Nicotinic acid chlorination

Trifluoromethylpyridine can be prepared ia 25—65% yield from nicotinic acid and sulfur tetrafluoride (434,439). An alternative method is the passage of chlorine iato a mixture of ( -picoline and hydrogen fluoride ia an autoclave (190°C, 3 MPa) (440). 4-Trifluoromethylpyridine is prepared ia 57% yield from isonicotinic acid and sulfur tetrafluoride. 

A limited number of pure substances are available from NIST, primarily clini-cally-relevant compounds such as cholesterol, urea, uric acid, creatinine, glucose, cortisol, tripalmitin, and bilirubin (NIST SRM website). These compounds are certified for purity (greater than 99 %) and are used as primary calibrants in definitive methods for these clinical analytes (see below). Several additional pure substances are available for specific applications such as microchemistry, i.e. elemental composition (acetanilide, anisic acid, cystine nicotinic acid, o-bromobenzoic acid, p-fluoro-benzoic acid, m-chlorobenzoic acid), polarimetric standards (sucrose and dextrose), acidimetric standard (benzoic acid and boric acid). Only three pure substance NIST RMs are available for environmental contaminants, namely the chlorinated pesticides, lindane, 4,4 -DDT, and 4,4 -DDE. 

Likewise, SOCL chlorinates 6-methylnicotinic acid (51) to trichloroni-cotinoyl chloride (52) (36JPRI88), whereas 4-methyl-nicotinic acid (53) is transformed by SOCL into the dichlorothio lactone 54 (44JAI456 ... 

An alternate synthesis was developed by E. Smissman and G. Hite2, using a modified Favorski rearrangement. Iso-nicotinic acid was methylated, reduced to 1-methyl-U-piperi-dinecarboxylic acid hydrochloride, and converted to the acid chloride hydrochloride. This was then condensed with benzene, chlorinated, treated with alkali, esterfied, and converted to the hydrochloride (See Figure 8). 

Use Nicotinic acid and nicotinamide, vinyl pyridines for copolymers, intermediates for germicides and textile finishes, corrosion inhibitor for chlorinated solvents. 

One understands especially the incorporation by living organisms of fluoroacetic acid in place of acetic ° acid or of 5-fluoro-nicotinic acid and 5-fluoro-uracil as antimetabolites. This fraudulent incorporation leads to lethal syntheses. This is generally not the case with the corresponding chlorinated, brominated, or iodinated analogs. 

We have largely been describing reactions on steroid substrates, which are conforma-tionally rigid and permit selective functionalizations by appropriate tethered templates. However, when the templates are linked to flexible chains, the results can be used to learn about the conformational preferences of such flexible chains. In one study [56], we examined the positional selectivities of insertion reactions into flexible chains by attached benzophenone units, a process we had also examined earlier [31], and compared the results with those from the intramolecular chlorination of such flexible chains by attached aryliodine dichlorides. The results were complementary. In another study [57] we used long-chain alkyl esters of nicotinic acid in radical relay chlorination, and saw some interesting selectivities reflecting conformational preferences in these nominally flexible cases. 

Pyridine is a tertiary amine its aqueous solution shows an alkaline reaction and precipitates the hydroxides of metals, some of which are soluble in an excess of the amine. Salts of pyridine like those of other amines form characteristic double salts with metallic halides. The ferrocyanide of pyridine and the addition-product of pyridine and mercuric chloride are difficultly soluble in water these compounds are used in the purification of the base. Pyridine is a very stable compound it can be heated with nitric acid or chromic acid without undergoing change but at 330° it is converted by a mixture of nitric acid and fuming sulphuric acid into nitropyridine, a colorless compound that melts at 41° and boils at 216°. At a high temperature pyridine is converted into a sulphonic acid by sulphuric acid. Chlorine and bromine form addition-products, e.g., C5H5N.CI2, at the ordinary temperature when these are heated to above 200°, substitution-products are formed. The hydroxyl derivative of pyridine is made by fusing the sulphonic acid with sodium hydroxide it resembles phenol in chemical properties. The three possible carboxyl derivatives of pyridine are known. The a-acid is called picolinic acid, the jS-acid nicotinic acid (664), and the 7-acid isonicotinic acid. 

Chlorine-tofidine (Rgt. No. 42) has proved to be a universal and sensitive reagent [8]. B, Bg, Bg, B g, nicotinic acid, nicotiaamide, pantothenic acid, folic acid, biotin and rutin appear as grey blue spots on a white background after a short while, B g turns violet and Bg greenish. Vitamin C yields no colour. The reaction depends however on the amount of substance, intensity of spraying, thickness and moisture content of the layer and the time at which the layer is inspected. 

Route A utilizes the easily available 2-mercaptonicotinic acid as starting material. First, the nicotinic acid is esterified with acidic methanol to afford methyl 2-mercaptonicotinate, which is oxidized chlorine in aqueous acetic acid, followed amination with tert-butylamine, to give methyl 2-t-butylaminosulfonylnicotinate. This, in turn, is subjected to reaction with N,N-dimethylaminodimethylaluminum to afford a nicotinamide, which is finally converted to the target intermediate by de-butylation using tri-fluoroacetic acid. 

Also surprising is the conversion of nicotinic acid chloride hydrochloride into 5-bromonicotinic acid in 87 per cent yield, by heating with bromine at 150-170°. Direct chlorination was much less successfuP . This may be a direct electrophilic substitution, but the nicotinic acid chloride hydrochloride was prepared from nicotinic acid and thionyl chloride (see p. 322), and it is just possible that the reaction is related to the substitutions into pyridine-thionyl chloride complexes discussed below (p. 228). It might even be that nicotinic acid chloride hydrochloride is not a simple salt but possesses a structure like the pyridine-thionyl chloride complex. 

Masuda, M., Suzuki, T., Friesen, M.D., Ravanat, J.L., Cadet, J., Pignatelli, B., Nishino, H., and Ohshima, H. (2001) Chlorination of guanosine and other nucleosides by hypochlorous acid and myeloperoxidase of activated human neutrophils. Catalysis by nicotine and trimethylamine. /. Biol. Chem., 276, 40486-40496. 

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