2-Benzimidazole carboxylic acid

Canderel aspartame, candesartan candesartancilexetil. eandesartan cilexetil (Amias ) is a benzimidazole-carboxylic acid derivative, an (AT,) ANGIOTENSIN RECEPTOR ANTAGONIST, used as an antihypertensive. It is an ethyl ester prodrug of candesartan (CV 11974). It has experimental renal protective effects. 

The invention [87] relates to the discovery that specific adamantyl or adamantyl group derivatives containing retinoid-related compounds induce apoptosis of cancer cells and therefore may be used for the treatment of cancer, including advanced cancer. It has been shown that such adamantyl compounds, e.g., 2-[3-(l-adamantyl)-4-methoxyphenyl]-5-benzimidazole carboxylic acid 135), can be used to treat or prevent cervical cancers. 

H-Benzimidazole, 2,2-pentamethylene-reduction, 5, 423 Benzimidazole-2-carbaldehyde oximes, 5, 436 Benzimidazolecarbaldehydes oxidation, 5, 437 Benzimidazole-2-carbamates 5-substituted as anthelmintics, 1, 202 Benzimidazole-1-carboxylic acid, 2-amino-methyl ester reactions, 5, 453... 

Benzimidazole-2-carboxylic acid decarboxylation, 5, 435 Benzimidazole-3-carboxylic acid, 1-hydroxy-ethyl ester synthesis, 6, 407 Benzimidazoles acidity, 5, 50, 385, 386 acylation, 5, 71, 391, 402, 417 2V-alkyl-... 

Alkylation of the cyclization product 115 and the following hydrolysis gave 9-alkyl substituted 6-oxo-6,9-dihydroimidazo[4,5-/i]quinoline-7-carboxylic acid derivatives 119, compounds useful as antibacterials (no data) [80JAP(K)1], 4(7)-Aminobenzimidazole can react with 1,3-diketones as a bidentate nucleophile, but with 2,4-pentanedione in glacial acetic acid it gives a Combes product, l//-6,8-dimethylimidazo[4,5-/i]quinoline 120, accompanied by 4(7)-acetamido-benzimidazole (91T7459). 

Benzimidazoles are generally synthesized from ortho-diamino-benzenes and carboxylic acid derivatives. The antihistaminic agent, clemizole (60), for example, can be prepared by first reacting ortho-diaminobenzene (57) with chloroacetic acid to form 2-chloro-methylbenzimidazole (58). Displacement of the halogen with pyro-... 

Reaction of benzimidazole-2-carboxylic acid hydrazide 590 with carbon disulfide gave triazine 591 (86JPR515) (Scheme 121). 

CN ( )-2-ethoxy-l-[[2 -(l/7-tetrazol-5-yl)[l,r-biphenyl]-4-yl]methyl]-lW-benzimidazole-7-carboxylic acid l-[[(cyclohexyloxy)carbonyl]oxy]ethyl ester... 

CN 4 -[(l,4 -Dimethyl-2 -propyl[2,6 -bi-l//-benzimidazol]-l -yl)methyl][l,l -biphenyl]-2-carboxylic acid... 

In analogy to the reaction of CDI with carboxylic acids, the even more reactive NJf -carbonyldi-1,2,4-triazole 5bl has been used instead of CDI in cases where specific structural effects require a higher reactivity of the azolide. On the other hand, the example of the last paragraph of the preceding section showed that A -carbonyldi-benzimidazole 151 141 and AyV -carbonyldibenzotriazole 151 have been useful for the syntheses of azolides with reduced reactivities when these are essential and sufficient for the specific reaction in question. 

Three different microwave-assisted synthetic routes to benzimidazole derivatives are summarized in Scheme 6.205, involving the condensation of 1,2-phenylenedi-amines with either carboxylic acids (Scheme 6.205 a and b) [368, 369] or two equivalents of aldehydes (Scheme 6.205 c) [370], or by cyclization of N-acylated-diamino-pyrimidines mediated by a strong base (Scheme 6.205 d and e) [371, 372],... 

Cyclization of the hydrazinotriazinobenzimidazole 764 with carboxylic acids gave [l,2,4]triazolo[3,4 6,l][l,2,4]triazino[4,3-a]benzimidazoles 765 (87SC1533). 

Page 202, Table III, entry 9 and page 424, first entry. For Benzimidazole, 2 - [o-gluco-3 - (a-D - glucopyranosyl) -1,2,4,5-tetrahydroxypentyl] -, 4-carboxylic acid read Benzimidazole, 2-(3-0-a-D-glucopyranosyl-D- Zuco-pentahydroxypentyl)-, 4(or 7)-carboxylic acid. ... 

When the reactions were carried out in chloroform for 2 hr, isopropyli-dene methoxymethylenemalonate reacted on the active methylene group of 2-benzimidazolylacetate and acetonitrile (1666) in the first step, and in the next step, one of the ring nitrogens was involved in a cyclization to give pyrido[l,2-a]benzimidazole-2-carboxylic acids (1667) in 86-89% yields (88YZ856). 

Fig. 10 Synthesis of imidazolines or benzimidazoles by condensation of an additional amine with the carboxylic acid-derived carbonyl...

Thiabendazole Thiabendazole, 2-(4 -thiazolyl)benzimidazole (38.1.9), is also made in the same manner—heterocyclization which occurs upon reacting o-phenylendiamine with l,3-thiazol-4-carboxylic acid [4-6]. 

A variety of methods have been developed for the preparation of substituted benzimidazoles. Of these, one of the most traditional methods involves the condensation of an o-phenylenediamine with carboxylic acid or its derivatives. Subsequently, several improved protocols have been developed for the synthesis of benzimidazoles via the condensation of o-phenylenediamines with aldehydes in the presence of acid catalysts under various reaction conditions. However, many of these methods suffer from certain drawbacks, including longer reaction times, unsatisfactory yields, harsh reaction conditions, expensive reagents, tedious work-up procedures, co-occurrence of several side reactions, and poor selectivity. Bismuth triflate provides a handy alternative to the conventional methods. It catalyzes the reaction of mono- and disubstituted aryl 1,2-diamines with aromatic aldehydes bearing either electron-rich or electron-deficient substituents on the aromatic ring in the presence of Bi(OTf)3 (10 mol%) in water, resulting in the formation of benzimidazole [119] (Fig. 29). Furthermore, the reaction also works well with heteroaromatic aldehydes. 

Bruice and Schmir (3) have shown that for a series of imidazole derivatives, klm depends on the base strength of the catalyst and since pKA is an approximate measure of base strength, the value of klm should increase with increase in pKA. Table I shows that this is indeed the case. Imidazole, pKA = 7.08, has a catalytic constant eight times larger than that of benzimidazole, pKA = 5.53. Bronsted and Guggenheim (2) have obtained a linear relationship between log k/ and pKA for a series of carboxylic acids in the pKA range of 2 to 5, where kB is the carboxvlate anion basic catalytic constant for the mutarotation of glucose and Ka is the acid dissociation constant of the acid. Our results for imidazole and benzimidazole fit fairly well into the Bronsted plot. 

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