzimidazole (1.0 g, 2.90 mmol), Et3N (5 mL), and NaHCO3 (about 1 g) in CH2Cl2
(20 mL) was added 3-chlorosulfonyl-benzoic acid 2-(toluene-4-sulfonyl)ethyl ester (1.4 g, 3.48 mmol,
1.2 eq) in CH2Cl2 (20 mL) at room temperature, and then the mixture was stirred for 2 h. Thereafter
water (40 mL) was added, the mixture was extracted with CH2Cl2 (50 mL), and the organic layers were
dried, and concentrated. The oil was purified by column chromatography (CH2Cl2 to 1% MeOH in
CH2Cl2) to yield 1.67 g (81%) of a mixture of the title compounds 8c and 8d as an off-white foam (1:1
ratio). 1H-NMR (CDCl3) δ: 2.25 (s, 3 H), 2.27 (s, 3 H), 2.33 and 2.43 (s, 3 H, 5- and 6-isomers), 3.81
and 3.93 (s, 6 H, 5- and 6-isomers), 4.66 (m, 2 H), 5.07 (m, 2 H), 7.0-8.6 (m, 12 H, 5- and 6-isomers).
3.4.18. 3-[5-Methoxy-2-(4-methoxy-3,5-dimethyl-pyridin-2-yl-methanesulfinyl)-benzimidazole-1-
sulfonyl]-benzoic acid sodium salt (9c) and 3-[6-methoxy-2-(4-methoxy-3,5-dimethyl-pyridin-2-yl-
methanesulfinyl)-benzimidazole-1-sulfonyl]-benzoic acid sodium salt (9d)
To the solution of
a
mixture of 3-[5-methoxy-2-(4-methoxy-3,5-dimethylpyridin-2-
ylmethanesulfinyl)-benzimidazole-1-sulfonyl]-benzoic acid 2-(toluene-4-sulfonyl)ethyl ester (8c) and
3-[6-methoxy-2-(4-methoxy-3,5-dimethylpyridin-2-ylmethanesulfinyl)-benzimidazole-1-sulfonyl]-
benzoic acid 2-(toluene-4-sulfonyl)ethyl ester (8d) (1.6 g, 2.25 mmol) in CH3CN (15 mL) was added a
solution of NaHCO3 (225 mg, 2.7 mmol, 1.2 eq) in H2O (8 mL) at room temperature, and then the
mixture was heated to 65 °C for 2 h. Thereafter most of CH3CN was removed, the mixture was
extracted with EtOAc (50 mL) and then the aqueous layer was lyophilized overnight. The resulting
solid was dissolved in CH2Cl2 (200 mL) and then the mixture was filtered to remove insoluble solids.
The filtrate was concentrated to near dryness. The resulting residual oil was dissolved in CH2Cl2 (about
2 mL) and EtOAc (2 mL) was added to the mixture to precipitate a white solid. The white precipitate
was collected by filtration, washed with EtOAc-ether (3:1), and dried under vacuum to give 900 mg
1
(72%) of mixture of compounds 9c and 9d as a white solid (1:1 ratio of 5- and 6-isomers). H-NMR
(D2O) δ: 1.77 (m, 6 H, 5- and 6-isomers), 3.33-3.54 (m, 6 H, 5- and 6-isomers), 4.57 (d, 1 H), 4.76 (m,
