Enantiomers production

In order to illustrate an example of process design for the manufacture of enantiopure drug substances on an industrial SMB system, consider manufacturing 10 ton/ year of an enantiopure drug. The racemic drug by definition is a 50 50 mixture of each enantiomer (products A and B). The goal is to process enantiopure drug substances in order to obtain 99 % purity for both the extract and the raffinate. 

To explain the observed optical induction, a substrate was incorporated into the molecular model of the protein. A substrate such as a-ketoglutarate could be included in the protein model with a geometry that allowed stereoselective protonation of the quinoid intermediate by solvent, consistent with the enantiomeric excess (ee) of the 1-stereoisomer product. Moreover, the geometry consistent with production of the d-enantiomer appeared too sterically crowded for most substrates. However, pyruvic acid, which was the only substrate to favor the d-enantiomer product, was small enough to adopt the alternative geometry and also had the potential to interact with an arginine group. 

Figure 3.5 Measurement of the chiral purity of commercially available Jacobson s catalyst using a cyclodextrin-based CSP. (a) Lower trace / ,/ -enantiomer product upper trace / ,/ -enantiomer product artificially enriched with S -enantiomer and (b) lower trace S. S -enantiomer product upper trace S. S -enantiomer product artificially enriched with / ,/ -enantiomer. (Conditions CYCLOBOND 1 2000RSP 25 cm X 0.46 cm i.d. mobile phase acetonitrile triethylamine glacial acetic acid [1000 0.5 2.5, v/v] flow rate 1 ml/min temperature ambient detection UV at 240 nm sample preparation 1 mg/ml in acetonitrile injection volume 10 fxl). Reprinted from [19], copyright 1998, with permission of Wiley-Liss, Inc., a subsidiary of John Wiley and Sons, Inc.

A similar approach was employed in our laboratory for the development of molecularly imprinted catalysts for the enantio-selective reduction of prochiral ketones with borane (CBS reaction) [122]. A stable, polymerisable transition state analogue of this reaction leading to the formation of one particular enantiomer product was prepared (Fig. 4.9). After polymerisation, the template molecule can... 

To recover the strongly bound enantiomer product and the extractant, the loaded solvent stream can be treated in a back-extraction unit (Figure 6). A convenient way to achieve back extraction by pH shift without producing salts is the addition of low-pressure CO2 [14]. The model results for back-extraction of PEA (left) and PG (right) by pH shift are... 

If rate for f -enantiomer> S-enantiomer Unreacted material is enriched in S-enantiomer product enriched in derivative of f -enantiomer... 

The challenges of capillary electromigration techniques in enantiomer analysis are obvious, and in opposition to their potential in enantiomer production [173]. 

It is interesting to note that all levels of theory predict the (5)-isomer as the major enantiomer product as found experimentally except with PM3//PM3. On this level of theory the unsolvated activated complex (/ )-TS is favoured (entry 16). Also, at the B3LYP/6-31 + G(d)//PM3 level of theory the THE-solvated activated complex built from a dimer of lithium amide 4 yielding the (/ )-isomer is favoured (entry 8). At most levels of theory the calculated AG values for the THE-solvated activated complexes are in closer agreement... 

Asymmetric epoxidation ranks as one of the most reliable and selective methods for the formation of single enantiomer products. In particular, the asymmetric epoxidation of allylic alcohols with tert-butyl hydroperoxide (t-BuOOH),... 

In addition to new drug development, a number of estabUshed agents, previously marketed as racemates, have been reevaluated as single stereoisomer products. This process, known as a chiral switch, has resulted in the remarketing of a number of compounds as single enantiomer products in a number of countries, examples of which are presented in Table 5 [11]. 

The examples cited above indicate that the removal of isomeric ballast from a mixture may have considerable financial consequences. For example, it has been estimated that the research and development costs of dilevalol represented an investment of 100 million [176]. In some instances, it could be argued that the development of single-enantiomer products from previously marketed racemates does not provide a genuine therapeutic benefit [177]. However, a number of commercially successful drugs are marketed as racemates, and the potential economic significance of singleenantiomer forms of these agents is obvious. 

Unreacted material is enriched in 5-enantiomer product is enriched in -enantiomer. 

So, after the formation of the intermediate, the bromide ion attacks it only from one side, which finally results in the inhibition of the formation of enantiomer products. 

Once again, consideration of the chelated, cyclic transition state, known as the Zimmerman-Traxler model, provides the rationale for this diastereo-selectivity. In the most favorable chair-Uke transition state, the aldehyde R group is in an equatorial position. This preferred orientation produces the syn product from the (Z)-enolate and the anti product from the (i )-enolate. Each transition state shown is forming a single enantiomer product attack by the enolate to the opposite face of the aldehyde would give rise to the other enantiomer. 

In their quest for enantiomerically pure compounds, organic chemists have developed several new techniques for the preparation of enantiomerically pure materials. One approach is to use enzymes. Enzymes are themselves chiral, so they can produce single enantiomer products. A class of enzymes used for this purpose is the esterases, which catalyze the hydrolysis of esters to give an alcohol and a carboxylic acid. 

The Sharpless epoxidation is used when a single enantiomer product is required. Predict the structure of the predominant product of the following transformation. 

It is quite common to create chiral products during aldol reactions, as well as in the other enolate reactions we discuss in this chapter. The products will be formed as racemic mixtures unless one of the reactants is chiral and present as a single enantiomer. In cases when two chiral centers are created in the reaction, four stereoisomers are produced as two 1 1 mixtures of enantiomers. A great deal of work has gone into learning how to carry out aldol and other enolate reactions that give predominantly a single enantiomer product, but that work is beyond the scope of this text. 

Scheme 2.16 Frank s Scheme for the asymmetric amplification where A is substrate R, S are enantiomer products and RS is heterochiral dimer.

Basically, the SMB operation points should be close to the theoretical optimal point in order to achieve a high production rate, yet far away from it within the boundaries of the operating area to assure robustness. Since (S) -propranolol hydrochloride is the desired enantiomer product which is enriched in the raffinate stream, productivity based on raffinate rather than on the feed to... 

The pharmaceutical industry can also use enzymes to promote stereoselectivity and produce single-enantiomer products. The specific shape and the nature of the molecular interactions at the active site of an enzyme ensure only one enantiomer will be formed (as in living things). The enzymes are often immobilised (fixed in place) on inert supports. This enables the reactants to be passed over them without the need to separate the product from the enzymes after the reaction. 

Subsequent work by Zhang optimized the reaction further, obtaining a 53% ee of the (S)-enantiomer product (with some racemization of the product under reaction conditions) using precatalyst 40, Figure 19.12, and changing the solvent to EtOAc [118]. Zhang has also proposed a reaction model to explain the observed... 

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