1-Arylsulfonyl-2-(Pyridylmethylsulfinyl) Benzimidazoles as New Proton Pump Inhibitor Prodrugs

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.


OPEN ACCESS
Proton pump inhibitors are weak bases with a pK a 1 between 3.8 and 4.5. This weak base pK a 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 pK a 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][10][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 Nsubstituent or formation of something other than the PPI, even though a study showed that Nmethylomeprazole 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 therapy of acid related diseases due to prolongation of the presence of the parent proton pump inhibitors in the body.  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. 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.
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.
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 arylsulfonylprodrug 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 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].

Biology
PPIs are acid-activated prodrugs [1,18]. They are all membrane permeant weak bases with one pK a (pK a 1) at about 4.0, with the exception of rabeprazole that has this pK a at ~5.0. This pK a 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 pK a 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 (pK a 2), 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 t 1/2 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 1arylsulfonyl 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. 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 benzimidazole 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].

General
All reactions were carried out under an atmosphere of nitrogen. All commercial reagents were used without further purification. NMR spectra were acquired using a Bruker 400 MHz spectrometer. 1 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 aluminabacked 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].

Phenoxyacetic acid 2-(toluene-4-sulfonyl)ethyl ester
To a solution of phenoxyacetyl chloride (5.0 g) and triethylamine (3 g) in CH 3 CN (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 CH 2 Cl 2 . The combined organic layers were washed with 1 N HCl solution and saturated NaHCO 3 solution, dried over MgSO 4 , and concentrated to give 8.0 g (97%) of the ester as light-yellow solid. 1

(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 CH 2 Cl 2 (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 vacuum overnight to yield 3.4 g (87%) of the title compound as white powder. 1

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'-dicyclohexylcarbodiimide (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-CH 2 Cl 2 to CH 2 Cl 2 ) to yield 4.1 g (82%) of a clear oil. 1  To a mixture of phenoxy-2-butyric acid 2-(p-toluenesulfonyl)ethyl ester (4.0 g, 11.0 mmol) and CH 2 Cl 2 (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 CH 2 Cl 2 (500 mL). The organic layer was dried over MgSO 4 , and concentrated to yield 4.1 g (81%) of the thick yellow oil. 1

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 CH 2 Cl 2 (1.5 mL) was added dropwise ClSO 3 H (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 CH 2 Cl 2 (500 mL). The organic layer was dried over MgSO 4 , 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. 1

6-[2-(3,5-Dimethylphenoxy)acetylamino]hexanoic acid
After the mixture of the 3,5-dimethylphenoxyacetic acid (9.3 g, 51.6 mmol) and SOCl 2 (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 CH 3 CN (100 mL) and a solution of NaHCO 3 (6.5 g, 77.0 mmol, 1.5 eq) in H 2 O (80 mL) were both added dropwise with ice-bath cooling to a solution of 6amino-n-caproic acid (13.5 g, 103 mmol, 2.0 eq) and NaOH (4.2 g, 105 mmol) in H 2 O (100 mL) and CH 3 CN (130 mL). The mixture was stirred vigorously overnight. After most of CH 3 CN 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 H 2 O followed by hexane, and dried under high vacuum to yield 14.5 g (95%) of white solid. 1  To a cooled solution of 6-[2-(3,5-dimethyl-phenoxy)acetylamino]hexanoic acid 2-(3nitrobenzenesulfonyl)ethyl ester (4.6 g, 9.1 mmol) in CH 2 Cl 2 (3 mL) was added dropwise ClSO 3 H (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 CH 2 Cl 2 (300 mL), and the organic layer was dried over anhydrous MgSO 4 , and concentrated to give 2.2 g (40%) of white foam. 1

3-Chlorosulfonylbenzoic acid 2-(3-nitrobenzenesulfonyl)ethyl ester
To the solid 3-chlorosulfonylbenzoic acid (3.2 g, 14.4 mmol) was added solid PCl 5 (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 POCl 3 was removed by vacuum distillation, the brown oil was dissolved in CH 3 CN (15 mL) and then 2-(3nitrobenzenesulfonyl) 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 CH 2 Cl 2 (500 mL). The organic extract was dried over anhydrous MgSO 4 , and concentrated. The resulting oil was purified by short column chromatography (eluent: CH 2 Cl 2 to 1% MeOH in CH 2 Cl 2 ) to give a brown semisolid, which was solidified by treating with ether-EtOAc to yield 2.75 g (53%) of a white solid.

