Solubility, enantiomers

Molecules which exhibit optical activity are molecules which have a handedness in their structure. They are chiral . Chemists often have reasons to obtain chemical pure aliquots of particular molecules. Since the chirality of molecules can influence biological effect in pharmaceuticals, the chiral purity of a drug substance can pose a challenge both in terms of obtaining the molecules and in assaying the chiral purity by instrumental methods. While diastereomers can have different physical properties including solubility, enantiomers have the same physical properties and the same chemical composition. How then to separate optically active molecules ... 

Specific rotation is a physical property of a substance just as melting point boil mg point density and solubility are For example the lactic acid obtained from milk is exclusively a single enantiomer We cite its specific rotation m the form [a]o =+3 8° The temperature m degrees Celsius and the wavelength of light at which the measure ment was made are indicated as superscripts and subscripts respectively... 

Propranolol. Propranolol hydrochloride, considered the prototype of the P-adrenoceptor blocking agents, has been in use since 1964. It is a nonselective, highly Hpid-soluble P-adrenoceptor blocker having no ISA. It is a mixture of (+) and (—) enantiomers, and the (—) enantiomer is the active moiety. The local anesthetic effects of propranolol are equipotent to those of Hdocaine [137-58-6] C 4H22N20, (see Anesthetics). Therapeutic effects include termination of catecholamine-induced arrhythmias, conversion of SA nodal tachycardias (including flutter and fibrillation) and AV nodal tachyarrhythmias to normal sinus rhythm, digitahs-induced arrhythmias, and ventricular arrhythmias (1,2). The dmg also has cardioprotective properties (37,39). 

Acidimetric, spectrophotometric and HPLC assays were developed for determination of 2,3,5,6,7,8-hexahydro-l//-pyrido[l,2-c]pyrimidine-l,3-diones 135 (98M133). Its solubility properties were also characterized. Resolution of the enantiomers of 4-phenyl-2- 4-[4-(2-pyrimidinyl)piperazi-nyl]butyl perhydropyrido[l,2-c]pyrimidine-l,3-dione was achieved on hep-takis(2-N, V-dimethylcarbamoyl)- 6-cyclodextrines (01 JC(A)249). 

Another possibility of constructing a chiral membrane system is to prepare a solution of the chiral selector which is retained between two porous membranes, acting as an enantioselective liquid carrier for the transport of one of the enantiomers from the feed solution of the racemate to the receiving side (Fig. 1-5). This system is often referred to as membrane-assisted separation. The selector should not be soluble in the solvent used for the elution of the enantiomers, whose transport is driven by a gradient in concentration or pH between the feed and receiving phases. As a drawback common to all these systems, it should be mentioned that the transport of one enantiomer usually decreases when the enantiomer ratio in the permeate diminishes. Nevertheless, this can be overcome by designing a system where two opposite selectors are used to transport the two enantiomers of a racemic solution simultaneously, as it was already applied in W-tube experiments [171]. 

Another important issue that must be considered in the development of CSPs for preparative separations is the solubility of enantiomers in the mobile phase. For example, the mixtures of hexane and polar solvents such as tetrahydrofuran, ethyl acetate, and 2-propanol typically used for normal-phase HPLC may not dissolve enough compound to overload the column. Since the selectivity of chiral recognition is strongly mobile phase-dependent, the development and optimization of the selector must be carried out in such a solvent that is well suited for the analytes. In contrast to analytical separations, separations on process scale do not require selectivity for a broad variety of racemates, since the unit often separates only a unique mixture of enantiomers. Therefore, a very high key-and-lock type selectivity, well known in the recognition of biosystems, would be most advantageous for the separation of a specific pair of enantiomers in large-scale production. 

Natural Occurrence of ( — )-proto-Quercitol. Although the dextrorotatory form (12) of proto-quercitol was discovered in acorns more than a century ago by Braconnot (5), who at first thought that it was lactose, the levorotatory form (13) remained unknown until 1961. In that year, Plouvier isolated it from leaves of the tree Eucalyptus populnea the yield was 0.55% (36). The optical rotation of the new compound was equal and opposite to that of the dextro enantiomer, and it was identical to the latter in its crystal form, melting point, solubilities, molecular formula and infrared spectrum. 

Meso compounds contain chirality centers but are achiral overall because they have a plane of symmetry. Racemic mixtures, or racemates, are 50 50 mixtures of (+) and (-) enantiomers. Racemic mixtures and individual diastereomers differ in their physical properties, such as solubility, melting point, and boiling point. 

The resultant mixture can be separated by fractional crystallization as the trans-isomer is more soluble the m-isomer can be resolved into its enantiomers using optically active anions like a-bromocamphor 7r-sulphonate. These chlorides can be converted into the bromide or iodide complex by refluxing with a solution of the appropriate potassium halide. 

