Scale space-time yield

As an example for continuous process design, 2-keto-3-deoxy-D lycero-D-galacto-nonosouate (KDN) (S) has been produced on a 100-g scale from D-mannose and pyruvate using a pilot-scale EMR at a space-time yield of 375 gl d and an overall crystallized yield of 75% (Figure 10.6) [47]. Similarly, L-KDO (6) can be synthesized from L-arabinose [48]. 

In this way, the operational range of the Kolbe-Schmitt synthesis using resorcinol with water as solvent to give 2,4-dihydroxy benzoic acid was extended by about 120°C to 220°C, as compared to a standard batch protocol under reflux conditions (100°C) [18], The yields were at best close to 40% (160°C 40 bar 500 ml h 56 s) at full conversion, which approaches good practice in a laboratory-scale flask. Compared to the latter, the 120°C-higher microreactor operation results in a 130-fold decrease in reaction time and a 440-fold increase in space-time yield. The use of still higher temperatures, however, is limited by the increasing decarboxylation of the product, which was monitored at various residence times (t). 

In spite of several drawbacks (i.e. expensive and laborious handling procedures, low space-time yields (Table 2.1), high demand on biosafety, potential contaminations, limited applicability for continuous fermentations [129], and problems obtaining the same glycosyla-tion profile from batch to batch [130]), mammalian cell cultures are widely used for small-scale expression and more recently even on a multi-cubic-meter scale. The system works like insect... 

Because the thermal separation of products has been substituted by a liquid-liquid separation, the two phase technology should be best suited for hydroformylation of longer chain olefins. But with rising chain length of the olefins the solubility in the aqueous catalyst phase drops dramatically and as a consequence the reaction rate. Only the hydroformylation of 1-butene proceeds with bearable space-time yield. This is applied on a small scale for production of valeraldehyde starting from raffinate II. Because the sulfonated triphenylphosphane/rhodium catalyst exhibits only slow isomerization and virtually no hydroformylation of internal double bonds, only 1-butene is converted. The remaining raffinate III, with some unconverted 1-butene and the unconverted 2-butene, is used in a subsequent hydroformy-lation/hydrogenation for production of technical amylalcohol, a mixture of linear and branched C5-alcohols. 

The gram-scale preparation of rare sugars by E. coli transketolase was demonstrated successfully for (S)-erythrulose from glycolaldehyde and hydroxypyruvate in an enzyme membrane reactor which allowed the continuous production of (S)-erythrulose with high conversion and a space-time yield of 45 g L" d was reached [12]. 

The influence of eutectic media on the kinetics and productivity of biocatalysts has yet to be fully elucidated. Syntheses in eutectic suspensions have been scaled up to the pilot scale in a rotating drum reactor. The bioactive peptide Na-Cbz-L-Lys(Ne-Cbz)-Gly-L-Asp(OAll)-L-Glu(OAll)OEt was synthesized via a sequential N-to-C strategy in a heterogeneous solid-liquid mixture of the substrates in the presence of chymopapain and subtilisin as well as 16-20% (w/w) water and ethanol (Gill, 2002). At substrate concentrations of around 1 m, yields of 67-74% per step at product concentrations of 0.36, 0.49, and 0.48 kg kg-1 were achieved. The corresponding space-time yields were between 0.30 and 0.64 kg (kg d)-1 and biocatalyst reuse provided productivities of 166-312 kg product (kg enzyme)-1. 

Several biotechnological synthetic methods for D-pantothenic add and its precursor D-pantolactone have been developed over the past 15 years. Although all have reached preparative scale and might result in cost-effective production processes, they differ considerably in their process characteristics - for example educts and space-time yields, especially when a fermentation and biotransformation are compared. Compared with the chemical process, the biotechnological processes reduce waste production and provide the possibility of a more environmentally friendly yet still competitive means of production of D-pantothenic acid. 