1 H), 6.6-8.3 (m, 8 H, 5- and 6-isomers).
3.4.19. 3-{2-[4-(3-Methoxypropoxy)-3-methylpyridin-2-yl-methanesulfinyl]-benzimidazole-1-sulfon-
yl}benzoic acid 2-(toluene-4-sulfonyl)ethyl ester (8e)
To
a
solution
of
2-[4-(3-methoxypropoxy)-3-methylpyridin-2-yl-methanesulfinyl]-1H-
benzimidazole sodium salt (1.0 g, 2.62 mmol), Et3N (5 mL), and NaHCO3 (about 1 g) in CH2Cl2

Molecules 2009, 14
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(15 mL) was added 3-chlorosulfonylbenzoic acid 2-(toluene-4-sulfonyl)ethyl ester (1.27 g, 3.15 mmol,
1.2 eq) in CH2Cl2 (30 mL) at room temperature, and then the mixture was stirred for 1.5 h. Thereafter
water (30 mL) was added, the mixture was extracted with CH2Cl2 (50 mL) and the organic layers were
dried, and concentrated. The resulting residual oil was purified by column chromatography (CH2Cl2 to
1% MeOH in CH2Cl2) to yield 1.5 g (76%) of 8e as an off-white foam. 1H-NMR (CDCl3) δ: 2.09 (m, 2
H), 2.24 (s, 3 H), 2.29 (s, 3 H), 3.34 (s, 3 H), 3.57 (m, 4 H), 4.13 (t, 2 H), 4.65 (m, 2 H), 5.05 (dd, 2 H),
6.75 (d, 1 H), 7.20 (d, 2 H), 7.41 (t, 1 H), 7.50 (t, 1 H), 7.58 (t, 1 H), 7.77 (m, 3 H), 8.01 (t, 2 H), 8.19
(d, 1 H), 8.37 (d, 1 H), 8.60 (s, 1 H).
3.4.20. 3-[2-[4-(3-Methoxypropoxy)-3-methylpyridin-2-yl-methanesulfinyl]-benzimidazole-1-
sulfonyl]-benzoic acid sodium salt (9e)
To the solution of the 3-[2-[4-(3-methoxypropoxy)-3-methylpyridin-2-yl-methanesulfinyl]-
benzimidazole-1-sulfonyl]benzoic acid 2-(toluene-4-sulfonyl)ethyl ester (1.5 g, 2.0 mmol) in CH3CN
(15 mL) was added a solution of NaHCO3 (200 mg, 2.4 mmol, 1.2 eq) in H2O (7 mL) at room
temperature, and then the mixture was heated to 65 °C for 2.5 h. Thereafter most of CH3CN was
removed, the mixture was extracted with EtOAc (50 mL) and the aqueous layer was lyophilized
overnight. The solid was dissolved in CH2Cl2 (200 mL) and then the mixture was filtered to remove
insoluble solids. The filtrate was concentrated to near dryness. The residual oil was dissolved in
CH2Cl2 (about 2 mL) and EtOAc-ether (1:1) was added to precipitate a white solid. The precipitate
was collected by filtration, washed with EtOAc-ether (1:1), and dried under vacuum to give 700 mg
(60%) of compound 9e as a white solid. 1H-NMR (D2O) δ 1.66 (m, 2 H), 1.72 (s, 3 H), 3.02 (s, 3 H),
3.22 (t, 2 H), 3.70 (m, 2 H), 4.56 (d, 1 H), 4.78 (d, 1 H), 6.44 (d, 1 H), 7.11 (t, 1 H), 7.19 (t, 1 H), 7.32
(t, 1 H), 7.43 (d, 1 H), 7.62 (d, 1 H), 7.77 (m, 2 H), 7.93 (d, 1 H), 8.29 (s, 1 H).
3.4.21. 3-{2-[3-Methyl-4-(2,2,2-trifluoroethoxy)-pyridin-2-yl-methanesulfinyl]-benzimidazole-1-
sulfon-yl}-4-methylbenzoic acid 2-(toluene-4-sulfonyl)ethyl ester (8f)
To a heterogeneous mixture of 2-[3-methyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl-methanesulfinyl]-
1H-benzimidazole (700 mg, 1.89 mmol), Et3N (3 mL), and NaHCO3 (about 1 g) in CH2Cl2 (15 mL)
was added 3-chlorosulfonyl-4-methylbenzoic acid 2-(p-tolylsulfonyl)ethyl ester (1.03 g, 2.47 mmol,
1.3 eq) in CH2Cl2 (5 mL) at room temperature, and then the mixture was stirred for 2 h. Thereafter
water (50 mL) was added, the mixture was extracted with CH2Cl2 (50 mL) and the organic layers were
dried and concentrated. The resulting residual oil was purified by column chromatography (CH2Cl2 to
1
1% MeOH in CH2Cl2) to yield 1.1 g (78%) of compound 8f as a yellow foam. H-NMR (CDCl3)
δ: 2.31 (s, 3 H), 2.33 (s, 3 H), 2.58 (s, 3 H), 3.57 (m, 2 H), 4.38 (q, 2 H), 4.67 (t, 2 H), 4.80 (d, 1 H),
4.97 (d, 1 H), 6.61 (m, 1 H), 7.31 (m, 3 H), 7.42 (m, 2 H), 7.50 (m, 1 H), 7.79 (d, 2 H), 7.83 (m, 1 H),
7.93 (m, 1 H), 8.17 (m, 1 H), 8.65 (s, 1 H).

