Pantoprazole sodium, DZ-2352a, B-8510-29(free acid), By-1023/SK&F-96022(free acid), B-8610-23/SK&F-96022-Z, Pantorc, Rifun, Pantozol, Zurcal, Ulcotenal, Inipomp, Pantecta, Anagastra, Pantoloc, Pantopan, Inipomp, Peptazol, Protonix, Protium

合成路线: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).

参考文献标题:Dialkoxypyridines,process for their preparation,their use and medicines containing them
文献作者:Kohl,B.; Sturm,E.; Klemm,K.; Riedel,R.; Figala,V.; Rainer,G.; Schaefer,H.; Senn-Bilfinger,J.(Altana Pharma Deutschland GmbH )
参考来源:AU 8543640; EP 0166287; JP 1986022079; US 4758579


合成路线: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.

参考文献标题:Chemical process for the production of sulphinyl derivs.by oxidation of the corresponding co-derivs.with perborates
文献作者:Brennan,J.P.; Turner,A.T.(Abbott Laboratories Inc.)
参考来源:WO 9947514


合成路线: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.

参考文献标题:Method for oxidizing a thioether group into a sulfoxide group
文献作者:Coppi,L.; Campon Pardo,J.; Berenguer Maimo,R.(Laboratorios del Dr.Esteve,SA)
参考来源:ES 2163372; WO 0168594


合成路线: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.

合成路线: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).

参考文献标题:Method for obtaining derivs.of [[pyridyl substd.)methyl]thio]benzimidazol
文献作者:Coppi,L.; Berenguer Maim? R.(Laboratorios del Dr.Esteve,SA)
参考来源:ES 2171116; WO 0179194


合成路线: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.

参考文献标题:Processes for the production of substd.2-(2-pyridylmethyl) sulfinyl-1H-benzimidazoles
文献作者:Mendelovici,M.; Avrutov,I.(Teva Pharmaceutical Industries Ltd.; Teva Pharmaceuticals USA,Inc.)
参考来源:WO 0262786


合成路线: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).

参考文献标题:Synthesis of pharmaceutically useful pyridine derivs.
文献作者:Chen,L.; Zoghbi,M.(PDi-Research Laboratories,Inc.)
参考来源:WO 9850361