Drug enantioselectivity

Antichoiesteroi Drug Enantioselective Enzymatic Acylation of Racemic Alcohol 54... 

When chiral, drugs and other molecules obtained from natural sources or by semisynthesis usually contain one of the possible enantiomeric forms. However, those obtained by total synthesis often consist of mixtures of both enantiomers. In order to develop commercially the isolated enantiomers, two alternative approaches can be considered (i) enantioselective synthesis of the desired enantiomer or (ii) separation of both isomers from a racemic mixture. The separation can be performed on the target molecule or on one of its chemical precursors obtained from conventional synthetic procedures. Both strategies have their advantages and drawbacks. 

Table 5-1. Enantioselectivities determined for several drugs. All experiments were performed at room temperature, except those marked with, which were performed at 4 °C. In some cases a lipophilic anion was used to facilitate the solubilization of the drug in the organic phases (PFj = hexafluorophosphate BPh = tetraphenyl borate). DHT = dihexyl tartrate DBT = dibenzoyl tartrate PLA = poly (lactic acid). ...

To evaluate the economics of this process, a cost model has been developed to estimate the separation costs for a specific racemate [68, 69]. For this purpose, the sensitivity of the separation costs for several key process parameters have been established as compared to a base-case separation in which a purity of 99 % is required at an enantioselectivity of 1.15. The maximum solubility of the drug is set... 

The latter approach is used in the enantioselective determination of a Phase I metabolite of the antihistaminic drug, terfenadine. Terfenadine is metabolized to several Phase I compounds (Fig. 7-13), among which the carboxylic acid MDL 16.455 is an active metabolite for which plasma concentrations must often be determined. Although terfenadine can be separated directly on Chiralpak AD - an amy-lose-based CSP - the adsorption of the metabolite MDL 16.455 is too high to permit adequate resolution. By derivatizing the plasma sample with diazomethane, the carboxylic acid is converted selectively to the methyl ester, which can be separated in the presence of all other plasma compounds on the above-mentioned CSP Chiralpak AD [24] (Fig. 7-14). Recently, MDL 16.455 has been introduced as a new antihistaminic drug, fexofenadine. 

The second system studied was the separation of the chiral epoxide enantiomers (la,2,7,7a-tetrahydro-3-methoxynaphth-(2,3b)-oxirane Sandoz Pharma) used as an intermediate in the enantioselective synthesis of optically active drugs. The SMB has been used to carry out this chiral separation [27, 34, 35]. The separation can be performed using microcrystalline cellulose triacetate as stationary phase with an average particle diameter greater than 45 )tm. The eluent used was pure methanol. A... 

Determination of the drug substance is expected to be enantioselective, and this may be achieved by including a chiral assay in the specification or an achiral assay together with appropriate methods of controlling the enantiomeric impurity. For a drug product where racemization does not occur during manufacture or storage, an achiral assay may suffice. If racemization does happen, then a chiral assay should be used or an achiral method combined with a validated procedure to control the presence of the other enantiomer. 

Of course, the influence of organic solvents on enzyme enantioselectivity is not limited to proteases but it is a general phenomenon. Quite soon, different research groups described the results obtained with lipases [28]. For instance, the resolution of the mucolytic drug ( )-trans-sobrerol (11) was achieved by transesteriflcation with vinyl acetate catalyzed by the lipase from Pseudomonas cepacia adsorbed on celite in various solvents. As depicted in Scheme 1.3 and Table 1.5, it was found that t-amyl alcohol was the solvent of choice in this medium, the selectivity was so high ( >500) that the reaction stopped spontaneously at 50% conversion giving both +)4rans-sobrerol and (—)-trans-sobrerol monoacetate in 100% optical purity [29]. 

The modifier in these cases seems to generate enantioselective sites at the metal surface and helps the molecule to adsorb in a preferred fashion so that the formation of only one stereo- product is possible. There are several milestones that have contributed to this state-of-the-art technology. Discovery of Wilkinson s catalyst led to the feasibility of asymmetric hydrogen transfer with the aid of an optically active Wilkinson-type catalyst for L-DOPA (Monsanto s anti-Parkinson disease drug) synthesis (Eqn. (21)). 

These data clearly illustrate the enantioselectivity of the (-l-)-isomers of MDA, MDMA, and MBDB in producing an MDMA-like stimulus and underscore the fact that in vitro studies of the biochemical pharmacology of these substances should reveal similar selectivity, once the primary pharmacological process underlying the interoceptive cue is identified. The data also indicate that (-l-)-MDA is the most potent of all the drugs tested in MDMA- or in (-t)-MBDB-trained animals. The faet that (-l-)-MDA does not substitute in amphetamine-trained animals in our studies supports the argument that the pharmacology of this enantiomer of MDA is MDMA-like and is not like amphetamine. 

Enantioselective additions of (3-dicarbonyl compounds to (3-nitrostyrenes have been achieved using to-oxazolidine catalysts. This method was used in an enantioselective synthesis of the antidepressant drug rolipram.325... 

Suggest an enantioselective synthetic route to the antidepression drug rolipram from the suggested reactant. 

Section B shows some Hofmann rearrangements. Entry 9, using basic conditions with bromine, provided an inexpensive route to an intermediate for a commercial synthesis of an herbicide. Entry 10, which uses the Pb(OAc)4 conditions (see p. 949), was utilized in an enantiospecific synthesis of the naturally occurring analagesic (-)-epibatidine. Entry 11 uses phenyliodonium diacetate as the reagent. The product is the result of cyclization of the intermediate isocyanate and was used in an enantioselective synthesis of the antianxiety drug (tf)-fluoxetine. 

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