3-Pyridylacetic acid

The first experiments were carried out with nicotinic acid (61), and it was found that mitochondrial oxidation of cholesterol was enhanced in rats fed this compound. It was later found (62) that addition of nicotinic acid (8 X 10 moles, 10 mg) to the incubation mixture enhanced oxidation of cholesterol. Of a large series of nicotinic acid and nicotinamide homologues tested, only 3-pyridylacetic acid also stimulated oxidation of cholesterol (62,63). This compound has also been shown to be hypocholesterolemic in man (64,65). Pyridinol carbamate, 2,6-bis(hydroxymethyl)pyridine-di-A -methylcarbamate, fed to rats as 1 % of their diet also enhanced in vitro oxidation of cholesterol by rat liver mitochondria (66). 

The decarboxylation of a-pyridylcinnamic adds yielded a variety of stilbazoles. Beard and Katritzky reported that they obtained the trans-stilbazole (XI-72) (as shown by i.r.) by the decarboxylation of the a-3-pyridylcinnamic acid (XI-71) which itself was obtained by the condensation of benzaldehyde with 3-pyridylacetic acid. Clarke and co-workers found, however, that the... 

Variant b) shows the Friedel-Crafts reaction between 3-pyridylacetic acid chloride and 1,3-dichlorobenzene. With excess aluminium chloride at a temperature of 100-120 C a good selectivity for the desired ketone is observed. The chemical yield in preliminary trials howeva was only about 30%. This poor yield and the high price of the 3-pyridylacetic acid building block did not motivate to study this pathway in more detail. 

Besides their action on cholesterol biosynthesis, nicotinic acid and chloro-phenoxyisobutyrate (CPIB) could also interfere with cholesterol degradation. In fact, nicotinic acid enhances cholesterol side-chain oxidation by rat-liver mitochondria, an action shared by 3-pyridylacetic acid which has also been reported to have hypocholesterolaemic properties. 

Interpretation of KIEs on enzymatic processes (see Chapter 11) has been frequently based on the assumption that the intrinsic value of the kinetic isotope effect is known. Chemical reactions have long been used as models for catalytic events occurring in enzyme active sites and in some cases this analogy has worked quite well. One example is the decarboxylation of 4-pyridylacetic acid presented in Fig. 10.9. Depending on the solvent, either the zwitterionic or the neutral form dominates in the solution. Since the reaction rates in D20/H20 solvent mixtures are the same (see Section 11.4 for a discussion of aqueous D/H solvent isotope effects), as are the carbon KIEs for the carboxylic carbon, it is safe to assume that this is a single step reaction. The isotope effects on pKa are expected to be close to the value of 1.0014 determined for benzoic acid. This in mind, changes in the isotope effects have been attributed to changes in solvation. 

Table 10.9 Heavy atom KIEs on decarboxylation of 4-pyridylacetic acid at 25 °C in water-dioxane solvents (Sicinska, D., Truhlar, D. G. and Paneth, P., J. Am. Chem. Soc. 123, 7683 (2001) and J. Phys. Chem. B 106, 2708 (2002)) ...

Anhydro-acylation of l,2-dihydro-2-oxo-l-pyridylacetic acid with acid anhydrides yields bicyclic meso-ionic 4-acyl-l,3-oxazol-5-ones (67). Huisgen and his co-workers have reported extensive studies of the monocyclic meso-ionic l,3-oxazol-5-ones (66), which they have lightheartedly named munchnones. Cyclodehydration of N-benzoyl-A -methyl-C-phenylglycine using acetic anhydride at 55° gives the 3-methyl-2,4-diphenyl derivative (66, R = = Ph R = Me) as... 

Problem 20.47 Prepare (a) 3-aminopyridine from /3-picoline, (b) 4-aminopyridine from pyridine, (c) 8-hydroxyquinoline from quinoline, (d) 5-nitro-2-furoic acid from furfural, (e) 2-pyridylacetic acid from pyridine. 

Carboxylation, e.g., 2-picoline 649 2-pyridylacetic acid 653 (best esterified before isolation cf. Section 3.2.3.4.2). 

In order to broaden the scope we also examined [30] a combination of lipase-catalyzed acylation with penicillin acylase-catalyzed hydrolysis (deacylation). Good results (high enantioselectivity in the acylation and smooth deacylation) were obtained, with a broad range of both aliphatic amines and amines containing an aromatic moiety, using pyridylacetic acid ester as the acyl donor (Fig. 9.21). 

Decarboxylation. 4-Pyridylacetic acid hydrochloride is decarboxylated at 30° in DMSO.311 Reflux temperature is required in neutral aqueous solution.311... 

A soln. of 3 gm. a-phenacylpyridine oxime in abs. ether shaken while gradually treated with no more than 3 gm. of PCI, shaking continued for 3 hrs., then made faintly alkaline with K2C0s — crude a-pyridylacetic acid anilide (Y 90%) dissolved in abs. alcohol, HCl-gas passed in, and boiled 3 hrs. —ethyl a-pyridyl-acetate (startg. m. f. 356) (Y 80-85%). (F. Galinovsky and G. Kainz, M. 77, 137 (1947).)... 

Plazek and Sucharda29 and Colonna3 prepared thioindigo dyes from 2-pyridylacetic acids it may be assumed that 3-hydroxythieno[2,3-6]-pyridines were intermediates, but they were not isolated. An improvement in yield of hydroxythienopyridines in the cyclization of carboxy-pyridylthioacetic acids with acetic anhydride is achieved if the intermediate acetoxy compound is isolated20 (Scheme 7). 

Pyridyl-substituted pyrimidines 44 could be obtained by reacting pyridylacetic acid derivatives with 1,3,5-triazine (94AP(327)533I. 4-Function-alised imidazoline derivatives of type 45 which are conveniently available from A(-acyI-a-amino ketones have been found to undergo rearrangement to arylpyrimidine derivatives 46 (93JOC(58)6354. ... 

Another popular basic catalyst, particularly in carbohydrate chemistry, is pyridine, which has the ability to promote smooth reactions, and additionally has great solvent power and acts as an acceptor for the acetic acid formed in the reaction. However, it may also react with acetic anhydride with the formation of N-acetyl-l,2-dihydro-2-pyridylacetic acid [16], so that care must be taken that this does not interfere in subsequent analyses. Some examples of the use of pyridine follow. 

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