Racemates diastereomeric salts

Unlike enantiomers, diastereomers have different solubilities in an achiral environment. Many chiral counterions, such as arginine and lysine, are commonly used to prepare salts of an ionic drug in order to improve its pharmaceutically relevant properties. However, when the drug is chiral, a chiral counterion should be used with caution. If the drug or the counterion is racemic, diastereomeric salts will be formed, constituting a heterogeneous system. Because the solubilities of diastereomers differ, a diastereomeric mixture of chiral salts is undesirable in a formulation. 

At present moment, no generally feasible method exists for the large-scale production of optically pure products. Although for the separation of virtually every racemic mixture an analytical method is available (gas chromatography, liquid chromatography or capillary electrophoresis), this is not the case for the separation of racemic mixtures on an industrial scale. The most widely applied method for the separation of racemic mixtures is diastereomeric salt crystallization [1]. However, this usually requires many steps, making the process complicated and inducing considerable losses of valuable product. In order to avoid the problems associated with diastereomeric salt crystallization, membrane-based processes may be considered as a viable alternative. 

The products 4 are formed as racemic mixtures, but can be resolved by recrystallization of diastereomeric salts.23 - 25 Syntheses starting from optically active biphenyl compounds are also known.26 -28 l,l -Binaphthyl-2,2 -diamine(5) can be transformed to the dinaphtho[1,4]di-azocine 6 by melting with benzil.29... 

Racemic mixtures of sulfoxides have often been separated completely or partially into the enantiomers. Various resolution techniques have been used, but the most important method has been via diastereomeric salt formation. Recently, resolution via complex formation between sulfoxides and homochiral compounds has been demonstrated and will likely prove of increasing importance as a method of separating enantiomers. Preparative liquid chromatography on chiral columns may also prove increasingly important it already is very useful on an analytical scale for the determination of enantiomeric purity. 

Most resolution is done on carboxylic acids and often, when a molecule does not contain a carboxyl group, it is converted to a carboxylic acid before resolution is attempted. However, the principle of conversion to diastereomers is not confined to carboxylic acids, and other groupsmay serve as handles to be coupled to an optically active reagent. Racemic bases can be converted to diastereomeric salts with active acids. Alcohols can be converted to diastereomeric esters, aldehydes to diastereomeric hydrazones, and so on. Even hydrocarbons can be converted to diastereomeric inclusion... 

Chiral Recognition. The use of chiral hosts to form diastereomeric inclusion compounds was mentioned above. But in some cases it is possible for a host to form an inclusion compound with one enantiomer of a racemic guest, but not the other. This is caUed chiral recognition. One enantiomer fits into the chiral host cavity, the other does not. More often, both diastereomers are formed, but one forms more rapidly than the other, so that if the guest is removed it is already partially resolved (this is a form of kinetic resolution, see category 6). An example is use of the chiral crown ether (53) partially to resolve the racemic amine salt (54). " When an aqueous solution of 54 was... 

An overall efficiency of TRISPHAT 8 and BINPHAT 15 anions as NMR chiral shift agents for chiral cations has been demonstrated over the last few years. Additions of ammonium salts of the A or A enantiomers of 8 and 15 to solutions of racemic or enantioenriched chiral cationic substrates have generally led to efficient NMR enantiodifferentiations [112-121]. Well-separated signals are usually observed on the spectra of the diastereomeric salts generated in situ. 

The results reviewed in this section demonstrate that chiral recognition in complexes between chiral crown ethers and racemic ammonium salts and vice versa occurs both in polar and in apolar solvents. The maximum values of 2.9 found for the enantiomeric distribution constants correspond to a difference in free energy of the two diastereomeric complexes of 0.6 kcal mol-1. 

Ondansetron (17) is a racemic compound not easy to resolve by chemical means because the carbonyl function is poorly reactive so it is difficult to form chiral derivatives. However, a resolution was achieved by the classical method of forming diastereomeric salts with an optically active acid and then separating the salts by recrystallisation. A number of acids were tried, but only the salts prepared from (-f)- and (—)-di-p-toluoyltartaric acid could be separated in this way. Each isomer was obtained in greater than 95 %ee. The absolute stereochemistry of the isomer from the (-E)-acid was determined by X-ray crystallography (Williams, D., personal communication) and shown to possess the 5-configuration (18). 

Chemical synthesis of racemates and subsequent resolution via crystallization of diastereomeric salts is employed in the preparation of rf-biotin and tocopherol (vitamins), dexchlorpheniramine (antihistaminic), levomepromazine (neuroleptic), levorphanol (analgesic), and naproxen (antiphlogistic), to note some examples4, threo-2-Amino-1 -(4-nitro-phenyl)-l,3-propanediol, an intermediate in the production of chloramphenicol, is resolved by crystallization with entrainment or via crystallization of the salt with camphorsulfonic acid4. Enzymatic resolutions are increasingly employed, normally via deacetylation of racemic acetates. This method has recently been used in the synthesis of carbacyclin derivatives5. 

Alternative synthetic approaches include enantioselective addition of the organometallic reagent to quinoline in the first step of the synthesis [16], the resolution of the racemic amines resulting from simple protonation of anions 1 (Scheme 2.1.5.1, Method C) by diastereomeric salts formation [17] or by enzymatic kinetic resolution [18], and the iridium-catalyzed enantioselective hydrogenation of 2-substituted quinolines [19]. All these methodologies would avoid the need for diastereomer separation later on, and give direct access to enantio-enriched QUINAPHOS derivatives bearing achiral or tropoisomeric diols. Current work in our laboratories is directed to the evaluation of these methods. 

The reaction of a racemic form with a chiral reagent, for example, a racemic ( ) acid with a (-) base, yields two diastereomeric salts ( + )(-) and (-)(-) with different solubilities. These salts can be separated by fractional crystallization, and then each salt is treated with a strong acid (HCI) which liberates the enantiomeric organic acid. This is shown schematically ... 

Racemic Form Chiral Base Diastereomeric Salts... 

The P-cyanodiester 4 was prepared by condensation of isovaleraldehyde with diethyl malonate followed by the addihon of potassium cyanide. The cyanodiester 4 was hydrolyzed and decarboxylated to give the P-cyano acid 5. Reduction with Raney nickel gave racemic pregabalin (6), which was resolved with (S)-mandelic acid. The diastereomeric salt was split with wet TH F under neutral conditions to give pregabalin, which was recrystallized from isopropanol (IPA) to give the final Active Pharmaceutical Ingredient (API). 

Whenever possible, the chemical reactions involved in the formation of diastereomers and their conversion to separate enantiomers are simple acid-base reactions. For example, naturally occurring (S)-(-)-malic acid is often used to resolve amines. One such amine that has been resolved in this way is 1-phenylethylamine. Amines are bases, and malic acid is an acid. Proton transfer from (S)-(-)-malic acid to a racemic mixture of (/ )- and (5)-1-phenylethylamine gives a mixture of diastereomeric salts. 

The principle is the same as for the resolution of a racemic acid with a chiral base, and the choice of acid will depend both on the ease of separation of the diastereomeric salts and, of course, on the availability of the acid for the scale ... 

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