Enantioselective resolution of chiral drugs

Major advances have been made in recent years in the development and optimization of chiral resolutions of derivatized CD-based CSPs [68]. It has been reported that CSPs based on CD derivatives were more enantioselective than CSPs obtained from native CDs [68]. An acetyl /CCD column exhibited enhanced separation for scopolamine in comparison to the native / -CD CSP in the reversed-phase mode [69]. The enantiomeric resolution of some drugs was compared on the native [l-CD and on CSPs based on (S)- and (i )-2-hydroxy-propyl /I-CD, and the best resolution was reported on the derivatized CSPs [44]. Five types of natural and chemically modified [>- or y-C D stationary phases were developed and used for the chiral resolution of dansyl amino acids. The best resolution of dansyl amino acids was provided by y-CD CSPs [70]. 

Easwar, S., and Argade, N. P. 2003. Amano PS-catalyzed enantioselective acylation of (+)-cx-methyl-l,3-benzodioxole-5-ethanol an efficient resolution of chiral intermediates of the remarkable antiepileptic drug candidate, (-)-talampanel. Tetrahedron Asymm., 14(3), 333-337. 

Capillary electrophoresis offers a set of important advantages that make it a premier technique for the investigation of enantioselective effects in the affinity interactions between chiral drugs and cyclodextrins. The most important advantage of CE is the inherently high separation efficiency offered by this technique. As already known, the most important contributors to peak resolution (R) are a separation selectivity (a) and an efficiency (N). A relationship between these parameters in CE is described by the following equation (2) ... 

To test the feasibility of enzyme-catalyzed enantiosective reactions in solid/gas reactors and to evaluate the efficiency of the resolution obtained in the gas phase compared to liquid systems, resolution of racemic 2-pentanol, catalyzed by CALB, through alcoholysis with methyl propanoate as acyl donor has been investigated in both liquid media and the gas phase [24]. As CALB has an enantiopreference for R enantiomers of secondary alcohols, this last reaction leads to S-2-Pentanol. This compound is a chiral intermediate in the synthesis of several potential anti-Alzheimer s drugs that inhibit 3-amyloid peptide release and/or its synthesis [25]. The degree of enantioselectivity was measured by using the enantiomeric ratio E, which is defined as the ratio of the specificity constants kcat/KM for the enantiomers (R/S in this case). E can be determined from the enantiomeric excess of... 

The effect of various SFC parameters on chiral resolution were also studied. Modifiers can provide control over both retention and selectivity and, therefore, certain modifiers were used to optimize the separation in sub-FC and SFC. The effect of the enantioselectivity of carbon dioxide on acidic drugs (benzoxaprofen, temazepam, and mephobarbital), profen, and barbiturate derivatives was carried out on Chiralcel OJ, with acetonitrile or methanol as organic modifier [140]. Acetonitrile proved to be a good alternative to methanol, especially for the profen compounds that were not well resolved when methanol was used. Wilson [143] studied the effects of methanol, ethanol, and 2-propanol as organic modifiers on the chiral resolution of ibuprofen on Chiralpak AD CSPs. Methanol was found to be the best organic modifier. 

With chiral affinity phases, proteins undergo enantioselective interactions with a great variety of drugs. Thus, the resolution on chiral affinity stationary phases is due to interactions of the enantiomers with proteins bonded to the solid support. Typical proteins used for chiral affinity separa-... 

The types of enzymes used by organic chemists vary widely and include such well-known biocataiysts as lipases, esterases, oxidoreductases, oxinitrilases, transferases and aldolases [4]. An example which illustrates the industrial application of a lipase concerns the kinetic resolution of a chiral epoxy ester used as the key intermediate in the synthesis of the calcium antagonist Diltiazem, a major therapeutic in the treatment of high blood pressure [6] (Fig. 1). In developing the industrial process for the production of this drug, many different lipases were screened, but only the bacterial lipase from Serratia marescens showed both a sufficiently high activity and enantioselectivity. The intermediate is produced industrially on a scale of 50 tons/year. 

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