Despite its widespread application [31,32], the kinetic resolution has two major drawbacks (i) the maximum theoretical yield is 50% owing to the consumption of only one enantiomer, (ii) the separation of the product and the remaining starting material may be laborious. The separation is usually carried out by chromatography, which is inefficient on a large scale, and several alternative methods have been developed (Figure 6.2). For example, when a cyclic anhydride is the acyl donor in an esterification reaction, the water-soluble monoester monoacid is separable by extraction with an aqueous alkaline solution [33,34]. Also, fiuorous phase separation techniques have been combined with enzymatic kinetic resolutions [35]. To overcome the 50% yield limitation, one of the enantiomers may, in some cases, be racemized and resubmitted to the resolution procedure. 

In general, it may be said that enantiomers have identical properties in a symmetrical environment, but their properties may differ in an unsymmetrical environment. Besides the important differences previously noted, enantiomers may react at different rates with achiral molecules if an optically active catalyst is present they may have different solubilities in an optically active solvent., they may have different indexes of refraction or absorption spectra when examined with circularly polarized light, and so on. In most cases these differences are too small to be useful and are often too small to be measured. 

Our approach for chiral resolution is quite systematic. Instead of randomly screening different chiral acids with racemic 7, optically pure N-pMB 19 was prepared from 2, provided to us from Medicinal Chemistry. With 19, several salts with both enantiomers of chiral acids were prepared for evaluation of their crystallinity and solubility in various solvent systems. This is a more systematic way to discover an efficient classical resolution. First, a (+)-camphorsulfonic acid salt of 19 crystallized from EtOAc. One month later, a diastereomeric (-)-camphorsulfonic acid salt of 19 also crystallized. After several investigations on the two diastereomeric crystalline salts, it was determined that racemic 7 could be resolved nicely with (+)-camphorsulfonic acid from n-BuOAc kinetically. In practice, by heating racemic 7 with 1.3equiv (+)-camphorsulfonic acid in n-BuOAc under reflux for 30 min then slowly cooling to room temperature, a cmde diastereomeric mixture of the salt (59% ee) was obtained as a first crop. The first crop was recrystallized from n-BuOAc providing 95% ee salt 20 in 43% isolated yield. (The optical purity was further improved to -100% ee by additional recrystallization from n-BuOAc and the overall crystallization yield was 41%). This chiral resolution method was more efficient and economical than the original bis-camphanyl amide method. 

Conglomerate crystallization in the above case indicates that the inclusion approach may be further extended into the realm of the salt-type associates. Such an attempt is especially interesting due to the obvious role in enantiomer separation which relies heavily on the solubility difference of the enantiomeric salts under certain circumstances 137). 

An alternative to extraction crystallization is used to obtain a desired enantiomer after asymmetric hydrolysis by Evonik Industries. In such a way, L-amino acids for infusion solutions or as intermediates for pharmaceuticals are prepared [35,36]. For example, non-proteinogenic amino acids like L-norvaline or L-norleucine are possible products. The racemic A-acteyl-amino acid is converted by acylase 1 from Aspergillus oryzae to yield the enantiopure L-amino acid, acetic acid and the unconverted substrate (Figure 4.7). The product recovery is achieved by crystallization, benefiting from the low solubility of the product. The product mixture is filtrated by an ultrafiltration membrane and the unconverted acetyl-amino acid is reracemized in a subsequent step. The product yield is 80% and the enantiomeric excess 99.5%. 

Many compounds are less soluble as racemates than as their pure enantiomers. It thus appears probable that evaporation of an amino acid solution with a low ee should cause selective precipitation of the racemate crystals, which in turn should lead to an increase of the ee. Extremely simple manipulations, carried out in the chemistry department of Columbia University, led to a drastic increase in enantiomeric excess of phenylalanine 500 mg phenylalanine (with a 1 % ee of the L-component) was dissolved in water, and the resulting solution slowly evaporated until about 400 mg had crystallised out. The remaining solution contained a few mg of phenylalanine with 40% ee of the L-component (i.e., a 70 30 ratio of l to d). If 500 mg of such a solution (40% ee in water) is allowed to evaporate and is separated from the racemate, the result is about 100 mg, with 90% ee of the L-enantiomer (Breslow and Levine, 2006). 

The (n)-enantiomer of penicillamine is used clinically in man either as the hydrochloride or as the free amino acid [1], although the (L)-enantiomer also forms chelation complexes. Penicillamine is an effective chelator of copper, mercury, zinc, and lead, and other heavy metals to form stable, soluble complexes that are readily excreted in the urine [2,3]. 

Enantiomers have identical physical properties such as boiling points, melting points, refractive indices, and solubilities in common solvents except optical rotations. 

Enantiomers show different solubilities in chiral solvents that consist of a single enantiomer or an excess of a single enantiomer. 

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