2- Methoxy-1 - -1 //-benzimidazole

Zur Kondensation mit Acetalen ist ein Basen-Zusatz (Kaliumhydroxid oder Triethylamin) erforderlich. Ein Beispiel zur Methoxy-methylierung von 1-Methoxy-benzimidazol zu /-Methoxy-3-methoxymethyl-benzimidazolium-chlorid405 findet sich auf S. 327 und als praparative Vorschrift in ds. Handbuch, Bd. El4a, S. 190. Falls Substituenten im Aryl-Teil vorhanden sind, so werden durch die Deprotonierung beide N-Atome Equivalent, und man erhalt Isomeren-Gemische176,515. Im Falle der Furanosen lassen sie sich chromatographisch trennen515 ... 

Methyl-l-penten-3-one-l-ol 1 and glacial acetic acid in benzene was added to pyrrolidine to give 2-methyl-l-pen ten-1-[N-pyrrolidinyl]-3-one 2. Compound 2 when treated with oxalyl chloride and methanol was added, 3,5-dimethyl-2-methoxycarbonyl-4-pyrone 3 was produced. Treatment of compound 3 with sodium borohydride in methanol gives 3,5-dimethyl-2-hydroxymethyl-4-pyrone 4. Compound 4 was converted to 3,5-dimethyl-2-hydroxymethyl-4-pyridone 5 by heating compound 4 with aqueous ammonia in a sealed flask. Compound 5 was converted to 4-chloro-2-chloromethyl-3,5-dimethyl pyridine 6 by treatment with phosphorous oxychloride. Treatment of compound 6 with 5-methoxy-2-mer-captobenzimidazole in tetrahydrofuran gave 2-[2-(4-chloro-3,5-dimethyl pyridinyl)methylthio]-5-methoxy benzimidazole 7. When compound 7 was treated with potassium hydroxide in dimethyl sulfoxide containing methanol, 2-[2-(3,5-dimethyl-4-methoxypyridinyl)methylthio]-5-methoxy... 

A large number of a-hydroxybenzylbenzimidazole [50-97-5] (HBB, 39), C24H22N2O, derivatives has been prepared and extensively studied as selective inhibitors of the RNA containing enterovimses (91). Although none of these derivatives have shown any antiviral activity in animals, l,2-bis(5-methoxy-2-benzimidazol-2-yl)-l,2-ethanediol [16656-27-2] (40), C2gH2gN404, was found to be active against an experimentally induced rhino vims infection in chimpanzees (92). However, the in vivo antiviral efficacy was accompanied by significant toxicity. 

H-Pyrido[3,2-c]azepine, 7-methoxy-nucleophilic displacement reactions, 7, 514 Pyridoazepines synthesis, 7, 535, 540 Pyridoazepinones synthesis, 7, 531 Py rido[2,1-a]benzazepin-6-one physiological properties, 7, 546 Py rido[ 1,2-a]benzimidazoles reactions, 6, 1041... 

The first compound of this class with inhibitory activity on the enzyme and on acid secretion was the 2-(pyridylmethyl)sulfinylbenzimidazole, timopra-zole, and the fust pump inhibitor used clinically was omeprazole, 2-[[3,5-dimethyl-4-methoxypyridin-2-yl] methylsulfinyl]-5-methoxy- lH-benzimidazole. Omeprazole is an acid-activated prodrug. Omeprazole and the other PPIs are accumulated in the acidic space of the parietal cell due to the pKa of the pyridine nitrogen and these are converted due to protonation of the benzimidazole nitrogen first to a thiol-reactive cationic sulfenic acid and then dehydrated to form the sulfenamide (Fig. 1). These thiophilic cations then bind to luminally... 

CN 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-l//-benzimidazole... 

Esomeprazole is the S-isomer of omeprazole (Prilosec), which is a mixture of the S- and R-isomers. Prilosec, for many years a best selling drug, is 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-IH-benzimidazole. Its empirical formula is (Ci7Hi8N303S)2Mg-3H20 with a molecular weight of 767.2 as a trihydrate and 713.1 on an anhydrous basis. 

