Substituted 2-aminopyridine

Cyclocondensation of 4-substituted 2-aminopyridines and ethyl 3-dimethylamino-2-[2-(4-methoxybenzyl)tetrazol- 5-yl)acrylate in boiling EtCOOH for 4h afforded 8-substituted [2-(4-methoxybenzyl-2//-tetrazol-... 

Syntheses of naphthyridone derivatives follow the same procedures as those of quinolones, except that substituted 2-aminopyridines (Gould-Jacobs modification) or substituted nicotinic ester/nicotinoyl chloride are used instead of anilines or o-halobenzoic acid derivatives. Most of the recently introduced quinolone antibacterials possess bicyclic or chiral amino moieties at the C-7 position, which result in the formation of enantiomeric mixtures. In general, one of the enantiomers is the active isomer, therefore the stereospecific synthesis and enantiomeric purity of these amino moieties before proceeding to the final step of nucleophilic substitution at the C-7 position of quinolone is of prime importance. The enantiomeric purity of other quinolones such as ofloxacin (a racemic mixture) plays a major role in the improvement of the antibacterial efficacy and pharmacokinetics of these enan-... 

Other simple chelate ligands which have been found to give six-coordinate complexes NiX2L2 are 2-acetylpyridine N-oxide oxime,2495 2-acetamidopyridine,2496 pyridine-2-(acetic acid methyl ester)2497 and -substituted 2-aminopyridine N-oxides.2498... 

The addition of propiolic esters to substituted 2-aminopyridines has been examined by three groups.303-305 The most recent study305 is definitive. The 1 2 molar adduct was first303 thought to be 132 but is, in fact,305 130, which cyclizes to 131. In two cases,305 compounds with structure 132 were obtained, and the NMR spectra for all these adducts were compared. 

Pyrido[l,2-n]pyrimidinium salts (6), which are of aromatic character, are easily formed from 2-aminopyridines and 1,3-dioxo compounds2 5 or the acetal and ketal equivalents of the latter,4 10 in acidic media (perchloric acid and concentrated hydrobromic acid). The acidic conditions may also be provided by using the salts (hydroperchlorate and hydroiodide) of the 2-aminopyridines.2 4 When the reaction is conducted in the absence of acid, the intermediate enamine (5) can be isolated.5-6 The reaction of fi-oxo acetals and 2-aminopyridines unsubstituted in position 6 leads to 4-substituted pyrido[l,2-a] pyrimidinium salts (6 R1 = H),5 7 whereas the 6-substituted 2-aminopyridines give rise to 2-substituted pyrido[l,2-a]pyrimidinium salts (6 R2 = H).5... 

Reaction of 1,3-diketones and 2-aminopyridines led to 2,4-disubstituted pyrido[l,2-a]pyrimidinium salts (6 R1 and R2 H), but the 6-substituted 2-aminopyridine failed to provide the bicyclic product.4,5 The irregular behavior of the 6-substituted 2-aminopyridines is explained by the steric hindrance effect of the 6-substituent. 

By reacting 2-aminopyridine and epichlorohydrin, Knunjanz187 obtained the hydrochloride of 3-hydroxy-3,4-dihydro-2H-pyrido[l,2-a]pyrimidine (131 R = OH). Analogous products from 4-methyl-, 5-methyl-, 5-halo- and 3,5-dibromo-substituted 2-aminopyridines have been prepared by Soviet workers.188,189 The same products arose from the reaction of 2-aminopyridines and l,3-dichloro-2-propanol.188 189 Klusis and Kuthevicius190 reacted 2-aminopyridine with 3-chloro-1,2-propanediol (127) or 2,3-... 

Oxo-3,4-dihydro-2//-pyrido[l,2-ci]pyrimidines (142) and their hydrogen halide salts can be prepared by reacting 2-aminopyridine or methyl-substituted 2-aminopyridines with alkyl 3-halopropionates,20,196-200 3-halopropionic acids,200-203 or alkyl acrylates18,20 197,204 205... 

Treatment of 5-cyanomethylisoxazolines 1 with a catalytic amount of DBU in boiling xylene gives good to excellent yields of 6-substituted-2-aminopyridine N-oxides. 

Since the introduction in 1963 of nalidixic acid (N -ethyl-7-methyl-4-oxo-l,4-dihydro[l,8]-naphthyridinyl-3-carboxylic acid) as a systemic Gram-negative antibacterial agent, many related derivatives have been synthesized. These types of compounds have received much attention and interest by virtue of their chemical and clinical properties. The methods reported in the chemical literature for preparing C-6- and C-3-substituted 4-oxo[1.8]naphthyridines are somewhat limited. These methods involve the condensation of substituted 2-aminopyridines with suitable 3-ethoxyacrylates, followed by cyclization. Recently, such substituted 4-oxo-l,4-dihydro[1.8]naphthyridines have been obtained using the Suzuki reaction (Eq. (38)) [69]. 

