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A new synthesis of [14C]-labeled pantoprazole has been described: The cyclization of potassium [14C]-ethylxanthate (I) with the diaminobenzene (II) by means of NaOH gives the imidazole (III), which is condensed with 2-(chloromethyl)-3,4-dimethoxypyridine (IV) by means of NaOH in ethanol to afford the sulfide (V). Finally, this compound is oxidized with m-chloroperbenzoic acid (mcpba) in dichloromethane.

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Using [14C]-labeled (IV) in the preceding synthesis, pantoprazole labeled in the methylene was obtained. Intermediate (IV) labeled in the methylene attached to the pyridine ring can be prepared as follows: The reaction of 2-bromo-3,4-dimethoxypyridine (V) with [14C]-labeled CuCN gives 3,4-dimethoxypyridine-2-carbonitrile (VI), which is hydrolyzed with NaOH and methylated with diazomethane to the methyl ester (VII). Finally, this compound is reduced with LiAlH4 to the corresponding alcohol and treated with SOCl2 to give the chloromethylpyridine (IV*) with the [14C] label. Then this compound is condensed with benzimidazole (III) as usual.

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The precursor 5-(difluoromethoxy)-2-mercaptobenzimidazole (V) was prepared by the following route. Nitration of N-(p-difluoromethoxyphenyl)acetamide (I) provided nitro anilide (II), which was hydrolyzed to the corresponding nitro aniline (III) employing methanolic NaOMe. Reduction of (III) to the phenylenediamine (IV) was performed by catalytic hydrogenation over Pd/C. Then, cyclization of diamine (IV) with potassium O-ethyl dithiocarbonate gave rise to the benzimidazole (V).

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3-Methoxy-2-methylpyridine (VII), prepared by methylation of 2-methyl-3-pyridinol (VI), was converted to the N-oxide (VIII) employing peracetic acid. Nitration of the pyridine N-oxide (VIII) with concentrated nitric acid gave the 4-nitro derivative (IX). Subsequent displacement of the nitro group of (IX) by sodium methoxide led to the dimethoxypyridine N-oxide (X). Rearrangement of the N-oxide group of (X) in hot acetic anhydride produced the acetoxymethyl pyridine (XI). After basic hydrolysis of the acetate ester (XI), the resultant hydroxymethyl pyridine (XII) was chlorinated by SOCl2, yielding chloride (XIII). Condensation between mercapto benzimidazole (V) and the chloromethyl pyridine (XIII) in ethanolic NaOH led to the sulfide adduct (XIV). This was finally oxidized to the desired sulfoxide by using meta-chloroperbenzoic acid in CH2Cl2. The oxidation of sulfide (XIV) has also been performed employing sodium perborate, sodium percarbonate in the presence of ammonium molybdate, or tert-butyl hydroperoxide in the presence of vanadyl acetylacetonate.

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A related method for the preparation of the intermediate 3,4-dimethoxy-2-(hydroxymethyl)pyridine (XII) has been disclosed. 3-Methoxypyridine (XV) was chlorinated to (XVI) by refluxing in SOCl2. Radical carboxylation of pyridine (XVI) was carried out by reaction with ethyl pyruvate in the presence of hydrogen peroxide and iron(II) sulfate. The resultant ethyl 4-chloro-3-methoxypicolinate (XVII) was then converted to the dimethoxypicolinate (XVIII) by treatment with sodium methoxide. Then, ester group reduction in (XVIII) by means of DIBAL provided the target hydroxymethyl pyridine (XII).

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In an alternative procedure, the nitropyridine N-oxide (IX) was rearranged to the (mesyloxymethyl)pyridine (XIX) by treatment with methanesulfonic anhydride. Condensation of mesylate (XIX) with mercaptobenzimidazole (V), with concomitant nitro group displacement in the presence of sodium methoxide led to the sulfide precursor (XIV). This was then oxidized to the title sulfoxide employing sodium percarbonate and ammonium molybdate. An analogous synthetic route starting from the chloropyridine N-oxide (XX) provided mesylate (XXI), which was condensed with (V) in the presence of Et3N, leading to the sulfide adduct (XXII). The 4-chloro group of (XXII) was then displaced by sodium methoxide producing the dimethoxypyridine derivative (XIV).

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Similarly, rearrangement of the chloropyridine N-oxide (XX) using acetic anhydride produced acetate ester (XXIII), which was further hydrolyzed to the pyridine alcohol (XXIV). The chloromethyl pyridine (XXV), obtained by treatment of alcohol (XXIV) with SOCl2, was condensed with the mercaptobenzimidazole (V) in the presence of tetramethylguanidine producing sulfide (XXII). Conversion of (XXII) to the title compound was then performed by oxidation to sulfoxide (XXVI) employing sodium percarbonate, followed by chloride displacement with potassium methoxide.