A facile method for the synthesis of N-substituted 2-benzimidazolinones 142 has been developed by Romero et al. (96TL2361) using A-substituted ureas 139, which are cyclized to 142 with IBTA as an oxidant. The reaction probably proceeds via intermediates 140 and 141. Besides the iV-alkyl or aryl substituent, presence of the 1-methoxy group is necessary for the success of this cyclization. Another benzimidazoles synthesis involves cycli-zation of N-phenyl-C-alkyl formimidamides with IBD [95JCS(P1)615]... 

Omeprazole 5 -Methoxy-2- [(4 -methoxy-3,5-dimethyl-2-pyridinyl) methyl] sulfinylj -17/-benzimidazol O-methylation, imidazole ring formation using thiourea, A-oxidation, nucleophilic displacement, A-methylation, S -oxidation... 

X = Cl 2-[2- (4-Chior-phenyt) -2-oxo-ethylidcn -1 -methyl-2,3-dihydro-benzimidazol (V) 42% X = OCH3 2-[2-(4-Methoxy-phenyl)-2-oxo-ethyl]-I-methyl-benzimidazol (VI) 40%... 

Die Umsetzung von 1,2-Diamino-benzol mit (4-Methoxy-benzyliden)-malonsaure-dinitrilen zu 2-(4-Methoxy-phenyl)-benzimidazol (96%)155 verlauft unter C,C-Spaltung ... 

Eine effektive, reversible Schutzgruppe fur Benzimidazole ist l-Chlormethoxy-2-trimethylsilyl-ethan (SEM — Cl), das in Dimethylformamid zu l-[(2-Trimethylsilyl-ethoxy)-methoxy]-benz-imidazol [50% Sdp. 220°/0,2 Torr (26,7 Pa)] kondensiert. Die so geschiitzten Heterocyclen sind wesentlich weniger feuchtigkeitsempfindlich als die (l-Diethoxy-methyl)-Derivate (s.S.357). Man kann die SEM-Schutzgruppe in siedendem Tetrahydrofuran mit Tetrabutyl-ammonium-fluorid leicht wieder entfernen508. 

JLnM=A0CH3 Cl-CH2-OCH3 N(C2Hs)3 Benzol 0° - 4 h Ruckfl. I-( Methoxy-methyl)-2-(4-me thoxy-phenyl)-5-methyl-benzimidazol + l-( Methoxy-methyl)-6-methyl-benzimidazol 90a 176... 

In general, benzimidazole-2-methyl carbamate derivatives (28) can be synthesized by the reaction of an appropriate diamine (26) with 1,3-dicarbo-methoxy-5-methylisothiourea (27) [43], This is the most general and economic synthesis for benzimidazole carbamates. However, the same reaction was less than satisfactory when the aza analogues of o-phenylenediamines (29) were used. In order to synthesize the aza analogues of mebendazole (2) or flubendazole (3), the reactions of methoxycarbonyl isothiocyanate (30) with a wide variety of diamines such as 3,4-diaminopyridines, 4,5-diaminopyrimi-dines, o-phenylenediamines have been investigated in the presence of dicyclo-hexylcarbodiimide [44, 45] and were found to be quite successful in the synthesis of carbamates (31). 

Dimethyl-4-methoxy-2-pyridyl)methyl]sulfinyl-5-methoxy]-lH-benzimidazole [1-4]... 

Cotton etal. [14] described an asymmetric synthesis of esomeprazole. Esomeprazole, the (S)-enantiomer of omeprazole, was synthesized via asymmetric oxidation of prochiral sulfide 5-methoxy-2-[[(4-methoxy-3,5-dimethyl pyridin-2-yl)methyl]thio]-lH-benzimidazole 1. The asymmetric oxidation was achieved by titanium-mediated oxidation with cumene hydroperoxide in the presence of (S,S)-diethyl tartarate (DET). The enan-tioselectivity was provided by preparing the titanium complex in the presence of sulfide 1 at an elevated temperature and/or during a prolonged preparation time and by performing the oxidation of sulfide 1 in the presence of amine. An enantioselectivity of 94% ee was obtained using this method. 

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