Drugs, racemic, preparative resolution

Rhizopus arrhizus dead mycelium was found to be very active in organic solvents as a naturally immobilized lipase. Triglycerides hydrolysis and interesterification, esters and glycerides synthesis, natural flavour esters preparation and racemic mixtures resolution in pharmaceutical drugs synthesis are among the successfully designed processes, each of one with a specific reactional medium. 

Table 6.2 Preparative resolutions of racemic drugs and drug intermediates.

Compared with other resolution techniques utilized in drug discovery, preparative chiral HPLC is normally applied to the separation of relatively complex materials such as polycyclic compounds containing two or more chiral centres. The method is frequently employed after preliminary biological screening of racemates and diastereomeric mixtures to identify lead compounds. After a second round of biological tests have identified a single en-... 

The preparation of enantiomerically pure drugs is one factor that makes enantioselective synthesis and the resolution of racemic drugs (separation into pure enantiomers) active areas of research today. 

A series of flavan-4-ols, e.g., 108, was conveniently prepared by metal hydride reduction of the corresponding flavanone. The flavan-4-ols were converted into the 4-methoxyflavans, e.g., 109, by acid-catalyzed solvolysis in methanol. Both these classes of compounds are currently evaluated as anticancer drugs. Enantiomerically enriched cA-flavan-4-ols have been prepared by lipase-catalyzed kinetic resolution of racemic counterparts. ... 

Chiral amines are valuable synthons that dominate agrochemicals and pharmaceutical drug pipelines. Current methods for the preparation of amines are largely based upon resolution, and this is an excellent example of an industrial success. BASF makes a range of chiral amines by acylating racemic amines with proprietary esters, whereby one enantiomer is acylated to the amide, which can be easily separated from the unreacted amine [7]. For example, the resolution of racemic 15 in... 

The Pirkle-type chiral stationary phases are quite stable and exhibit good chiral selectivities to a wide range of solute types. These CSPs are also popular for the separation of many drug enantiomers and for amino acid analysis. Primarily, direct chiral resolution of racemic compounds were achieved on these CSPs. However, in some cases, prederivatization of racemic compounds with achiral reagents is required. The applications of these phases are discussed considering re-acidic, re-basic, and re-acidic-basic types of CSP. These CSPs have also been found effective for the chiral resolution on a preparative scale. Generally, the normal phase mode was used for the chiral resolution on these phases. However, with the development of new and more stable phases, the reversed phase mode became popular. 

Machida et al. presented a method for the immobilization of CCE on silica gel in 1998 [45]. They reported the covalent binding of (+)-(18-crown-6)-tetracarboxylic acid to 3-aminopropylsilanized silica gel and the prepared CSP was tested to separate enantiomers of amino acids, amino alcohols and other drugs (containing primary amino group). In 1998, the same CSP was prepared by Hyun et al. [46]. The developed CSP was used extensively for the chiral resolution of a variety of racemic compounds having a primary amino group... 

In 1998, Machida et al. [45] and Hyun et al. [46] developed a new CCE-based CSP (covalently bonded to silica gel see Sect. 8.2). This CSP was used successfully for the chiral resolution of certain racemic compounds using a variety of mobile phases. The most important applications of this CSP are for the resolution of amino acids, amino esters, amino alcohols, amines, amides, quinolone antibacterials, and other drugs having primary amino groups [46-51,64,65]. The typical chromatograms of the chiral resolution of amino acids on (+)-(18-crown-6)-2,3,ll,12-tetracarboxylic acid CSP are shown in Figure 4. The enantiomeric resolution of the racemic compound on CCE-based CSPs are listed in Table 2. There is no report available on the chiral separations at the preparative scale using these CSPs. 

There have been several papers offering overviews of the route from crystalline to universal dissymmetry,174-176 one including a brief discussion of its importance for medicine.177 The need for asymmetric syntheses in drug preparation has been discussed with reference to their historical development.178 Industrial processes using steroids include fermentation techniques and also resolution of racemic mixtures of drugs where one enantiomer may have harmful effects.179... 

A number of the major pharmaceutical companies have used biocatalytic approaches based on esterases and lipases to prepare target drugs or intermediates.107 183 187 Most of these approaches involve resolutions that use a racemic ester or amide as substrate, whereby yields of 50% can only be realized. Examples of resolutions applied to pharmaceutical intermediates such as the paclitaxel (Taxol ) sidechain and J -(+)-BMY-14802, an antipsychotic agent, have been described by the Bristol-Myers Squibb group.107... 

Menthyl chloroformate, [17], is commercially available and has been used in several applications. For example, Seeman et al. (72) carried out the preparative chromatographic resolution of nornicotine using [17] as a CDA. The diastereomeric carbamates formed via the reaction of racemic nornicotine with [17] were separated by preparative silica gel LC, and the pure enantiomers of nornicotine were liberated by acid-catalyzed hydrolysis of the carbamates (72). Several reports have described the use of [17] in the enantiospecific determination of drug concentrations in biological fluids thus, the reagent has been used in the analysis of encainide and some of its metabolites (73), flecainide (74), and propranolol (75), and other drugs (76). 

But what about stereoisomers Not too long ago the question was considered largely theoretical, since many synthetic drugs were racemates for which there were no practical means of resolution. Efforts to prepare and isolate pure enantiomorphs were generally perceived as interesting chemical exercises of little practical pharmaceutical importance because it was presumed that both enantiomorphs were equally active, or one of the pair was totally inert, or the enantiomorphs would spontaneously race-mize in solution. Now we know better. The d versus I forms of amphetamine are perhaps one of our best and oldest examples of important pharmacological differences between enantiomorphs of the same agent. 

In recent years, enantioselective chromatography was extended to semipreparative separations and now simulated moving-bed technology (SMB) has become available for the resolution of some synthetic racemates in preparative scale. In the pharmaceutical industry this progress is of considerable interest with respect to enantiopure drug applications. 

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