Direct Crystallization of Enantiomers and

The current volume contains profiles on Buclizine, Chitin, Ezetimibe, Gemfloxacin, Glimepiride, Lomoxicam, Magnesium Silicate, and Tadalafil. The volume also contains a chapter reviewing the direct crystallization of enantiomers and dissociable diastereomers and a review of the literature published during 2009 that pertains to cocrystal systems having pharmaceutical interest. 

The theory and experiment of direct crystallization of enantiomers is quite well understood at present [10]. There are a number of variables which affect the resolution by direct crystallization in practice. Several technological schemes based on this principle are realized on the commercial scale. These are, for example, the Merck process used for the production of antihypertensive drug methyldopa [11], a process developed by Harman and Reimer for (-)-menthol, which is separated as an ester [12], the process patented by Industria Chimica Profarmaco for the resolution of naproxen enantiomers as the ethylamine salt [13], the production of L-glutamic acid by the Japanese company Ajinomoto on a scale in excess of 10000 tons annually as early as the 1960s [14], etc. In general, it seems that spontaneous crystallization is a very useful technique for the enantioseparation of the naturally occurring a-amino acids. All of them may be resolved either directly or as derivatives [10]. 

Collet, A., Brienne, M-J. and Jacques, J. (1980) Optical resolution by direct crystallization of enantiomer mixtures. Chemical Reviews, 80, 215-230. 

Ordinarily, the rate-determining step during phase conversion is the formation of nuclei of the new phase. If suitable nuclei cannot be formed at the conditions of study, then the phase transformation is effectively suspended until the nuclei either form spontaneously or are added by the experimenter. 8ynthetic chemists have long used seed crystals of their desired phase to obtain a sufficient crop of that material and to suppress the formation of unwanted by-products. This procedure is especially important during the resolution of enantiomers and diastereomers by direct crystallization. 

These schemes have been frequently suggested [105-107] as possible mechanisms to achieve the chirally pure starting point for prebiotic molecular evolution toward our present homochiral biopolymers. Demonstrably successftd amplification mechanisms are the spontaneous resolution of enantiomeric mixtures under race-mizing conditions, [509 lattice-controlled solid-state asymmetric reactions, [108] and other autocatalytic processes. [103, 104] Other experimentally successful mechanisms that have been proposed for chirality amplification are those involving kinetic resolutions [109] enantioselective occlusions of enantiomers on opposite crystal faces, [110] and lyotropic liquid crystals. [Ill] These systems are interesting in themselves but are not of direct prebiotic relevance because of their limited scope and the specialized experimental conditions needed for their implementation. 

Molecular asymmetry, chirality and enantiomers The observation of Louis Pasteur (1848) that crystals of certain compounds exist in the form of mirror Images laid the foundation of modem stereochemistry. He demonstrated that aqueous solutions of both types of crystals showed optical rotation, equal in magnitude (for solution of equal concentration) but opposite in direction. He believed that this difference in... 

The phenylalanine-derived oxazolidinone featured here enjoys three practical advantages over the valine-derived oxazolidinone developed earlier in this laboratory. First, both the intermediate g-amino alcohol and the derived oxazolidinone are crystalline solids which can be purified conveniently by direct crystallization. Second, the oxazolidinone contains a UV chromophore which greatly facilitates TLC or HPLC analysis when it is employed as a chiral auxiliary. Finally, both enantiomers of phenylalanine are readily available, enabling stereocontrol in either sense simply by using the oxazolidinone derived from the appropriate enantiomer. 

It must be emphasized that only conglomerates can be resolved into the enantiomers by direct crystallization. For racemic compounds, pure enantiomers can be crystallized only from partially resolved mixtures (vide infra). Which type is present in a given case is best decided by trial and error. For a complete list of conglomerates forming chiral compounds, see reference 5. 

The overall process, illustrated in Scheme 10.4, intercepts the racemate (2) by crystallization from heptane. After separation of the enantiomers using the MCC process, the radafaxine free base is converted to the desired salt directly on treatment with anhydrous HCl. Any mixed fractions from the MCC separation are combined with the epimerized R,R)-enantiomer and fresh racemate for processing, hence generating further radafaxine free base for conversion to the hydrochloride salt. These results were subsequently confirmed in a Proof of Concept study performed on the medium- to large-scale in-house MCC equipment prior to scale-up. 

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