Optimization, intermediate concentration

Table 6.5 Hybrid-Process. Influence of Membrane Thickness on Process Costs and Optimal Intermediate Concentration Xi< of the Hybrid Process...

Conra.d-Limpa.ch-KnorrSynthesis. When a P-keto ester is the carbonyl component of these pathways, two products are possible, and the regiochemistry can be optimized. Aniline reacts with ethyl acetoacetate below 100°C to form 3-anilinocrotonate (14), which is converted to 4-hydroxy-2-methylquinoline [607-67-0] by placing it in a preheated environment at 250°C. If the initial reaction takes place at 160°C, acetoacetanilide (15) forms and can be cyclized with concentrated sulfuric acid to 2-hydroxy-4-methylquinoline [607-66-9] (49). This example of kinetic vs thermodynamic control has been employed in the synthesis of many quinoline derivatives. They are useful as intermediates for the synthesis of chemotherapeutic agents (see Chemotherapeuticsanticancer). 

However, in most cases enzymes show lower activity in organic media than in water. This behavior has been ascribed to different causes such as diffusional limitations, high saturating substrate concentrations, restricted protein flexibility, low stabilization of the enzyme-substrate intermediate, partial enzyme denaturation by lyophilization that becomes irreversible in anhydrous organic media, and, last but not least, nonoptimal hydration of the biocatalyst [12d]. Numerous methods have been developed to activate enzymes for optimal use in organic media [13]. 

At a fixed temperature, a single, reversible reaction has no interior optimum with respect to reaction time. If the inlet product concentration is less than the equilibrium concentration, a very large flow reactor or a very long batch reaction is best since it will give a close approach to equilibrium. If the inlet product concentration is above the equilibrium concentration, no reaction is desired so the optimal time is zero. In contrast, there will always be an interior optimum with respect to reaction time at a fixed temperature when an intermediate product in a set of consecutive reactions is desired. (Ignore the trivial exception where the feed concentration of the desired product is already so high that any reaction would lower it.) For the normal case of bin i , a very small reactor forms no B and a very large reactor destroys whatever B is formed. Thus, there will be an interior optimum with respect to reaction time. 

Suppose we perform an organic synthesis in a batch reactor where the desired molecule is the intermediate and not the end product. It is then very important that we know how long we should let the reaction run to obtain the highest yield of the intermediate. Setting the differential d[I]/dt in Eq. (99) equal to zero and substituting Eq. (102) into Eq. (99) we find the time, at which the maximum is reached - and by inserting Wx in Eq. (102) the corresponding optimal concentration of the intermediate ... 

The results indicate that the zeolite can selectively extract specific compounds from the reaction medium, due to the different affinity towards each of them. This makes possible to develop reactant concentrations inside pores which are different from the bulk ones. This property is a function of the zeolite hydrophobic characteristics, which are affected by the Si/Al ratio. The best zeolite is that one which does not interact too strongly neither with more polar molecules, so to allow activation of formaldehyde to proceed faster, nor with the least polar ones. The intermediate Si/Al ratio in H-mordenites is able to develop the optimal concentration ratio between reactants inside the pores, and to reach the highest yield to vanillols. 

Several attempts have been made to estimate the dose required in humans in relation to a drug s potency, and to put this into the context of solubility and permeability for an optimal oral drug [2, 3]. A relatively simple example of this is where a 1.0 mg kg-1 dose is required in humans, then 52 pg mL"1 solubility is needed if the permeability is intermediate (20-80%) [3]. This solubility corresponds approximately to 100 pM of a compound with a MW of 400 g mol-1. Most screening activities for permeability determinations in, e.g., Caco-2, are made at a concentration of 10 pM or lower due to solubility restrictions. The first implication of this is that the required potency for these compounds needs to correspond to a dose of <0.1 mg kg-1 in humans if the drug should be considered orally active. Another implication would be the influence of carrier-mediated transport (uptake or efflux), which is more evident at low concentrations. This could result in low permeability coefficients for compounds interacting with efflux transporters at the intestinal membrane and which could either be saturated or of no clinical relevance at higher concentrations or doses. 

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