Repetitive batch

Figure 4.14 Chemical adducts for by-product removal synthesis of isopropyl-cis-Ag-hexadecanoate from isopropylpalmitate applying a repetitive batch process using a sequence of stirred-tank reactor, extraction module, filtration step and chromatographic downstream processing...

Continuous production is achieved in elution chromatography by repetitive batch injection or cyclic batch elution. The injection cycle is timed so that the emergence of the last-eluted component of one batch at the column exit is immediately followed by the emergence of the first-eluted component to be collected from the next batch as shown, for example, in Figure 19.2b. At any one time there is more than one batch moving through the column. 

In summary, the synthesis and in situ regeneration of nucleotide sugars by combinatorial biocatalysis suffers from the main disadvantage that each enzyme has to be produced in sufficient amounts. This affords efficient recombinant protein produchon hosts being a bottleneck for some genes [25]. However, once a multi-enzyme system has been developed, the productivity can be improved by repetitive use of the biocatalysts as demonstrated for repetitive batch syntheses with soluble enzymes [25, 38] or with immobilized enzymes [48]. The advantage... 

Continuous reactors are not always beneficial to achievement of good reactor performance (Woltinger, 2002) in the asymmetric opening of meso-anhydrides, due to product inhibition of the cinchona alkaloid catalyst the conversion and enantiomeric excess decreased rapidly during a continuous reaction. Even optimization of reaction parameters to decrease residence time to a very low value (1 h) did not improve the situation sufficiently. In contrast, performing the reaction in repetitive batch mode allowed a modest 60% e.e. to be sustained over 18 cycles. 

In summary, an efficient synthesis of nucleotide sugars could be achieved by using the repetitive batch technique. The estimated costs for enzymes and chemicals can be reduced by a factor of between 4 and 8 for the synthesis of 1 g of activated glucose [272],... 

We also combined further the enzymatic synthesis of dUDP from dUMP by NMPK with SuSy and dTDP-Glc 4,6 dehydratase (Fig. 24) [272], Using again the repetitive batch technique for enzymatic synthesis, 120 mg dUDP-6-deoxy-4-ketoglucose was obtained after product isolation (49% overall yield). 

Table 7. Comparison of parallel and repetitive batches for the enzymatic synthesis of LacNAc (7) [275]...

Figure 14 Repetitive batch hydrolysis of penicillin-G to 6-aminopenicillanic acid. Plot shows batch number versus time required for complete hydrolysis of starting material.

Since this supported catalyst is stable, insoluble and composed of mechanically strong particles of 1 mm diameter, it can be easily recovered by filtration and be reused. The high stability and activity of silica supported guanidinium salts, along with the ability to reuse the solid catalyst were demonstrated on repetitive batch phosgena-tions of carboxylic acids. 

A plug flow reactor may be realized using immobilized enzymes within a column reactor or using soluble enzymes within a cascade of membrane reactors. A batch or a repetitive batch process with soluble enzymes (see below) has the same productivity as the plug flow reactor. 

For synthesis on a preparative scale, repetitive batch processing has proved to be an effective and easy-to-handle method1128. The repeated use of the enzyme is possible after concentration of the solution by means of commercially available ultrafiltration equipment and adding fresh substrate solution. Some of the advantages given for the Enzyme Membrane Reactor (see below) are also valid for the repetitive batch technique. 

The second step of the 7-aminocephalosporanic acid (7-ACA) process is the deamidation of glutaryl-7-ACA (Fig. 19-22), the first step is described in Sect. 19.3.2.2. 7-ACA is an intermediate for semi-synthetic cephalosporins. Hoechst Marion Roussel uses the glutaryl amidase immobilized on a spherical carrier. Toyo Jozo and Asahi Chemical immobilize the glutaryl amidase on porous styrene anion exchange resin with subsequent cross-linking with 1% glutardialdehyde. The catalyst is applied in a fixed bed reactor in a repetitive batch mode (70 cycles). Here, an enzymatic process has replaced an existing chemical process for environmental reasons (Fig. 19-23) ... 

By this method 13.6 tonnes have been produced in fifty-eight repetitive batch cycles with 97 % conversion and 96 % selectivity. This biotransformation was chosen over the chemical transformation because of the higher conversion and selectivity, production of more product per catalyst weight (3 150 kg per kg dry cell weight), and less waste. The catalyst consumption is 0.006 kg per kg product. 

A new chemoenzymatic synthesis of UDP-GalNAc consists of a multi-enzyme catalyzed generation of UDP-galactosamine from uridine-5 monophosphate (UMP) and sucrose in a repetitive batch mode, followed by a chemical acetylation step [164],... 

Chemferm is one of among several companies which apply penicillin acylase for the kinetically controlled industrial synthesis of semisynthetic antibiotics in aqueous environments (Scheme 37) [109-111]. Ampicillin (119) and amoxicillin (120) can be obtained by the enzyme-catalyzed condensation of 6-aminopenicillic acid (6-APA, 117) with the amide or ester of D-(-)-4-hydrox-yphenylglycine and D-(-)-phenylglycine, respectively. In a similar way, cephalexin (121) can be obtained by reaction of D-(-)-phenylglycine with 7-aminodesacetoxycephalosporanic acid (7-ADCA, 118). Penicillin acylase from diverse microbial strains such as E. colU Klyveromyces citrophiluy and Bacillus megabacterium was successfully applied for this transformation and was used in its immobilized form based on a gelatin carrier. The immobilization allows an easy separation from the reaction medium and the reuse of the enzyme for at least 50 cycles. Impressive characteristics of this transformation are yields >90%, a selectivity of >95%, and an optical purity of >99% ee. The industrial manufacture takes place in repetitive batch reactors at many locations worldwide with an annual production volume of 2,000 t. 

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