Tu and co-workers [56] have developed a facile and selective synthesis of A-substituted 2-aminopyridines 5 via a microwave-assisted MCR which is controlled by the basicity of the amine and the nature of the solvent. When reacted in a solvent mixture of DMF/HOAc (1 1), the desired aminopyridine 5 was formed next to 2,6-dicyanoanilines in nearly equal amounts. However, when the volume ratio was increased to 1 4, compound 5 was obtained as the main product. The elaborated... 

Treatment of M2C1i0 with 4 eq substituted 2-aminopyridines in tol or under melt conditions produced pseudo-pentagonal bipyramidal complexes bis(amidopyridine)MCl3 (Scheme 8).89-92... 

The reaction of j8-oxo acetals and 2-aminopyridines unsubstituted in position 6 leads to 4-substituted pyrido[l,2-u] pyrimidinium salts (6 R = H), whereas the 6-substituted 2-aminopyridines give rise to 2-substituted pyrido[l,2-a]pyrimidinium salts (6 = H). ... 

In a similar kind of overall transformation but using different reagents, Ram and coworkers replaced both oxygen atoms in substituted 2//-pyranone (3) to make substituted 2-aminopyridine (4) (Scheme 2) (94JCR(S)86>. 

Using FBS by X-ray, 2-amlnoquinoline was identified as a very weak (2 mM), but novel recognition motif for an aspartic protease. A combination of database mining, virtual screening, and X-ray analysis then led to the discovery of a 6-substituted 2-aminopyridine compound with improved affinity which was further optimized to sub-micromolar potency using structure-based design. 

The triazolo[l,5-a]pyridine-2-sulfonanilides (30) can be prepared by the general route as outlined in Scheme 2.4.5 [49, 50]. The intermediate 2-benzylthio-triazolo[l,5-a]pyridine (31) is prepared starting from an appropriately substituted 2-aminopyridine. The 2-aminopyridine is reacted with 0-mesitylenesulfonylhy-droxylamine to give the N-aminopyridinium mesitylate (32). Compound 32 is then reacted with thiocarbonyldiimidazole followed by benzyl chloride to give 31. Conversion of the benzyl sulfide, 31, into the corresponding sulfonyl chlorides (33) is accomplished with chlorine and water. The sulfonyl chlorides are converted into the desired sulfonanilide (30) by reaction with aniline in the presence of pyridine and a catalytic amount of dimethyl sulfoxide. 

The N-triazolo[l,5-a]pyridine sulfonamides (37) are prepared by the general methods outlined in Scheme 2.4.7 [32, 36]. A substituted 2-aminopyridine (38) is reacted with ethoxycarbonylisothiocyanate to give the thiourea (39). Reaction of 39 with hydroxylamine in the presence of a base yields the 2-aminotriazolo[l,5-a]-pyridines (40). Compound 40 is then reacted with substituted sulfonyl chloride in the presence of a catalytic amount of dimethyl sulfoxide and pyridine to give 37. 

Aminopyridines combine with arenas to form pyrido[l,2-benz-imidazoles in the absence of metal catalysts but with hypervalent iodine reagents (Scheme 42). Both electron-rich and electron-poor arenas will combine with the 2-aminopyridines in good yields.The reaction proceeded with regiocontrol even with unsymmetrically di-substituted arenes. Electron-rich and electron-poor 2-aminopyridines were also weU-tolerated under these reaction conditions. Even tri-substituted 2-aminopyridines reacted with high yields.The reaction also could be extended to 2-aminoquinolines (6 examples, 39-60% yields) (14AG(I)8163). 

The thermal decomposition of oximes of -y-nitro or 7-cyano ketones results in a complex mixture of products, the major component of which is a substituted 2-aminopyridine (IX-32). ... 

Photolysis of aminopyridines has been studied by Taylor and his co-workers. Ultraviolet irradiation of 2-aminopyridine (and several substituted 2-aminopyridines) in hydrochloric acid solution results in the formation of the 1,4-dimer having the anti-trans configuration IX-SS. 

Conversion of enaminolactone nitriles with primary amines has been reported to give substituted 2-aminopyridine (Scheme 214). ° ... 

Novel selective CB2 receptor ligands, Part X Substituted 2-aminopyridines... 

Substituted 2-fluoro-5-fluoroaIkoxypyridines (23) were prepared in good to high yields by diazotization of substituted 2-aminopyridines 22 with NaN02 in HF. Snbseqnently they were nsed as starting materials for the synthesis of some herbicides and insecticides [24] (Scheme 9). 

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