Nicotinic nitrile

Figure 7.2 illustrates the phosphorus pentoxide-mediated dehydration of a primary amide to a nitrile, using the transformation of nicotine amide (A) into nicotine nitrile (B) as an example. The reaction of phosphorus pentoxide at the carboxyl oxygen furnishes the partially ring-opened iminium ion E (simplified as F) via the polycyclic iminium ion C. E is deprotonated to give the mixed anhydride G from imidic acid and phosphoric acid. Imidic acids are characterized by the functional group R-C(=NH)-OH. This anhydride is transformed into the nitrile B by an El elimination via the intermediate nitrilium salt D. Nitrilium salts are iV-pro-tonated or V-alkylated nitriles. 

Fig. 7.2. Phosphorus pent-oxide-mediated dehydration of nicotinic acid amide (A) to nicotinic nitrile (B) with the reagent forming polyphospho-ric acid (HP0 )r...

Other applications of the ammoxidation include the reactions of isobutene (—> a-methacrylonitrile), a-methylstyrene (- atropanitrile), y5-picoline nicotine nitrile and nicotinamide), toluene benzonitrile), and xylenes (—> phthalo-nitrile, terephthalonitrile, and isophthalonitrile on the way to fiber- grade diamines). 

Nicotinic acid has also been produced by microbial means from the nitrile. Phodococcus (44,45) has frequendy been used in this regard. Interestingly, irradiation of a CoTynebacterium suspension during the fermentation led to higher yields of nicotinic acid (46). 

Owing to poor volatihty, derivatization of nicotinic acid and nicotinamide are important techniques in the gc analysis of these substances. For example, a gc procedure has been reported for nicotinamide using a flame ionisation detector at detection limits of - 0.2 fig (58). The nonvolatile amide was converted to the nitrile by reaction with heptafluorobutryic anhydride (56). For a related molecule, quinolinic acid, fmol detection limits were claimed for a gc procedure using either packed or capillary columns after derivatization to its hexafluoroisopropyl ester (58). 

Nicotinyl alcohol (3-pyridinylcarbinol, 3-pyridinemethanol) (27) has use as an antilipemic and peripheral vasodilator. It is available from either the reductions of nicotinic acid esters or preferably, the reduction of the nitrile to the amine followed by dia2otation and nucleophilic displacement. It is frequently adininistered in the form of the tartrate (Eig. 7). Nicotinic acid is frequently used as a salt in conjunction with basic dmgs such as the peripheral vasodilator xanthinol niacinate (28). Nicotinic acid and its derivatives have widespread use as antihyperlipidemic agents and peripheral vasodilators (1). 

Craig s synthesis of nicotine (V to VII, p. 42) proceeds via nomicotine. Nicotinic acid nitrile reacts with the Grignard reagent derived from ethyl y-bromopropyl ether to give 3-pyridyl-y-ethoxypropyl ketone (V). This yields an oily oxime (VI) reducible to a-(3-pyridyl)-a-amino-8-ethoxy-w-butane (VII), which with 48 per cent, hydrobromic acid at 130-3° gives womicotine, and this on methylation yields dZ-nicotine. 

The influence of other groups in a pyridine or similar ring system is more difficult to assess because no kinetic data are available. The deactivating effect of the bromine atom in the 2-position is greater than that in the 3-position, while 2,6-dibromopyridine is very slow to react with dimethyl sulfate. Esters, amides, and nitriles of nicotinic and isonicotinic acids undergo fairly easy quaternization at about... 

Another example of a biocatalytic transformation ousting a chemical one, in a rather simple reaction, is provided by the Lonza nitotinamide process (Fig. 2.34) (Heveling, 1996). In the final step a nitrile hydratase, produced by whole cells of Rh. rhodoccrous, catalyses the hydrolysis of 3-cyano-pyridine to give nitotinamide in very high purity. In contrast, the conventional chemical hydrolysis afforded a product contaminated with nicotinic acid. 

Nicotinamide is prepared by partial hydrolysis of the nitrile, or by animation of nicotinic acid chloride or its esters, Some of the compounds mentioned in the foregoing aie shown below. 

Nicotinic acid undoubtedly provides the basic skeleton for some other alkaloids. Ricinine (Figure 6.35) is a 2-pyridone structure and contains a nitrile grouping, probably formed by dehydration of a nicotinamide derivative. This alkaloid is a toxic constituent of castor oil seeds (Ricinus communis Euphorbiaceae), though the toxicity of the seeds results mainly from the polypeptide ricin (see page 434). Arecoline (Figure 6.36) is found in Betel nuts (Areca catechu Palmae/Arecaceae) and is a tetrahydronicotinic acid derivative. Betel nuts are chewed in India and Asia for the stimulant effect of arecoline. 

Similarly, DuPont employs a nitrile hydratase (as whole cells of P. chlororaphis B23) to convert adiponitrile to 5-cyanovaleramide, a herbicide intermediate [122]. In the Lonza nitrotinamide (vitamin B6) process [123] the final step (Fig. 1.42) involves the nitrile hydratase (whole cells of Rh. rhodocrous) catalysed hydration of 3-cyanopyridine. Here again the very high product purity is a major advantage as conventional chemical hydrolysis affords a product contaminated with nicotinic acid, which requires expensive purification to meet the specifications of this vitamin. 

Fungal nitrilases immobilized on these columns were applicable to continuous biotransformation of heteroaromatic nitriles like 3- and 4-cyanopyridine, the products of which, nicotinic and isonicotinic acid, respectively, are of commercial interest. The enzyme from F. solani exhibited a higher stability than that from A. niger at 35 °C. The conversion of 3-cyanopyridine by the former enzyme was nearly quantitative within 24h [50], while it decreased by 30% within 15h in the case of the latter [49]. Similar differences in operational stabiUties were observed during conversion of 4-cyanopyridine. The stabiUty of the enzymes depended on the substrate used, both nitrilases being more stable during the conversion of 4-cyanopyridine in comparison with 3-cyanopyridine. 

Similar data were obtained for 3-cyanopyridine biotransformation into nicotinamide and nicotinic acid (unpublished data). The higher dependence of the nitrile hydratase deactivation process on temperature has already been observed with other substrates, such as in acrylonitrile bioconversion into acrylamide where the nitrile hydratase half-Ufe dropped from 33 h to approximately 7h when the temperature was varied from 4 to 10 °C [37]. 

The conversion of 2,5-pyridinedicarboxylic acid Af oxide (284) inaceto-nitrile/acetic anhydride to the corresponding 6-amino-nicotinic acid (288) seems to be a Ritter reaction of intermediate cation 285 with acetonitrile, followed by rearrangement of intermediate 286 to 287, which is then saponified by potassium hydroxide to give 49% of 6-aminonicotinic acid (2M) and 8% of 6-hydroxynicotinic acid (289) (83EUP90I73). 

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