Racemic compounds crystallization-based enantiomer

One area of chirotechnology which is undergoing rapid development is chiral HPLC, whereby the use of chiral stationary phases (CSPs) permits the direct separation of racemic compounds into constituent enantiomers. Despite the capital outlay required, for example, for columns costing upwards of 3000, the use of preparative chiral HPLC in drug discovery has a number of benefits. After development of an appropriate method based on a previously defined analytical separation has been carried out, rapid and quantitative separation of racemates can be achieved, with evaporation of solvent from column fractions affording pure enantiomers directly. Although preparative chiral HPLC is less amenable to scale-up than other resolution techniques, it may be ideal for preliminary screening of both enantiomers in circumstances where manipulation of small quantities of material, for example, by crystallization, is impractical and prone to contamination problems. 

The second important observation on stereoisomer separation also involved ammonium sodium tartrate. Thirty-four years after Pasteur s observation, Jungfleisch (1882) observed that carefully introducing crystals of the individual isomers into different areas of a supersaturated solution of ammonium sodium tartrate resulted in the growth of isomerically pure crystals. These two observations form the basis for most industrial scale crystallizations for the purification of enantiomers or diastereoi-somers. However, it is more common for a solute to crystallize with the thermodynamically stable crystal form being a compound of the two isomers. This is typically denoted as a racemic compound. Secor (1963) made the first systematic review of optical isomer separation by crystallization, based upon phase behavior. Collet, Brienne, and Jacques (1980) applied systematic thermodynamics to the phase behavior, and developed straightforward methods for correlating the solubilities of isomers. 

Preparation of enantiopure (ee 100%) compeimds is one of the most important aims both for industrial practice and research. Actually, the resolution of racemic compounds (1 1 mixture of molecules having mirror-imagine relationship) still remains the most common method for producing pure enantiomers on a large scale. In these cases the enantiomeric mixtures or a sort of their derivatives are separated directly. This separation is based on the fact that the enantiomeric ratio in the crystallized phase differs from the initial composition. In this way, obtaining pure enantiomers requires one or more recrystallizations. (Figure 1). 

When the racemic acid or base is treated with less than an equivalent amount of chiral compound (resolving agent) one can obtain a good enantiomer separation if crystallization occures in the mixture. For example, at the resolution of racemic ibuprofen (TBU) with (R)-PEA, the free enantiomer (S)-IBU can be separated from the salt ((R)-IBU.(R)-PEA) by extraction with a supercritical fluid, most often with carbon dioxide ... 

The racemic intermediate of chloramphenicol (AD.HCl) is obtained as a hydrochloride salt during the synthesis, and it is dissolved in water (the free base is low-soluble in water). In this case the resolving agent (0,0 -dibenzoyl-(K,R)-tartaric acid N,N-dimethylamide (DBTADA)) is practically insoluble in water but its ammonium salt is well soluble and it can be prepared easily. The two aqueus solutions are mixed so that the molar ratio between the racemic compound and the resolving agent sould become 1/0.5. The diastereoisomeric salt containing the desired enantiomer (R,R)-AD crystallizes while the hydrochloride salt of (S,S)-AD remains in solution. 

The antihistamine dmg cetirizine, which is a piperazine derivative, is a racemic mixture, and has been used in the treatment of rhinitis and hay fever. It is available over the counter as the well-known ZYRTEC (McNeil-PPC, Inc). However the levo-rotatory R-enantiomer (10.29) was later found to be the more active form and is now on the market as the prescription dmg XYZAL (Sanofi-Aventis U.S. LLC). An approach for the synthesis of the enantiomers of cetirizine is expressed by Scheme 10.11, wherein chiralty in the dmg is introduced at an early stage in the synthesis. Thus, compound 10.28 was synthesized in racemic form then converted into diastereoisomeric salts with an optically active tartaric acid. To procure the (—)-enantiomer of 10.28, the resolution was performed with (-l-)-tartaric acid for the (-l-)-enantiomer, the resolution employed (—)-tartaric acid. After separation of the salts by crystallization, the 10.28 enantiomers were released by treatment with base and each then converted to optically active cetirizine enantiomers or related compounds by use of the general reaction suggested by Scheme 10.11 for the synthesis of the (R)-isomer of cetirizine. 

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