Pyridine acidity

This is an example of the acid chloride - pyridine - acid method referred to in the theoretical section. 

As with pyridine acids, the presence of a positive center or an electron accepting group facilitates decarboxylation that must proceed by way of the anion. 

The initial route to taranabant relied on a late stage amide bond coupling between racemic amine rac-2 and pyridine acid 3 mediated by (benzotriazol-l-yloxy)tripyr-rolidinophosphonium hexafluorophosphate (Py-Bop), followed by chiral HPLC separation of the product to afford a single enantiomer (Scheme 9.1). 

The synthesis of the pyridine acid 3 is outlined in Scheme 9.3. The 2-chloro-5-trifluoromethylpyridine was coupled with hydroxybutyric acid in the presence of an excess of sodium hydride to afford acid 3 in around 35% yield after necessary purification. 

Use of sodium hydride in DMF to prepare the pyridine acid 3 Safety concerns with use of sodium hydride, and a low yield of acid... 

Pharmaceuticals. A wide variety of pyridine compounds, with varying, and often multiple, drug action are used commercially. A few examples are given. A number of antihistamines contain the pyridine moiety in their structure, as exemplified by chlorpheniramine maleate (2-[p-chloro-a-(2-dunethylaminoethyl)benzyl] pyridine acid maleate) doxylamine succinate (2-[cM2-dimethylamino)ethoxy- -methylbenzyl]-pyridine add succinate) and pyrilamine maleate (2-(2-dimethyl-aminoethyl-2-p-methoxybenzyl) aminopyndine acid maleate). These products are synthesized, e.g., from... 

Chem, 30, 881-99 (1956). Dipole moment pyridine-acids in benzene, also acids-quino-line, acridine, triethylamine. 

Carboxylic acids. Of these pyridine acids there are mono-, di-, and tri-carboxylic acids known, which are obtained by oxidation of the corresponding mono-, di-, and tri-methyl homologues. One of the mono-carboxylic acids is known as nicotinic acid and is obtained... 

Properties Amorphous solid. Mp 102-108C. Freely soluble in water, pyridine, acid solutions moderately soluble in methanol, ethanol, and acetone practically insoluble in benzene and halogenated hydrocarbons. 

Nicolai, E., Goyard, J., Benchetrit, T., Teulon, J. M., Caussade, F., Virone, A., Delchambre, C., Cloarec, A. Synthesis and structure-activity relationships of novel benzimidazole and imidazo[4,5-h]pyridine acid derivatives as thromboxane A2 receptor antagonists. J. Med. Chem. 1992, 36, 1175-1187. 

There are disadvantages in carrying out the hydrogenation of pyridines as salts. When the corresponding piperidine bases are desired, isolation of some of them in good yield is difficult because of their extreme water solubility. The isolation of pure piperidinecarboxylic and piperidine-alkanoic acids after reduction as hydrochloride salts is troublesome and often extremely difficult. The reduction of the corresponding pyridine acids now no longer requires the presence of an acid. This will be discussed in a subsequent section. 

With pyridine, acid chlorides and acid anhydrides yield A-acyl pyridinium salts 6 which are very reactive and sensitive to hydrolysis, unlike the quaternary salts 2-5 they are involved in the acylation of alcohols and amines in pyridine as solvent (Einhorn variant of the Schotten-Baumann reaction). However, 4-dimethylaminopyridine 12 (Steglich reagent) and 4-(pyrrolidin-l-yl)pyridine 13 are better acylation catalysts by a factor of 10 [46a]. Reactions with sulfonyl chlorides in pyridine proceed via A-sulfonylpyridinium salts 14. 

Properties. Demissine, C5oH s02 N, melts at 305-308° when recrystallized from methanol or ethanol [a]n — 20° (pyridine). Acid hydrolysis yields one mole each of D-xylose and D-galactose and two of D-glucose as well as demissidine, C27H<(ON which proved to be solanidan-3/3-ol (31). 

A particularly elegant example of the pyridine/acid approach is shown in Figure 30, which represents a very simple situation, namely, that of a complex (32) between an alkoxybenzoic acid and an alkyl pyridine and which shows a nematic phase close to room temperature. These materials have added significance and are discussed again later. 

Acetic acid, alcohols, aniline, combustible materials, dehydrating agents, ethyl benzene, hydriotic acid, hydrochloric acid, iodides, ketones, organic material, oxidizers, pyridine Acids (organic or mineral)... 

With heterocyclic acid amides With pyridine acid amides Ni(3-C5H4N-C0NHCH20H)2Cl2 room 3.41 74W5... 

The physical properties of pyridine-containing acids make them particularly attractive starting points for combinatorial libraries for herbicide screens. Pyridines are relatively polar (log P = 0.60 for pyridine vs. 2.13 for benzene) (4) and the sinq>le unsubstituted acids are weakly acidic (nicotinic acid pKa 4.8). (5) Perhaps for these reasons, pyridine-containing acids have found considerable utility as herbicides. Representative examples of commercially successful, phloem mobile, pyridine acids (or dieir derivatives) include picloram, clopyralid, and triclopyr (synthetic auxins) imazethapyr and nicosulfuron (ALS inhibitors) clodinafop and haloxyfop (ACCase inhibitors). Each has a direct counterpart in the conesponding benzene series but, in these instances, the pyridine analog is invariably the superior herbicide. 

E.g., reaction between alcohols and benzoyl chloride more rapid in pyridine Acid increases concentration of solvent cations SO3 4- + HS04 AICI3 + C0Cl2->C0Cl+ + AlCU ... 

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