Molecules 2009, 14
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3.4.22. 3-{2-[3-Methyl-4-(2,2,2-trifluoroethoxy)-pyridin-2-yl-methanesulfinyl]-benzimidazole-1-
sulfon-yl}-4-methylbenzoic acid sodium salt (9f)
To the solution of 3-{2-[3-methyl-4-(2,2,2-trifluoroethoxy)-pyridin-2-yl-methanesulfinyl]-
benzimidazole-1-sulfonyl}-4-methylbenzoic acid 2-(toluene-4-sulfonyl)ethyl ester (1.1 g, 1.46 mmol)
in CH3CN (8 mL) was added a solution of NaHCO3 (160 mg, 1.91 mmol, 1.3 eq) in H2O (4 mL) at
room temperature, and then the mixture was heated to 65 °C for 2 h. Thereafter most of the CH3CN
was removed, the mixture was extracted with EtOAc (50 mL) and then aqueous layer was lyophilized
overnight. The solid was dissolved in CH2Cl2 (200 mL) and then the mixture was filtered to remove
insoluble solids. The filtrate was concentrated to near dryness. The residual oil was dissolved in
CH2Cl2 (about 2 mL) and EtOAc (2 mL) was added to the mixture to precipitate a white solid. The
precipitate was collected by filtration, washed with EtOAc, and dried under vacuum to give 540 mg
(62%) of compound 9f as a light brown solid. 1H-NMR (D2O) δ: 1.68 (s, 3 H), 1.94 (s, 3 H), 4.21 (m, 2
H), 4.45 (d, 1 H), 4.73 (d, 1 H), 6.48 (d, 1 H), 6.90 (d, 1 H), 7.05 (m, 2 H), 7.31 (m, 1 H), 7.48 (m, 1
H), 7.75 (m, 2 H), 8.26 (s, 1 H).
3.4.23. 3-{2-[4-(3-Methoxypropoxy)-3-methylpyridin-2-yl-methanesulfinyl]-benzimidazole-1-
sulfonyl}-4-methylbenzoic acid 2-(toluene-4-sulfonyl)ethyl ester (8g)
To
a
solution of 2-[4-(3-methoxypropoxy)-3-methylpyridin-2-yl-methanesulfinyl]-1H-benz-
imidazole sodium salt (1.0 g, 2.62 mmol), Et3N (5 mL) and NaHCO3 (about 1 g) in CH2Cl2 (15 mL)
was added 3-chlorosulfonyl-4-methylbenzoic acid 2-(p-tolylsulfonyl)ethyl ester (1.30 g, 3.15 mmol,
1.2 eq) in CH2Cl2 (5 mL) at room temperature, and then the mixture was stirred for 0.5 h. Thereafter
water (15 mL) was added, the mixture was extracted with CH2Cl2 (50 mL) and the organic layers were
dried, and concentrated. The residual oil was purified by column chromatography (CH2Cl2 to 1%
1
MeOH in CH2Cl2) to yield 1.6 g (80%) of 8g as an off-white foam. H-NMR (CDCl3) δ 2.07 (t, 2 H),
2.22 (s, 3 H), 2.32 (s, 3 H), 2.58 (s, 3 H), 3.34 (s, 3 H), 3.57 (m, 4 H), 4.13 (t, 2 H), 4.67 (t, 2 H), 5.01
(dd, 2 H), 6.74 (d, 1 H), 7.30 (m, 3 H), 7.40 (m, 2 H), 7.79 (m, 5 H), 8.19 (d, 1 H), 8.64 (s, 1 H).
