Nicotinamide from 3-Cyanopyridine

The process is configured as a series of three stirred-tank reactors with the substrate 3-cyanopyridine continuously fed at 10-20 wt.% concentration and the biocatalyst flowing countercurrently. Enzymatic hydrolysis yields the desired nicotinamide at 99.3% selectivity, in contrast to the chemical alkaline hydrolysis process which results in about 3-5% nicotinic acid, an undesirable by-product because it causes diarrhea in farm animals (instead of supporting growth for animal feed supplements, see Chapter 6, Section 6.4). Thus, the enzymatic process competes well with the chemical hydrolysis. 

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Corynebacterium glutamicum (CGMCC No. 1464) cells immobilized in calcium alginate beads cross-linked with polyethenimine and glutaraldehyde have been employed for the production of nicotinamide from 3-cyanopyridine [21], The reaction was mn at 10-15 °C,... 

Unimmobilized Corynebacterium propinquum (CGMCC No. 0886) cells containing a cobalt-dependent NHase were employed in either batch or continuous reactions for the production of nicotinamide from 3-cyanopyridine [24]. In the continuous process, membrane filtration separated precipitated product (>5 wt%) and the microbial cell catalyst from the reaction mixture, where the catalyst was then recovered and returned to the reactor using a continuous addition of aqueous 3-cyanpyridine to maintain substrate concentration at <20% (w/v), a final conversion of >99% was obtained. 

In basic chemicals, nitrile hydratase and nitrilases have been most successful. Acrylamide from acrylonitrile is now a 30 000 tpy process. In a product tree starting from the addition of HCN to butadiene, nicotinamide (from 3-cyanopyridine, for animal feed), 5-cyanovaleramide (from adiponitrile, for herbicide precursor), and 4-cyanopentanoic acid (from 2-methylglutaronitrile, for l,5-dimethyl-2-piperidone solvent) have been developed. Both the enantioselective addition of HCN to aldehydes with oxynitrilase and the dihydroxylation of substituted benzenes with toluene (or naphthalene) dioxygenase, which are far superior to chemical routes, open up pathways to amino and hydroxy acids, amino alcohols, and diamines in the first case and alkaloids, prostaglandins, and carbohydrate derivatives in the second case. 

Nitrile Hydratase Acrylamide from Acrylonitrile, Nicotinamide from 3-Cyanopyridine, and 5-Cyanovaleramide from Adiponitrile... 

Nagasawa, T., Mathew, C.D., Manger, 1., et al. 1988. Nitrile hydratase-catalysed prodnction of nicotinamide from 3-cyanopyridine in Rhodococcus rhodochrous 11. Applied and Environmental Microbiology, 54 1766-9. 

Rhodococcus sp. N-774 and Pseudomonas chlororaphis B23 resting cells have been used at industrial scale (as first- and second-generation biocatalysts) for the biological production of acrylamide from acrylonitrile since the 1980s [21]. Currently Rhodococcus rhodochrous J1 is being adopted as a third-generation biocatalyst (Mitsubishi Rayon Co.). The industrial production of nicotinamide from 3-cyanopyridine is also operated with this strain (Lonza AG). However, despite the enormous potentiality of nitrile-hydrolyzing biocatalysts for industrial applications, only a few commercial processes have been realized [22]. 

Biotransformations for the synthesis of asymmetric compounds can be divided into two types of reactions those where an achiral precursor is converted into a chiral product (true asymmetric synthesis) and those involving the resolution of a racemic mixture. Both types of reaction are used at Lonza, which is a leading producer of intermediates for the life science industry. Lonza also uses biocatalysis for the synthesis of achiral molecules, for example, an immobilized whole-cell biocatalyst is used for the nitrile hydratase-catalyzed synthesis of thousands of tons per year of nicotinamide from 3-cyanopyridine. 

Meanwhile, Yamada and his colleagues found that R. rhodochrous J1 contains another nitrile hydratase possessing different substrate specificity with preference for aromatic nitriles. By using this enzyme, they developed an industrial process to produce nicotinamide from 3-cyanopyridine (Fig. 4) [41]. The process... 

A thermally stable NHase from Comamonas testosteroni 5-MGAM-4D (ATCC 55 744) [22] was recombinantly expressed in Escherichia coli, and the resulting transformant cells immobilized in alginate beads that were subsequently chemically cross-linked with glutaraldehyde and polyethylenimine. This immobilized cell catalyst (at 0.5 % dew per reaction volume) was added to an aqueous reaction mixture containing 32wt% 3-cyanopyridine at 25 °C, and a quantitative conversion to nicotinamide was obtained. The versatility of this catalyst system was further illustrated by a systematic study of substrates, which included... 