3-Chlorosulfonylbenzoic acid 2-(toluene-4-sulfonyl)ethyl ester
A heterogeneous mixture of 3-chlorosulfonyl benzoic acid (11.0 g, 50.0mmol) in SOCl 2 (18 mL) was refluxed for 3 h. Thereafter the excess of SOCl 2 was removed, the residual brown oil was dissolved in CH 3 CN (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 CH 3 CN was removed, the resulting oil was purified by short column chromatography (silica gel, CH 2 Cl 2 ) to give light brown oil, which was dried further under vacuum to yield 19.1 g (95%) of a light brown solid. , 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 CH 2 Cl 2 (500 mL) The combined organic layers were washed with saturated NaHCO 3 solution (2 × 200 mL), dried over MgSO 4 , and concentrated to give the title compound (5.5 g, 88%) as a light brown liquid. 1 To a mixture of 3-(2-methoxyphenyl)propionic acid 2-(toluene-4-sulfonyl)ethyl ester (5.0 g, 13.8 mmol) and CH 2 Cl 2 (5 mL) was added dropwise chlorosulfuric acid (8.0 g, 69.0 mmol, 5.0 eq) with icebath 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 MgSO 4 , and concentrated by evaporation to give a thick oil, which was purified by column chromatography (CH 2 Cl 2 ) to yield 3-(5-chlorosulfonyl-2-methoxyphenyl)propionic acid 2-(toluene-4-sulfonyl)ethyl ester (4.7 g, 74%) as a light brown oil. 1

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 SOCl 2 (18 mL) was refluxed for 3 h. After the excess of SOCl 2 was removed, the residual brown oil was dissolved in CH 3 CN (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 CH 3 CN was removed, the resulting oil was purified by short column chromatography (CH 2 Cl 2 to 1% MeOH in CH 2 Cl 2 ) 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.  (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 CH 3 CN (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 washed with 1 N NaHCO 3 , dried, and concentrated to yield 7.7 g (93%) of a brown foam. 1 (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·H 2 O (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 CH 2 Cl 2 (500 mL). The combined organic layers were washed with saturated NaHCO 3 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, CH 2 Cl 2 ) to give the compound 13 ( (14) To a solution of [2-(2-benzenesulfonyl-ethoxycarbonylmethoxy)-phenoxy]acetic acid 2-benzenesulfonyl-ethyl ester (7.4 g, 13.2 mmol) in CH 2 Cl 2 (10 mL) was added dropwise ClSO 3 H (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 CH 2 Cl 2 (500 mL). The organic layer was dried over anhydrous MgSO 4 , and concentrated under reduced pressure. The residual oil was dried under vacuum overnight to give the title compound 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 under reduced pressure to yield 13 g (99%) of the title compound. 1   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.

(3,5-Dimethyl-4-{2-[3-methyl-4-(2,2,2-trifluoroethoxy)-pyridin-2-ylmethanesulfinyl]-benzimidazole-1-sulfonyl}phenoxy)acetic acid 2-(toluene-4-sulfonyl)ethyl ester (5c)
To a heterogeneous mixture of lansoprazole (500 mg, 1.36 mmol) in CH 2 Cl 2 (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 CH 2 Cl 2 (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 CH 2 Cl 2 (20 mL), and the organic layers were dried, and concentrated. The oil was purified by column chromatography (3% MeOH in CH 2 Cl 2 ) to yield 700 mg (65%) of white foam. 1  The solution of the ester (5c) (400 mg, 0.50 mmol) and NaHCO 3 (51 mg, 0.60 mmol, 1.2 eq) in THF-H 2 O (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 CH 3  To a solution of rabeprazole sodium salt (760 mg, 2.0 mmol) in CH 2 Cl 2 (10 mL) was added (4chlorosulfonyl-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 NaHCO 3 (~1 g) was added to the mixture. The reaction mixture was stirred at room temperature for 3h. After all the solvent and the solid NaHCO 3 were removed, the oil was purified by column chromatography (silica gel, CH 2 Cl 2 to 3% MeOH in The compound 5d ester (400 mg, 0.53 mmol) was dissolved in acetone (6 mL) and a solution of NaHCO 3 (50 mg, 0.597 mmol, 1.1 eq) in H 2 O (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 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. 1   To a heterogeneous solution of omeprazole (840 mg, 2.44 mmol) in CH 2 Cl 2 (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 NaHCO 3 (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, CH 2 Cl 2 to 4% MeOH in CH 2 Cl 2 ) to give 1.6 g (88%) of the product (1:1 ratio of 5-/6-methoxy isomers) as off-white foam. 1  The mixture of the ester compound 5e and 5f (2.2 g, 2.97 mmol) was dissolved in CH 3 CN (20 mL), and then a solution of NaHCO 3 (250 mg, 2.97 mmol, 1.0 eq) in H 2 O (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