3.4.24. 3-{2-[4-(3-Methoxypropoxy)-3-methylpyridin-2-yl-methanesulfinyl]-benzimidazole-1-
sulfonyl}-4-methylbenzoic acid sodium salt (9g)
To the solution of 3-{2-[4-(3-methoxypropoxy)-3-methylpyridin-2-yl-methanesulfinyl]-
benzimidazole-1-sulfonyl}-4-methylbenzoic acid 2-(toluene-4-sulfonyl)ethyl ester (1.5 g, 1.97 mmol)
in CH3CN (15 mL) was added a solution of NaHCO3 (200 mg, 2.36 mmol, 1.2 eq) in H2O (7 mL) at
room temperature, and then the mixture was heated to 65 °C for 2 h. Thereafter most of the CH3CN
was removed, the mixture was extracted with EtOAc (80 mL), and the aqueous layer was lyophilized
overnight. The solid was dissolved in CH2Cl2 (100 mL), and then the mixture was filtered to remove
insoluble solids. The filtrate was concentrated to near dryness. The residual oil was dissolved in about
2 mL of CH2Cl2 and EtOAc-hexane (7:1) was added to precipitate a white solid. The precipitate was
collected by filtration, washed with EtOAc-hexane (7:1), and dried under vacuum to give 950 mg
1
(80%) of compound 9g as a white solid. H-NMR (D2O) δ: 1.50 (s, 3 H), 1.72 (t, 2 H), 2.00 (s, 3 H),

Molecules 2009, 14
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3.08 (s, 3 H), 3.27 (t, 2 H), 3.74 (m, 2 H), 4.56 (d, 1 H), 4.75 (d, 1 H), 6.46 (d, 1 H), 7.01 (d, 1 H), 7.18
(m, 2 H), 7.40 (m, 1 H), 7.59 (m, 1 H), 7.69 (d, 1 H), 7.81 (d, 1 H), 8.38 (s, 1 H).
3.4.25. 2-(Carboxymethoxy)-5-{2-[3-methyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl-methanesulfinyl]-
benzimidazole-1-sulfonyl}-benzoic acid disodium salt (12a)
To a heterogeneous solution of 2-[3-methyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl-methanesulfinyl]-
1H-benzimidazole (lansoprazole, 3.0 g, 8.13 mmol) and Et3N (6 mL) in CH2Cl2 (70 mL) was added 5-
chlorosulfonyl-2-[2-(toluene-4-sulfonyl)-ethoxycarbonylmethoxy]-benzoic acid 2-(toluene-4-sulfon-
yl)-ethyl ester (7.0 g, 10.6 mmol, 1.3 eq). Solid NaHCO3 (about 3 g) was added after the chloro-
sulfonyl ester has dissolved completely in the reaction mixture. The mixture was stirred at room
temperature for 2 h. Thereafter the solvent was removed by evaporation and the residual oil was passed
through a short column (silica gel, CH2Cl2 to 1% MeOH in CH2Cl2) to remove a colored impurity and
Et3N. Concentration of the eluent gave 2-(carboxymethoxy)-5-{2-[3-methyl-4-(2,2,2-trifluoro-
ethoxy)pyridin-2-yl-methanesulfinyl]-benzimidazole-1-sulfonyl}-benzoic acid [bis{2-(toluene-4-
sulfonyl)ethyl} ester] (11a; about 9.0 g) as an off-white foam. To a solution of 11a (9.0 g, 8.13 mmol)
in CH3CN (80 mL) was added a solution of NaHCO3 (1.70 g, 20.3 mmol, 2.5 eq) in H2O (40 mL). The
mixture was heated to 65 °C for 5 h. Thereafter most of the CH3CN was removed, the mixture was
washed with EtOAc (2 × 100 mL), and then the aqueous layer was lyophilized overnight. The solid
was dissolved in CH2Cl2 (200 mL) and then the mixture was filtered to remove insoluble material. The
filtrate was concentrated and the residual oil was dissolved in CH2Cl2 (20 mL). EtOAc-Ether (1:1) was
added to the mixture to precipitate a white solid. The precipitate was collected by filtration, washed
with diethyl ether, and dried under vacuum to yield 4.5 g (82%) of 12 as a light brown solid. 1H-NMR
(D2O) δ: 1.96 (s, 3 H), 4.48 (m, 4 H), 4.70 (d, 1 H), 4.87 (d, 1 H), 6.68 (d, 1 H), 6.80 (d, 1 H), 7.25 (t, 1
H), 7.32 (t, 1 H), 7.53 (d, 1 H), 7.63 (d, 1 H), 7.83 (m,2 H), 7.97 (s, 1 H).
