Nicotinamide Lonza process

Interestingly, the by-product in the above-described hydrocyanation of butadiene, 2-methylglutaronitrile, forms the raw material for the Lonza process for nicotinamide (see earlier) [123]. Four heterogeneous catalytic steps (hydrogenation, cyclisation, dehydrogenation and ammoxidation) are followed by an enzymatic hydration of a nitrile to an amide (Fig. 1.50). 

Alternatively, 3-picoline is produced by vapor phase cyclization of 2-methyl-pentane-1,5-diamine (Fig. 2.25) over, for example, H-ZSM-5 followed by palladium-catalyzed dehydrogenation [78]. This diamine is a by-product of the manufacture of hexamethylenediamine, the raw material for nylon 6,6, and these two reactions are key steps in the Lonza process for nicotinamide production (see Chapter 1) [79]. 

Some companies are successfully integrating chemo- and biocatalytic transformations in multi-step syntheses. An elegant example is the Lonza nicotinamide process mentioned earlier (.see Fig. 2.34). The raw material, 2-methylpentane-1,5-diamine, is produced by hydrogenation of 2-methylglutaronitrile, a byproduct of the manufacture of nylon-6,6 intermediates by hydrocyanation of butadiene. The process involves a zeolite-catalysed cyciization in the vapour phase, followed by palladium-catalysed dehydrogenation, vapour-pha.se ammoxidation with NH3/O2 over an oxide catalyst, and, finally, enzymatic hydrolysis of a nitrile to an amide. 

Finally, the Lonza nicotinamide process (Figure 9.11), involves the integration of both heterogeneous catalysis with a final step employing enzymatic catalysis. 

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]. 

Scheme 15.5 Lonza s nicotinamide process (Guangzhou, China).

In contrast to the chemical alkaline hydrolysis of 3-cyanopyridine with 4% byproduct of nicotinic acid (96% yield) the biotransformation works with absolute selectivity and no acid or base is required. The biotransformation (a continuous process) is operated at low temperature and atmospheric pressure. In contrast to the old synthesis route of nicotinamide at Lonza, the new one is environmentally friendly and safe. There is only one organic solvent used throughout the whole process in four highly selective continuous and catalytic reactions. The process water, NH3 and H2 are recycled. 

The reported product end concentrations in these processes clearly disprove the very common and often-heard prejudice that biological reactions can be performed at low concentrations only. The reported value of 1465 g 1"1 reaction volume in the case of the nicotinamide fed batch process seems to represent the highest product end concentration of a bioreaction ever achieved. The nicotinamide process (see Fig. 13) is commercialized under license by Lonza (new production plant in Gangzhou, China). Some of the processes listed in Table 6 are discussed in more detail in section 7. 

Production of acrylamide (Fig. 13) by hydration of acrylonitrile under the action of the intracelluar nitrile hydratase in Rhodococcus rhodochrous (Nitto Chemical Industry Co., Ltd., fed-batch process). The annual production amounts to >30000 tons (see also Table 6). Acrylamide is one of the most important commodity chemicals and is required in large quantities as the pre-polymer of polyacrylamide that is widely used in polymer and floccu-lent applications. The advantages of this hydratase approach in comparison with the classical chemical nitrile hydration are higher product end concentration, quantitative yields, no formation of acrylic acid, no need for copper catalyst, and only five chemical/technical operations instead of seven [73,112,113,171]. An analogous process for nicotinamide is being commercialized by Lonza (see also section 6). 

FIGURE 9.11. Process integration Lonza nicotinamide process. 

Nitrile hydratases (NHases) catalyze the hydration of organic nitriles to amides under very benign reaction conditions (neutral aqueous environment and room temperature) and therefore offer a chemoselective alternative to classical approaches, where functional group compatibility is often limited due to the harsh acidic or basic solutions used [1], Starting with their application in acrylamide production [2,3], this enzyme class is one of the most prominent in industrial processes with respect to production volume (>3 X 10 kg/a for acrylonitrile hydration) [4]. Hence, Lonza (Switzerland) uses a nitrile hydratase to convert 3-cyanopyridine into nicotinamide (6 X 10 tons/year). Very recently, a one-pot industrial protocol for the synthesis of a chiral intermediate for dlastatin was published that employed a nitrile hydratease/amidase approach [5],... 

Lonza Fine Chemicals manufactures nicotinamide by a process in which 2-methyl-l,5-diaminopentane (a by-produa of nylon-6,6 manufacture) is first converted to 3-cyanopyridine 121 by a series of three chemically-catalyzed reactions, then the nitrile is hydrated to nicotinamide 122 (Figure 11.37) using Rhodococcus rhodochrous Jl cells immobilized in polyacrylamide particles [227-229]. A continuous feed of 3-cyanopyridine at concentrations of between 10-20 Avt /o is added in the direction of process flow, with a counter-current feed of biocatalyst in a series of stirred-tank batch bioreactors. The process generates... 

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