Lonza scale

A technical process was developed by Lonza for the Ir-catalyzed hydrogenation of an intermediate of dextromethorphan (Fig. 34.9) which was carried out on a > 100-kg scale [70]. Important success factors were ligand fine tuning and the use of a biphasic system chemoselectivity with respect to C=C hydrogenation was high, but catalyst productivity rather low for an economical technical application. Satoh et al. reported up to 90% ee for the hydrogenation of an intermediate of the antibiotic levofloxacin using Ir-diphosphine complexes. Best results were obtained with bppm and a modified diop in the presence of bismuth iodide at low temperature [71]. 

Lonza Process R D, custom manufacturing. One production process, several pilot- and bench-scale processes [42]. 

An Ir-catalyzed hydrogenation developed by Lonza for an intermediate of dextromethorphan was carried out on >100kg scale [29]. Here, the important success factors were the ligand fine tuning and the use of a biphasic system. The... 

Lonza (Switzerland) have successfully developed this process. They also run several other microbial oxidation processes on a commercial scale. One uses a bacterial strain in... 

A key step in the synthesis of the /3-lactamase inhibitor cilastatin (Bayer, Leverkusen, Germany) is the preparation of (S)-2,2-dimethylcyclopropane carboxamide. The chemically synthesized corresponding nitrile, l-cyano-2,2-dimethylcyclopropane, is hydrolyzed by a highly active but enanhounspecific nitrile hydratase to the racemic carboxamides. An amidase from Comomonas acidovorans overexpressed in E. coli selectively hydrolyzes the undesired (R)-isomer to the acid. The remaining (S) enantiomer is obtained with > 99% e.e. and 48% conversion (the resulting E value thus exceeds 100). The (R)-acid is recycled by chemical amidation with thionyl chloride and ammonia. The process has been developed by Lonza (Visp, Switzerland) and runs on a 15 m3 scale (Rasor, 2001). 

Two separate large-scale batches of SMZ were manufactured. In February 1997, 20 cubic meters (about 20 metric tons) of 14-40 mesh SMZ was prepared at the St. Cloud facility. In May 1998, nine cubic meters (nine metric tons) of 8-14 mesh SMZ was prepared. In each case, SMZ was manufactured at a rate of 3-4 m3 h 1. A 30% (by weight) aqueous HDTMA-C1 solution from Lonza Chemical Company was used as the feed solution for both batches. The target HDTMA loading for the 14-40 batch was 180... 

Lonza has performed the asymmetric hydrogenation of a cyclic imine 64 with iridium catalysts that contain 4j to form dextromethorphan (65), an antitussive, in 90% ee (Scheme 12.20) at the multi-kilogram scale (>100 kg produced).87... 

Air-lift bioreactors were popular in the 1990s, but currently their large-scale use is limited. Only the company Lonza (originally Celltech) uses this type of bioreactor on a large scale, for the production of monoclonal antibodies (mAbs) and other therapeutic proteins (Lonza, 2006). 

Methodologies for scale-out to phase II—III clinical trials are also given in Figure 5.12 [44]. One approach would be to scale up the c-SSP using static mixers and mini-heat exchangers, which are already in operation at Lonza. The possible... 

A microfluorimetric or microcolorimetric assay integrated into the rFC assay has allowed high-throughput screens of LPS in multiple samples. Currently, the rFC is used in an LPS-assay to sensitively and specifically detect LPS (Ding and Ho, 2001). The rFC has been incorporated into the PyroGene kit, which was launched in 2004 (Cambrex Inc., USA). Recently, Lonza Inc. (USA) applied rFC in PyroSense, which has potentials for continuous online monitoring of endotoxin in water and other fluids used for large-scale production of biomedical products. 

While these divestitures were taking place, traditional fine chemicals manufacturers were able to enjoy new contracts for the synthesis of active ingredients from companies involved in crop protection products and pharmaceuticals. Many European companies were the beneficiaries of the new trend. In Switzerland the leader was Lonza, which became independent in 1999 when its mother company, Alu Suisse, merged with the Canadian aluminum manufacturer Alcan. Other Swiss firms—such as Siegfried AG, EMS-Dottikon, Cilag, and Orgamol, Rohner, now part of Dynamit Nobel—took advantage of these developments. Clariant entered the field on a big scale in 2000 with its acquisition of BTP. 

For the direct hydroxylation of N-heterocycles a microbial oxidation is most suitable. Lonza developed a process to produce 6-hydroxynicotinic acid on a 10 tonnes scale [5]. The enzymatic production is carried out in two-steps. Firstly, Achromobacter xylosoxydans LK1 biomass is produced, which possesses a highly... 

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]. 