Capillary gap cell — The undivided capillary gap (or disc-stack) cell design is frequently used in industrial-scale electroorganic syntheses, but is also applicable for laboratory-scale experiments when a large space-time yield is required. Only the top and bottom electrodes of c.g.c. (see Figure) are electrically connected to - anode and cathode, respectively, whereas the other electrodes are polarized in the electrical field and act as -> bipolar electrodes. This makes c.g.c. s appropriate for dual electrosynthesis, i.e., pro duct-generating on both electrodes. 

The same combination of supercritical fluid extraction (SFE) and mediated electrooxidation (MEO) has an application potential for synthesis of organic compounds. In an industrial scale one limiting factor for the efficiency of the production of organic compounds is the amount of by-products. With the novel integrated method the selectivity of the desired reaction can be influenced and so the space-time-yield enhanced. 

The chlorination rate was found to be a function of the total copper concentration, cupric/cuprous ratio, and temperature. An empirical expression relating these variables to the space-time yield has been derived. Extensive oxygen mass transfer studies have been carried out in both process and sodium sulfite solutions these taken together make possible the scale-up and design of a commercial reactor with ample safety factor on O2 concentration level. 

Electrochemical reaction engineering deals with modeling, computation, and prediction of production rates of electrochemical processes under real technical conditions in a way that technical processes can reach their optimum performance at the industrial scale. As in chemical engineering, it centers on the appropriate choice of the electrochemical reactor, its size and geometry, mode of operation, and the operation conditions. This includes calculation of performance parameters, such as space-time yield,... 

The phenomenon of charge transport, which is unique to all electrochemical processes, must be considered along with mass, heat, and momentum transport. The charge transport determines the current distribution in an electrochemical cell, and has far-reaching implications on the current efficiency, space-time yield, specific energy consumption, and the scale-up of electrochemical reactors. 

Productivity during scale-up is therefore a major concern for efficiently getting an active compound to market. In scale-up operations, productivity is related to throughput, the amount of product that can be made per reactor volume per day. Sometimes this is referred to as space-time yield or volume efficiency [15],To increase productivity, conditions are developed to minimize reaction times, streamline operations, and simplify processing. 

The continuous enzymatic process generates the desired enantiopure product with a high space-time yield (560 g L d ) using a membrane reactor. The synthesis not only reduced the costs significantly at large scale but it can also be used to... 

Chemical or enzymatic hydrolysis of the chiral cyanohydrin gives access to 2-hy-droxycarboxylic acids. The most prominent examples are (S)- and (R)-mandclic acids, which are mainly used for racemate resolution. Other chiral acids, such as (R)-2-chlorom an del i c acid, are used as precursors for pharmaceuticals (see Fig. 11). Scale-up and production of (R)-2-chloromandelic acid was successfully performed with a space-time yield of 250 g/L/d (ee = 95%). 

While many methods have been reported for the synthesis of chiral 2-hydroxy acids, few have proven to be reliable toward the synthesis of the title compound in terms of overall yield and enantioselectivity. Herein we describe a continuous enzymatic process for an efficient synthesis of (R)-3-(4-fTuorophenyl)-2-hydroxy propionic acid at a multi-kilogram scale with a high space-time yield (560 g/L/d) using a membrane reactor. The product was generated in excellent enantiomeric excess (ee>99.9%) and good overall yield (68-72%). This process can also be adapted to the synthesis of a variety of chiral 2-hydroxy acids with high yield and stereoselectivity. 

An efficient and practical process has been described for the synthesis of (R)-3-(4-fluorophenyl)-2-hydroxy propionic acid at a multi-kilogram scale with good overall yields (68-72% for two steps), excellent stereoselectivity (>99.9% ee), and significant cost savings. The key to the process is the use of a continuous membrane reactor which was simple in concept, low cost in design, and provided high space-time yields. This method has a broad substrate spectrum in contrast to asymmetric chemical catalysis and a variety of chiral 2-hydroxy acids can be prepared. Moreover, by alternating d-LDH with l-LDH, both enantiomers can be synthesized. 

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