3.4.26. 2-(Carboxymethoxy)-5-{5-methoxy-2-(4-methoxy-3,5-dimethylpyridin-2-yl-methanesulfinyl)-
benzimidazole-1-sulfonyl}-benzoic acid disodium salt (12b) and 2-(carboxymethoxy)-5-{6-methoxy-
2-(4-methoxy-3,5-dimethylpyridin-2-yl-methanesulfinyl)-benzimidazole-1-sulfonyl}-benzoic acid di-
sodium salt (12c)
To
a
heterogeneous
solution
of
5-methoxy-2-(4-methoxy-3,5-dimethyl-pyridin-2-yl-
methanesulfinyl)-1H-benzimidazole (omeprazole, 1.0 g, 3.03 mmol) and Et3N (4 mL) in CH2Cl2 (20
mL) was added the chlorosulfonyl ester (2.6 g, 3.95 mmol, 1.3 eq). Solid NaHCO3 (about 1 g) was
added after the chlorosulfonyl ester has dissolved completely in the reaction mixture. The mixture was
stirred at room temperature for 2 h. Thereafter water was added and the mixture was extracted with
EtOAc (2 × 100 mL). The combined organic layers were washed with water, dried, and concentrated to
give a mixture of compounds 11b and 11c (about 2.9 g) as off-white foam, which were used without
further purification. To a solution of the mixture of 11b and 11c (about 2.9 g) in CH3CN (30 mL) was
added a solution of NaHCO3 (520 mg, 6.19 mmol, 2.2 eq) in H2O (15 mL). The mixture was heated to
65°C for 3 h. Thereafter all volatile materials were removed under vacuum, the mixture was washed
with EtOAc (2 × 30 mL), and the aqueous layer was lyophilized overnight. The solid was dissolved in
CH2Cl2 (150 mL) and then the mixture was filtered to remove insoluble material. The filtrate was

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concentrated and the residual oil was dissolved in CH2Cl2 (5 mL). EtOAc (5 mL) was added to the
mixture to precipitate a white solid. The precipitate was collected by filtration, washed with ether, and
dried under vacuum to yield 1.86 g (95%) of mixture of 12b and 12c as a light brown solid (1:1 ratio
1
between 5- and 6-isomer). H-NMR (D2Ο) δ: 1.77 (m, 6 H), 3.34 (m, 3 H), 3.46 and 3,54 (s, 3 H, 5-
and 6-OMe isomer), 4.45 (m, 2 H), 4.58 (d, 1 H), 4.74 (d, 1 H), 6.6-8.3 (m, 7 H).