Figure 9.6 Examples of fermenters, (a) Large-scale fermenter for the production of ethanol (Copsright Lurgi AG, Germany), (b) Hi -tech industrial scale fermenter only the top part with the connections for loading and downstream processing is shown, the lower part extends to the floor below (right). Source Lonza Biologies Portsmouth USA)...

In addition, the conversion of aromatic nitriles into carboxylic acids or amides has been applied for the production of fine chemicals. For example, Lonza reported the biocatalytic manufacture of niacinamide starting from 3-cyanopyri-dine [85]. It is said that this process will be carried out in the future on a multithousand tons scale. 

Another interesting commercial nonstereoselective application represents the biocatalytic conversion of methyl groups into carboxylic acids. This new technology, also developed at Lonza, is already successfully applied on an industrial scale in the production of 5-methylpyrazine-2-carboxylic acid, a versatile building block for pharmaceuticals [85]. 

Enzymatic reduction, oxidation, ligase, or lyase reactions, especially, provide us with numerous examples in which prochiral precursor molecules are stereo-selectively functionalized. Ajinomoto s S-tyrosinase-catalyzed L-dopa process [112], the formation of L-camitine from butyro- or crotonobetaine invented by Lonza [113], and the IBIS naproxen route oxidizing an isopropylnaphthalene to an (S)-2-arylpropionic acid are representative, classic examples for many successful applications of enzymatic asymmetric synthesis on an industrial scale. A selection of recent industrial contributions in this field are summarized below. 

Lonza is a major custom manufacturer of intermediates for the life science industries, and uses biocatalysis in many of its processes. Some of the products for which a biotransformation is used are achiral, however, an important characteristic of enzymes is their chirality, and this characteristic is used by Lonza to produce a number of chiral synthons. 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, and several examples of each type of reaction are described for large-scale syntheses of chiral molecules that use a biotransformation in one or more of the steps. 

The following examples illustrate Lonza s activities in large-scale biocatalysis for asymmetric synthesis. There are more examples of resolutions than true asymmetric syntheses, and this reflects the general current situation in the field of large-scale biotransformations. However, considerable research work is underway, both in universities and industry, to broaden the types of biocatalytic reactions that can be applied on a commercial scale. 

Since Lonza carried out its first homogeneous asymmetric hydrogenation on a 17 ton scale in 1994, the development and application of asymmetric hydrogenations has been a major strength in Lonza s technology portfolio. The applications in Lonza have varied from internally-generated projects, for end-products marketed by Lonza, to projects in the custom-manufacturing field, in which the Lonza Exclusive Synthesis department is active. This chapter will illustrate how process de-... 

The diastereoselectivity reached, even on a production scale, was remarkable. Although the chiral phenylethyl substituent certainly enhanced the selectivity of the hydrogenation, the results with the prochiral benzyl-substituted analogue were also very impressive. A licensing agreement was rapidly reached between Lonza and Ciba-Geigy for the commercial production. As a result of turbulence in the market price of (d) - (+) -biotin, Lonza did not continue with its production after the first campaign. 

In order to find conditions suitable for transfer to another Lonza plant, the performance of our process was further elaborated in a 30 L standard hydrogenation reactor. This reactor behaved very similarly to the laboratory autoclave and at 30 bar hydrogen pressure and an S/C ratio of 1500 good enantioselectivities and high conversions were possible. We could even conduct the reaction at 10 bar pressure, to deliver the acetate with content >99% and 98.3% ee with a TOF of 210 per hour, making the process amenable to the standard large scale hydrogenation reactors available at Lonza. 

The same whole cell catalyst can be used in the hydration of 3-cyanopyridine to nicotinamide (Scheme 12.1-17). This vitamin, broadly applied in animal feeding, is currently produced biocatalytically on an industrial scale (> 3000 t/a) by the Lonza AG. For this substrate Yamada and Kobayashi showed that the whole cell catalyst of Rhodococcus rhodocrous Jl, containing a nitrile hydratase induced with crotonamide, can even tolerate substrate concentrations up to 12 m 121 (see Fig. 12.1-3). 

Unihib . [Lonza] Organic phosphonates dispersant, corroskm and scale inhibitor. 

Production of L-carnitine by microbial hydroxylation of y-butyro-betaine (continuous process, yield > 130 g 1— 1 d 1, or repeated batch process) with amutant strain of Agrobac-terium/Rhizobium lacking L-carnitine dehydrogenase.This process (Fig. 17), developed by Lonza, operates on a 140 tons per year scale. L-Carnitine is used in pharmaceuticals as a thyroid inhibitor, as a slimming aid, and in sports foods and drinks [174,176,177]. 

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