Benzimidazole, reaction with sodium hydroxide

Preparation of the prototype drug departs from the phenylenediamine strategy used in all of the previous examples. Condensation of thiazolo nitrile (53-2) with aniline catalyzed by aluminum chloride affords the amidine addition product (53-3). This is then converted to its reactive A -chloro derivative (53-4) by reaction with sodium hypochlorite. Treatment of that intermediate with a base such as potassium hydroxide leads directly to the cyclization product and thus the benzimidazole thiabendazole (53-6) [56]. The reaction can be rationalized by invoking as the first step the abstraction of chloride to leave behind a nitrene species such as (53-5) this would then readily insert in the CH bond at the ortho position. 

All of these derivatives are 1,2-disubstituted benzenes, which are converted by chemical reaction, for example, in aqueous medium with sodium hydroxide or with dimethyl sulfate, into alkyl N-benzimidazol-2-yl-carbamates (Koyamada et ai, 1969 Adams and Wommack, 1970). Thiophanate derivatives themselves are inactive (Nogutsi et al., 1971), but in plants they are converted into benzimidazole derivatives, exerting their effect in this form (Selling et ai, 1970 Vonk and Kaars Sijpesteijn, 1971 Soeda et al., 1972). The lack of activity of 1,3- and l,4-bis(3-alkoxycarbonyl-l-thioureido)benzenescan be explained by their inability to cyclise the benzimidazole ring. Thioallophanic acid derivatives are thus the precursors of alkyl N-benzimidazol-2-yl-carbamates. Further substitutions on the benzene ring decrease the fungitoxicity of the compounds. 

Cambell [78] has described an isotope dilution method for the determination of vinyl acetate in vinyl acetate-vinyl chloride copolymers. In this method a known amount of acetic 2- C acid is added to a solution or suspension of the resin in methyl ethyl ketone and the ester is hydrolysed with sodium hydroxide. The major portion of the sodium acetate is isolated and converted to 2-methyl benzimidazole-methyl C by means of the Phillips reaction [79] with o-phenylene diamine. 

Omeprazole was prepared [19] by reaction of 4-methoxy-o-phenyl-enediamine 1 with potassium ethyl xanthogenate 2 to give 5-methoxy-2-mercapto-lH-benzimidazole 3. Treatment of compound 3 with 3,5-dimethyl-4-methoxy-2-chloromethyl pyridine 4 in sodium hydroxide... 

A mixture of 4-[4-(diphenylmethyl)-l-piperazinylmethyl]-Nl-ethyl-l,2-benzenediamine and acetic acid is stirred at room temperature till all solid enters solution. Then there are added pentyl ethanimidate hydrochloride and stirring is continued first for 1 h at room temperature and further for 1 h at reflux. The reaction mixture is evaporated and the residue is stirred in water. The whole is alkalized with a sodium hydroxide solution and the product is extracted with dichloromethane. The extract is dried, filtered and evaporated. The residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol as eluent. The pure fractions are collected and the eluent is evaporated. The product is filtered off and dried, yielding 5-[4-(diphenylmethyl)-l-piperazinylmethyl]-l-ethyl-2-butyl-lH-benzimidazole melting point 124.8°C (crystallized from 4-methyl-2-pentanone). 

Preparation of 2-(4-methyl-l-piperazinyl)benzimidazole. A mixture of 2-chlorobenzimidazole (10.00 g) and N-mehylpiperazine (20.00 g) is stirred at 125°C for 5 hours. A 10% aqueous sodium hydroxide (100 ml) is added to the reaction mixture, and the precipitated crystals are separated by filtration. The filtrate is extracted with chloroform, and the chloroform extract is evaporated to dryness to give the same crystals. The crystals are combined and recrystallized from water-methanol to give 2-(4-methyl-l-piperazinyl)benzimidazole (7.02 g) as colorless needles, m.p. 225°-226°C. 

Difluoromethoxy-2-[(4,5-dimethoxy-2-pyridyl)methylthio]-lH-benzimidazole (about 1 g) are dissolved in 10 ml of dioxane and 2 ml of 1 N sodium hydroxide solution. An equimolar amount of a titrated aqueous sodium hypochlorite solution, to which 1 mole per liter of sodium hydroxide solution has been added, is first added dropwise, while cooling with ice. After one hour a further equivalent and after 3 hours half the equimolar amount of sodium hypochlorite are added, to achieve complete reaction. After a reaction time of 4 hours, 5 ml of 5% strength sodium thiosulfate solution and another 25 ml of dioxane are added and the upper dioxane phase is separated off, washed once with 5 ml of sodium thiosulfate solution and concentrated on a rotary evaporator. The oily residue is dissolved in 20 ml of water and 10 ml of ethyl acetate and the solution is brought to pH 7 with about 100 ml of a buffer solution of pH 6.8. The solid which has precipitated out is filtered off with suction over a suction filter, washed with water, extracted by stirring at OC with acetone and dried. 5-Difluoromethoxy-2-[(4,5-dimethoxy-2-pyridyl)methanesulfinyl]-lH-benzimidazole is prepared yield about 85%. 