Nicotinic acid and nicotinamide, members of the vitamin B group and used as additives for flour and bread enrichment, and as animal feed additive among other applications, are made to the extent of 24 million pounds (nearly 11 million kilograms) per year throughout the world. Nicotinic acid (pyridine-3-caiboxylic acid), also called niacin, has many uses. See also Niacin. Nicotinic acid is made by the oxidation of 3-picolme or 2-mcthyl-5-cthylpyridine (the isocinchomcnc acid produced is partially deearboxylated). Alternatively, quinoline (the intermediate quinolinic acid) is partially deearboxylated with sulfuric add in the presence of selenium dioxide at about 300° C or with nitric acid, or by electrochemical oxidation. Nicotinic acid also can be made from 3-picoline by catalytic ammoxidation to 3-cyanopyridine, followed by hydrolysis. 

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]. 

A new route to prepare nicotinic acid starts from 2-methylglutaronitrile, a major side-product in the adiponitrile process and, as such, a readily available starting-material. It is easily hydrogenated to 2-methylpentanediamine, which is then condensed to methyl piperidine and dehydrogenated to 3-picoline. The gas-phase ammoxidation of the latter to cyanopyridine is followed by hydrolysis to either nicotinamide or nicotinic acid (Scheme 20.4). The cyanopyridine route for the production of nicotinic acid has the advantage of a significantly better selectivity with respect to the direct oxidation route from 3-picoline owing to the easy decar-... 

Scheme 20.4 Ammoxidation of 3-picoline and hydrolysis of cyanopyridine to niacinamide (nicotinamide) and niacin (nicotinic acid). Adapted from [106].

M-OH2 bond to reach a dissociative transition state is much smaller than would be the case for the ground-state labilisation arising from the effect of the presence of the Cp moiety. Taken together these factors do not permit the exclusion of a limiting D mechanism. The volume profiles for reactions of chloride ion, bromide ion, 4-cyanopyridine (py-CN) and nicotinamide (py-nia) with Cp Rh(H20)2+ are displayed in Fig. 14. 

The production of amides from nitriles has been studied by several workers, and most of them focused on the accumulation of acetamide from acetonitrile [126,133-136]. The enz3nnatic production of acrylamide from acrylonitrile by nitrile hydratase of P. chlororaphis B23, Rhodococcus sp. N-774, and Klebsiella pneumoniae, respectively has been reported [137-142]. These microorganisms exhibited a high nitrile hydratase activity and a low amidase activity, allowing the accumulation of the corresponding amide. Nagasawa et al. optimized the reaction conditions for the production of nicotinamide by a nitrile hydratase, found in Rhodococcus rhodochrous Jl. The enzyme contains cobalt, and shows high activity towards 3-cyanopyridine [143,144]. 

Even more important from a commercial standpoint was that o-, m-, and p-substituted cyanopyridines were accepted as substrates [664, 665] to give picolinamide (a pharmaceutical), nicotinamide (a vitamin), and isonicotinamide... 

Lonza, a fine chemical manufacturer, has developed a biotechnological route, starting with 3-cyanopyridine to nicotinamide (also known as niacin or vitamin B3) (see Fig. 9.11). Conversions are based on enzymatic hydrolysis with nitrile hydratase from Rhodo-coccus bacteria or by bioconversion with living bacterial cells. The reactions are very specific, and the yields are quantitative. Novo-zyme has introduced an extremely thermostable lipase from the yeast Candida (Pseudozyma) antarctica (Novozyme 435), which is extremely suitable for carrying out specific esterifications in organic solvents. 

Figure 13 Inactivation effect, evaluated as inactivation constant, of 3-cyanopyridine concentration on AMase activity. fcj-Values from long-term runs performed in a CSMR fed with buffered solution (50 mM Na-phosphate buffer, pH 7.0) of 3-cyanopyridine in the presence of lOOmM nicotinamide. These...

The retro-Hofmann consideration is based on the availability of pyridine-3-carboxamide on a large scale. Actually, this compound, known as nicotinamide or vitamin B3, is produced in multi-ton quantities from 3-methylpyridine [20, 21]. For this building block, the catalytic industrial process is based on the one-pot cyclization of acrolein, ammonia and propanal in the presence of oxides of Sb(II), Ti(IV) or V(V) as catalysts. 3-Methylpyridine is submitted to amoxidation, the combined action of oxygen and ammonia to obtain 3-cyanopyridine (Scheme 8.9) [22]. 

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