3.4.27. (2-(2-Benzenesulfonylethoxycarbonylmethoxy)-4-{2-[3-methyl-4-(2,2,2-trifluoroethoxy)-
pyridin-2-ylmethanesulfinyl]-benzimidazole-1-sulfonyl}phenoxy)acetic acid 2-benzenesulfonyl-ethyl
ester (15a)
To a heterogeneous mixture of 2-[3-methyl-4-(2,2,2-trifluoroethoxy)-pyridin-2-ylmethanesulfinyl]-
benzimidazole, (lansoprazole) (500 mg, 1.35 mmol) in CH2Cl2 (10 mL) was added NaH (40 mg,
1.63 mmol) at room temperature resulting in a clear solution. To this clear mixture was added [2-(2-
benzenesulfonyl-ethoxycarbonylmethoxy)-4-chlorosulfonyl-phenoxy]-acetic acid 2-benzenesulfonyl-
ethyl ester (1.0 g, 1.63 mmol, 1.2 eq) in CH2Cl2 (5 mL) at room temperature, and the mixture was
stirred for 3 h. Thereafter water (10 mL) was added, the mixture was extracted with CH2Cl2 (50 mL)
and the organic layers were dried and concentrated under reduced pressure. The residual oil was
purified by column chromatography (CH2Cl2 to 2% MeOH in CH2Cl2) to yield compound 15a (1.05 g,
1
78%) as an off-white foam. H-NMR (CDCl3) δ: 2.31 (s, 3 H), 3.45 (m, 4 H), 4.46-4.56 (m, 10 H),
5.03 (d, 1 H), 5.13 (d, 1 H), 6.80 (m, 1 H), 6.86 (d, 1 H), 7.40 (t, 1 H), 7.47 (t, 1 H), 7.56 (m, 4 H), 7.64
(m, 3 H), 7.78 (dd, 2 H), 7.88 (m, 4 H), 7.98 (d, 1 H), 8.28 (m, 1 H).
3.4.28. (2-Carboxymethoxy-4-{2-[3-methyl-4-(2,2,2-trifluoroethoxy)-pyridin-2-ylmethanesulfinyl]-
benzimidazole-1-sulfonyl}-phenoxy)-acetic acid di-sodium salt (16a)
A solution of (2-(2-benzenesulfonyl-ethoxycarbonylmethoxy)-4-{2-[3-methyl-4-(2,2,2-trifluoro-
ethoxy)-pyridin-2-ylmethanesulfinyl]-benzimidazole-1-sulfonyl}phenoxy)acetic
acid
2-benzene-
sulfonyl-ethyl ester (500 mg, 0.50 mmol) and NaHCO3 (90 mg, 1.10 mmol, 2.2 eq) in THF-H2O (6
mL-3 mL) was heated to 70 °C for 2 h. Thereafter volatile materials were removed by evaporation
under reduced pressure and the residual semi-solid was briefly treated with MeOH-CH2Cl2 (1:1). The
resulting solid was collected by filtration to give compound 16a (300 mg, 74 %) as an off-white solid.
1H-NMR (DMSO-d6) δ: 2.20 (s, 3 H), 4.14 (m, 4 H), 4.86 (m, 3 H), 5.10 (d, 1 H), 6.99 (m, 1 H), 7.05
(m, 1 H), 7.34 (m, 1 H), 7.50 (m, 1 H), 7.61 (m, 1 H), 7.72 (m, 2 H), 8.02 (m, 2 H).
3.4.29. {4-[5-Methoxy-2-(4-methoxy-3,5-dimethylpyridin-2-ylmethanesulfinyl)-benzimidazole-1-
sulfon-yl]-2-[2-(toluene-4-sulfonyl)-ethoxycarbonylmethoxy]-phenoxy}-acetic acid 2-(toluene-4-
sulfon-yl)ethyl ester (15b) and {4-[6-methoxy-2-(4-methoxy-3,5-dimethylpyridin-2-
ylmethanesulfinyl)-benzimidazole-1-sulfonyl]-2-[2-(toluene-4-sulfonyl)-ethoxycarbonylmethoxy]-
phenoxy}-acetic acid 2-(toluene-4-sulfonyl)ethyl ester (15c)
Chlorosulfonyl-2-[2-(toluene-4-sulfonyl)-ethoxycarbonylmethoxy]-phenoxy}-acetic
acid
2-
(toluene-4-sulfonyl)ethyl ester (7.6 g, 11 mmole) and 5-methoxy-2-(4-methoxy-3,5-dimethyl-pyridin-
2-ylmethanesulfinyl)-benzimidazole (3.5 g, 10 mmole) were added to a solution composed of