The route of synthesis of pantoprazole sodium, as described in US patent 4758579 (1988), is as follows. 2-chloromethyl-3,4 dimethoxypyridinium hydrochloride(I) is condensed with 5-difluoromethoxy-2-mercapto-benzimidazole(H) in ethanolic sodium hydroxide solution to yield 5-(difluoromethoxy)-2-(((3,4-dimethoxypyrolidine-2-yl) methyl) thio)-l/7-benzimidazole)(III). This compound is oxidized during reaction with m-chloroperbenzoic acid in methylene chloride, yielding pantoprazole base (IV). Further reaction with aqueous caustic soda solution gives pantoprazole sodium, which is then purified by crystallization from methanol. The various steps of this synthesis are illustrated in Scheme 1. 

Benzimidazoles, too, are readily alkylated either in neutral or basic medium. As with the uncondensed compounds, the former conditions are complicated by salt formation, but to a lesser extent since benzimidazoles are less basic. It is often valuable to vary the initial amounts of alkali and alkyl halide in order to improve yields. The best yields of 1-alkylbenzimidazole (76-83% for primary and 50-60% for secondary alkyl and aralkyl bromides) result with two moles of bromide and 1.5 moles of alkali per mole of benzimidazole (66RCRI22). There is severe steric hindrance to the alkylation of 2-arylben-zimidazoles in alkaline medium, but reactions with the silver salts seem more successful. The rapid and almost quantitative reaction between a benzimidazole and dimethylphenyl-alkylammonium chlorides in aqueous sodium hydroxide provides a very convenient method of introducing a primary aralkyl group (benzyl, a-naphthylmethyl). There has been little systematic study of the dkylation of unsymmetrical benzimidazoles, though much the same criteria should apply as in the uncondensed compounds. In this respect the observation that 1-bromopropane reacts with the anion of 2,6-dimethyl-4-nitrobenzimidazole to give... 

The reaction of chloroform with imidazoles > benzimidazoles and secondary amines (especially alicyclic amines) in the presence of alkoxides or hydroxides, as well as the reaction of chlorodifluoro-methane with sodium N-alkyl-iV-arylamides furnishes trisaminomethanes (525) and (526) (Scheme 95), respectively. Aziridine transforms fluorodialkyl sulfide (527) to the orthoamide (528 equation... 

In a 500-cc. round-bottomed flask 54 g. (0.5 mole) of d-phenylenediamine (p. 70) (Note i) is treated with 32 cc. (34.6 g.) of 90 per cent formic acid (0.75 mole) (Note 2). The mixture is heated in a water bath at 100° for two hours. After cooling, 10 per cent sodium hydroxide solution is added slowly, with thorough mixing by rotation of the flask, until the mixture is just alkaline to litmus. The crude benzimidazole is collected with suction in a 75-mm. Buchner fuimel ice-cold water is used to rinse all solid out of the reaction flask. The crude product is pressed thoroughly on the filter, washed with about 50 cc. of cold water, and then purified without previous drying (Note 3). 

Isolation of Product. Allow the reaction mixture to cool to room temperature. Add 630 gL of 10% aqueous sodium hydroxide solution (automatic delivery pipet). Crude benzimidazole predpitates at this point. Collect the produd by vacuum filtration using a Hirsch funnel and wash the filter cake with three 0.5-mL portions of cold water (calibrated Fhsteur pipet) ( -). 

It should be pointed out that there is only one paper (Kanoktanapom et al. 1980) in which the formation of 2,3-few(benzimidazol-2-yl)quinoxa]ine 100a as a by product in the reaction of tetrachloropyridazine 98 and 1,2-DAB 5a in iV-methylpyrroldone at 115 °C for 17 h is described (Scheme 6.31). The yield of the main product of this reaction 5,6,7,8,13,14-hexaazapentaphene 99 obtained as a free base after treatment of the corresponding hydrochloride with aqueous sodium hydroxide is 15 %. The yield of the by-product-2,3-fcw(benzimidazol-2-yl)quinoxaline 100a has not been given in this paper. Therefore this method cannot be used, as a preparative one for the synthesis of 2,3-6 (benzimidazol-2-yl)quinoxalines. The synthesis of other heterocyclic systems with two benzimidazole fragments cannot be used either. 

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